CLINICAL PICTURE

A 22 years old male patient presented clinically with bilateral cerebellar ataxia bilateral pyramidal manifestations lost tendon jerk reflexes peripheral neuropathy with peroneal muscular atrophy enlarged peripheral nerves kyphoscoliosis and pes cavus Peripheral nerve biopsy revealed diffuse demyelinating neuropathy with onion bulb formation The condition started at the age of 12 and is gradually progressive The clinical diagnosis of Friedreich ataxia was made (To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left pane) of the acrobat reader then double click on the attached file) (Click here to download the attached file)

RADIOLOGICAL FINDINGS

Figure 1 MRI of the brain showing normal findings

CASE OF THE WEEK

PROFESSOR YASSER METWALLY

CLINICAL PICTURE

RADIOLOGICAL FINDINGS

Figure 2 MRI T2 (AB) and MRI T1 (C) showing marked atrophy of the uppermost part of the cervical spinal cord

showing marked atrophy of the uppermost part of the cervical spinal cord

Figure 3 MRI T1 (A) and MRI T2 (B)

Figure 4 MRI T2 images showings cervical cord atrophy thinning with reduced anteroposterior diameter Notice the hyperintense line in posterior portion of cord The thinned spinal cord is seen lying on the posterior wall of spinal canal with increased signal intensity in its posterior and lateral compartments The anterior subarachnoid space is enlarged The intramedullary signal changes reflect loss of myelinated fibers and gliosis

Pathophysiology of Friedreich ataxia

The major pathophysiologic finding in FA is a dying back phenomena of axons beginning in the periphery with ultimate loss of neurons and a secondary gliosis The primary sites of these changes are the spinal cord and spinal roots There is a loss of large myelinated axons in peripheral nerves which increases with age and disease duration Unmyelinated fibers in sensory roots and peripheral sensory nerves are spared

The posterior columns corticospinal ventral and lateral spinocerebellar tracts all show demyelination and depletion of large myelinated nerve fibers to differing extents This is accompanied by a fibrous gliosis that does not replace the bulk of the lost fibers Overall the spinal cord becomes thin and the anteroposterior (AP) and transverse diameters of the thoracic cord are reduced The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells The posterior column degeneration accounts for the loss of position and vibration sense and the sensory ataxia The loss of large neurons in the sensory ganglia causes extinction of tendon reflexes

Large neurons of the dorsal root ganglia especially lumbosacral and nerve cells in Clarkes column are reduced in number The posterior roots become thin The dentate nuclei exhibit mild to moderate neuronal loss and the middle and superior cerebellar peduncles are reduced in size There is patchy loss of Purkinje cells in the superior vermis of the cerebellum and of neurons in corresponding portions of the inferior olivary nuclei There are mild degenerative changes in the pontine and medullary nuclei and optic tracts The cerebellar ataxia is explained by loss of the lateral and ventral spinocerebellar tracts involvement of Clarkes column the dentate nucleus superior vermis and dentatorubral pathways

The corticospinal tracts are relatively spared down to the level of the cervicomedullary junction Beyond this point the corticospinal tracts are severely degenerated which becomes progressively more severe moving down the spinal cord This explains the common finding of bilateral extensor plantar responses and weakness late in the disease Loss of cells in the nuclei of cranial nerves VIII X and XII results in facial weakness speech and swallowing difficulty

Myocardial muscle fibers also show degeneration and are replaced by macrophages and fibroblasts Essentially chronic interstitial myocarditis occurs with hypertrophy of cardiac muscle fibers fibers become hypertrophied and lose their striations This is followed by swelling and vacuolation and finally interstitial fibrosis The nuclei appear hyperchromatic and occasionally vacuolated The cytoplasm appears granular with frequent lipofuscin depositions Kyphoscoliosis is likely secondary to spinal muscular imbalance

Histologic Findings in Friedreich ataxia

A cross-section through the lower cervical cord clearly shows loss of myelinated fibers of the dorsal columns and the corticospinal tracts (Weil stain) Milder involvement of spinocerebellar tracts is also present The affected tracts show compact fibrillary gliosis (hematoxylin and eosin [HampE]) but no breakdown products or macrophages reflecting the very slow rate of degeneration and death of fibers The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells (HampE) The posterior roots are nearly devoid of large myelinated fibers Within the thoracic spinal cord degeneration and loss of cells of the Clarke column is apparent

Figure 6 Friedreich Ataxia Spinal cord

Comment on the radiology of the previously reported case

The decreased anteroposterior diameter of the spinal cord at the upper cervical region confirms that atrophy of the upper cervical part of the spinal cord is a characteristic feature of Friedreichrsquos ataxia as opposed to other forms of corticocerebellar and cerebellar-brainstem atrophy [3-6] This had been indicated on the basis of subjective evaluation in two previous studies [201204]

No direct pathologic correlation of the intramedullary signal abnormalities is available However the sensitivity of MR imaging to degeneration of white matter tracts in the brain and spinal cord after stroke or in degenerative diseases of the CNS - that is manifested on the MRI T2 images as hyperintense lines- has been cited in several reports [211-214] Because of the substantial similarities between the intramedullary signal abnormality pattern that is found in the reported patient and the distribution of demyelination and gliosis of white matter tracts in the histopathologic pictures of the spinal cord in cases of Friedreichrsquos ataxia [200] we think it reasonable to assume that the MR appearance could reflect these pathologic findings Obviously the intramedullary signal abnormality pattern we found is not exclusive to Friedreichrsquos ataxia and can be observed in subacute combined degeneration tabes dorsalis wallerian degeneration and AIDS myelopathy In these conditions however associated clinical and laboratory findings usually allow the correct diagnosis

Detection of signal changes in the white matter tracts of the spinal cord of patients with Friedreichrsquos ataxia could be an index of severity or progression of the disease and in this respect it is more useful than cord atrophy The

Figure 5 Friedreich Ataxia

association between the extent of intramedullary signal changes and the chronicity and severity of disease was not examined in the reported patient Although this analysis could be informative it requires quantitation of the signal changes in the white matter tracts and evaluation of the thoracolumbar spine which were not done in the reported patient Noteworthy is the fact that we found intramedullary signal changes only in patients with Friedreichrsquos ataxia No such findings were seen in any of the patients with corticocerebellar or cerebellar-brainstem atrophy in the author experience Thus it appears that evaluation of the cervical spinal cord for intramedullary signal changes might be useful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

In a broad sense our results confirm that MR examination of the cervical spinal cord is more informative than examination of the brain in patients with Friedreichrsquos ataxia Although spinal cord atrophy and intramedullary signal changes theoretically could be searched for in the thoracic spinal cord of patients with Friedreichrsquosrsquo ataxia [200] focusing on the cervical spinal cord is recommended because it usually allows concurrent evaluation of the brainstem and the cerebellum This may help in the differential diagnosis with corticocerebellar and cerebellar-brainstem atrophies

In conclusion MR imaging of the cervical spinal cord can show thinning of the cord and intramedullary signal changes consistent with degeneration of white matter tracts in the lateral and posterior columns of patients with Friedreichrsquos ataxia These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

DIAGNOSIS FRIEDREICHS ATAXIA

DISCUSSION

Hereditary ataxias are a heterogeneous group of neurological disorders Outstanding contributions by Holmes [1] Greenfield [2] and Harding [3] established a syndromic framework for these diseases and remarkable progress in the field now permits a definitive diagnosis in 60 to 70 percent of hereditary ataxia patients Although an increasing number of genetic tests are becoming available for the known ataxia genes phenotypic variability and clinical overlap have hampered development of a useful clinical algorithm for the differential diagnosis of ataxic patients Furthermore some patients with hereditary ataxia may have no family history of ataxia The diagnosis of genetic ataxia in apparently sporadic cases is especially difficult as a variety of nongenetic causes could be underlying the manifestation of the ataxic syndrome Most of the genetic ataxias are adult-onset disorders for which there are no effective treatments and it is not yet possible to offer satisfactory estimates concerning age of onset or prognosis in potentially affected relatives The results of DNA testing however may have dramatic ethical social and legal impact on the life of test subjects and their families For these reasons careful genetic and psychological counseling is required for the patients who undergo genetic testing It should also be noted that some genetic ataxias are treatable and correct diagnosis for these disorders should not be missed

In this article the author reviews the clinical features and current genetic understanding of inherited ataxias The readers may also refer to recent reviews of hereditary ataxias [4] and dominant hereditary ataxias [67116] As ataxia commonly presents in patients without family history we will discuss the clinical approach to differential diagnosis of hereditary and non-hereditary conditions

AUTOSOMAL DOMINANT ATAXIA

Spinocerebellar ataxias

Autosomal dominant spinocerebellar ataxias (ADCA see Table 1) have been clinically classified into three syndromes (ADCA-I II and III) based on the presence of cerebellar ataxia in combination with other symptomatology [89] ADCA-I is defined by a cerebellar syndrome variably accompanied by ophthalmoplegia pyramidal and extrapyramidal signs dementia and other neurological disorders ADCAII is defined by a cerebellar syndrome associated with pigmentary retinopathy and ADCA-III is defined by pure ataxia without other neurologic features While this classification scheme is still useful more recent definition of diseases by specific genetic loci or based on individual families (defined by specific Spinocerebellar ataxias (SCA) loci) only roughly correlates with Hardings classification SCA 7 is the only genetically defined disorder in the ADCA-II group ADCA-I would

DIAGNOSIS

DISCUSSION

classically include SCAs 1 2 3 4 12 13 and 17 but each of these disorders may have purely cerebellar features early Most patients with SCA 5 6 8 10 11 14 and 16 would be classified with ADCA-III but others develop extracerebellar neurological abnormalities consistent with ADCA-I Thus the SCA terminology based on genetic analysis is more commonly presented today

Many of the SCAs (1 2 3 6 7 17 and dentatorubro-pallidoluysian atrophy (DRPLA)) are caused by an expansion of CAG repeats in their respective genes In these disorders the mutation is an expansion of a naturally occurring

Table 1 Autosomal dominant cerebellar ataxia (ADCA)

Disease Locus Type of mutationGene product

Normal alleles

Pathogenic alleles

Distribution (number of families)

of total SCA

Db

ADCA I SCA-1 6p22-p23 CAG expansionataxin-1 6-44 40-81 worldwide 5-15 C

SCA-2 12q23-241 CAG expansionataxin-2 14-31 34-59 Cuba worldwide 5-15 C

SCA-3MJD

14q243-q321 CAG expansionataxin-3 14-33 56-200 Portugal

worldwide 30-50 C

SCA-4 16q221 unknown USA Japan (7 families) N

SCA-12 5p31-p33 CAG expansion5 UTR of PPP2R2B 17-28 55-78 USA India (2

families) rare R

SCA-13 19q133-134 unknown France (1 family) rare R

SCA-17 6q27 Impure CAG expansionTBPa 27-44 47-63 Japan Germany rare R

ADCA II SCA-7 3p12-p13 CAG expansionataxin-7 7-19 37-300 worldwide C

SCA-8 13q21 CTG expansion3 UTR region of SCA8 15-91 107-127 C

ADCA III SCA-5 11cen unknown USA (1 family) rare N

SCA-6 19p131 CAG expansionCACNL1A4a 4-20 21-33 worldwide 5-10 C

SCA-10 22q13 ATTCT expansionintron 9 Hh-E4a 10-22 800-4500 Mexico rare C

SCA-11 15q14-q213 unknown England (1

family) rare N

SCA-14 19q134-qter unknown Japan (1 family) rare N

SCA-16 8q221-q241 unknown Japan rare N

Episodic Ataxia EA type 1 12p13

Missense mutationsCACNL1A4a worldwide R

EA type 2 19p13

Missense mutationsCACNL1A4a worldwide R

DRPLA

[b] D Diagnosis available=Commercially (C) Research (R) Non-available (N)

[a] TBP (TATA binding proteins) CACNL1A4 (1A-voltage-gated calcium channel subunit) Hh-E4 (human homologous of mouse E4 gene)

CAG repeat in the protein coding region of a specific protein This leads to an abnormal expanded series of glutamines being translated in that specific protein The expansion is unstable over generations leading to progressive lengthening of the repeat Disease results when the repeat reaches a specific pathologic range and further expansion leads to progressively earlier age of onset Thus in each of these diseases the CAG repeat size correlates inversely with the age of onset The common pathogenic mechanism of these diseases involves a gain of toxic function [10] and neuropathological studies in ldquopolyglutaminerdquo diseases reveal the presence of neuronal nuclear protein inclusion [1112] which contain the polyglutamine-containing protein specific interacting proteins and proteins from the ubiquitin-degradation pathway [10] These aggregates do not appear to be responsible for the disease in SCA1 [13] although their direct role in other ldquopolyglutaminerdquo diseases is unclear The pathogenicity of the mutant protein in these diseases may involve defective ldquoprotein clearancerdquo sequestration of transcription co-activators and co-repressors andor other gain of function mechanisms [14]

The mutations for SCA8 and SCA12 are expansions of a CAGCTG repeat in untranslated regions of their respective genes Whether the trinucleotide expansion found in SCA8 is a causative mutation or a polymorphism in linkage disequilibrium is still a matter of debate (see SCA8 below) Individuals with SCA10 have a large expansion of an intronic ATTCT pentanucleotide repeat The pathogenic mechanisms of these SCAs remain to be investigated SCAs4 5 11 13 14 and 16 have been mapped but their mutations have not been identified SCAs1 2 3 6 7 and 17 are more frequent than others SCAs and a few SCA types have been recognized only in a single family The incidence of the different types of SCA around the world is variable and known SCAs constitute about 60ndash80 of the families with ADCA (Table 1)

SCA1

The SCA1 gene is located on chromosome 6p linked to the HLA gene complex [15] SCA1 was cloned and the CAG repeat expansion identified in 1993 [16] The number of CAG repeats in normal and pathological alleles of SCA1 are shown in Table 1 The progression of SCA1 has a pattern common to most of the ADCA [17] typical onset with a cerebellar syndrome (ie broad-based gait limb ataxia progressive dysarthria) hand tremor and oculomotor signs including intermittent nystagmus slowing in saccadic velocity followed by limitation of up-gaze The bulbar and upper motor neurons signs may include lingual fasciculations noncerebellar dysphagia and dysarthria brisk deep tendon reflexes and increased tone (spasticity) Later in the disease this constellations of symptoms becomes more severe with coughing overt choking sensory loss mild peripheral neuropathy and extensor plantar responses In SCA1 extrapyramidal signs may be evident by the time the patient becomes wheelchair bounded The phenotype of the disease appears to be relatively homogeneous within and between families Variability observed in age of onset and progression appears to be attributable to the size of the CAG repeat expansion [1819] Bradykinesia and parkinsonism which may be prominent features in SCA3MJD have not been observed in SCA1 Cognitive decline does not appear to be severe in SCA1 Neuroimaging studies typically show atrophy of cerebellar cortex vermis and brainstem

SCA2

The SCA2 gene was mapped by linkage analysis of a homogeneous population of Holguin province (Cuba) to chromosome 12q24 [20] and later cloned independently by three groups [21ndash23] Clinical features of the disease include slow saccades kinetic or postural tremor and decrease of muscle tone and tendon reflexes Variable incidence of dystonia chorea and dementia has also been recognized Nonspecific cerebellar or pontocerebellar atrophy has been observed on MRI Nerve conduction studies show evidence of axonal sensory-motor neuropathy

SCA3MJD (Machado-Joseph disease)

Originally described in Portuguese families and named the ldquoAzorean diseaserdquo [24] SCA3 is now recognized worldwide The mutation in the SCA3 gene localized to 14q311 is an expanded CAG repeat in a novel protein designated ataxin-3 [25] Variable phenotypes are found in SCA3[2627] in addition to cerebellar ataxia and ophthalmoplegia early-onset disease can present with spasticity dystonia and an akinetic syndrome whereas late-onset SCA3 presents mainly with minimal extrapyramidal symptomatology The extrapyramidal signs are a characteristic but not exclusive feature of the SCA3 phenotype [27] There is an inverse correlation between the age of onset and the expanded CAG repeat length The severity of the disease as well as the presence of some symptoms (ie peripheral neuropathy) may depend on the length of the expansion with short and very large pathological alleles lacking neuropathy [28]

SCA4

A five-generation Utah kindred with an autosomal dominant late-onset spinocerebellar ataxia with the invariable presence of prominent axonal sensory neuropathy and normal eye movements demonstrated linkage to chromosome 16q221 [29] Six Japanese families with pure cerebellar ataxia without sensory neuropathy also showed linkage to this locus [3031]

SCA5

SCA5 was assigned to chromosome 11 in a single family descending from the grandparents of President Abraham Lincoln [32] In this family 56 individuals had cerebellar ataxia with onset at 10 to 68 years Anticipation is evident and progression of the disease is slow SCA5 does not affect life span probably because severe bulbar disease is generally absent A second apparently unrelated SCA5 family of French origin showed a similar phenotype with marked global cerebellar atrophy similar to SCA6 on MRI [33]

SCA6

SCA6 classically presents with pure cerebellar ataxia although patients with a prolonged disease course may show other clinical features including dystonic postures involuntary movements and abnormalities in tendon reflexes [34] Patients with SCA6 especially those with late onset disease may present without a family history The diagnosis of SCA6 should be considered in sporadic cases with horizontal and oblique gaze nystagmus and an abnormal vestibulo-ocular reflex without other ocular movement abnormalities or those with pure cerebellar atrophy [3435] Some phenotypic overlap with the allelic disease EA-2 (see the section of Episodic Ataxia) has been noted [3637] Brain MRI shows atrophy of the cerebellum and in some patients pons middle cerebellar peduncles and red nucleus [343839] The SCA6 mutation is a small CAG repeat expansion within the 1A-voltage-dependent calcium channel subunit (CACNL1A4) gene [40] The number of CAGs in mutant alleles ranges 20 to 30 while normal alleles are 4 to 17 CAGs (Table 1) [4041] An allele with 19 CAGs has been reported in a Japanese patient with ataxia [42] Although the age of onset inversely correlates with the expanded repeat size in different families the expanded repeat is usually stably transmitted within each family [414344] In rare cases however mild expansions have been reported [4546] Sisters homozygous for (CAG)2525 showed a similar age of onset but different progression rate suggesting pathogenic contribution of factors other than the repeat size [47] Homozygous cases suggested a gene dosage effect on the age of onset [3648ndash50] Anticipation in the absence of changes in the CAG repeat size has been described in French [51] Japanese [41] and Taiwanese kindreds

Although the expansion size of the CAG repeat falls into the normal ranges of other SCAs the polyglutamine tract in a densely packed membrane protein may allow the 1A subunits with small expansions to aggregate [5253] A key question is whether the SCA6 mutation causes disease by making the 1A subunit toxic or it does so by perturbing the gating of PQ-type channels [54] To reconcile these two different mechanisms it has been postulated that protein interactions altered by the expanded polyglutamine tract might cause gating abnormalities [55]

SCA7

SCA7 is characterized by progressive ataxia and pigmentary maculopathy with anticipation and is the only disease classified as an ADCA-II These features are accompanied by other clinical features including pyramidal and extrapyramidal signs ophthalmoplegia dementia hypoacusis hypotonia and auditory hallucinations [56] Slowing of voluntary and involuntary saccades is also an early sign of SCA7 [57] Specific juvenile and infantile forms of SCA7 have been defined Juvenile SCA7 occurs with maternal and paternal transmission whereas the infantile form occurs only with paternal transmission The infantile form shows severe hypotonia cerebral and cerebellar atrophy early visual loss congestive heart failure and patent ductus arteriosus [58] SCA7 is caused by an expansion of a CAG repeat in the SCA7 (ataxin-7) gene on chromosome 3p [5960] The normal range is 7 to 19 CAG repeats and pathogenic alleles range from 37 to approximately 306 repeats The expansion size correlates with the severity of the disease and inversely correlates with the age of onset [6162] Alleles with 28 to 36 repeats are intermediate alleles that are prone to further expansion accounting for de novo mutation cases [6364] Different disease-associated haplotypes segregated among SCA7 kindreds suggesting multiple origins of the mutation [63] Paternal transmission is underrepresented and when it does occur is associated with significant intergenerational expansion of the CAG repeat [65] The expanded CAG repeat in male germline is biased toward massive size increases potentially leading to putative embryonic lethality or dysfunctional sperm [66] The available data suggest that the mutant ataxin-7 protein is pathogenic due to a gain of toxic function by the polyglutamine expansion [67ndash70]

SCA8

SCA8 presents with slowly progressive ataxia with marked cerebellar atrophy [71] The disease is variably associated with pyramidal and cognitive dysfunctions [72] SCA8 patients have an expansion of a CTG repeat on chromosome 13q21 to the pathogenic range of 100 to 152 repeats while normal individuals have 15 to 91 CTGs [73] Affected individuals usually inherit an expanded allele from their mothers SCA8 alleles show an instability bias toward expansion with maternal transmission whereas paternal transmissions mostly result in smaller alleles which appear to be due to contraction of the expanded alleles to the normal range (lt100 CTGs) in the sperm [717475] Variable penetrance has been identified in SCA8 pedigrees [7176] There has been no evidence of correlation between the repeat size and the age of onset Haplotype analyses showed multiple origins for the SCA8 expansions [72]

The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract with the configuration (CTA)1-21(CTG)n in the 3 untranslated region of the SCA8 gene Many SCA patients have expanded alleles with interruptions by cryptic repeats (CCG CTA CTC CCA or CTT) which may have newly arisen or changed from generation to generation [74] SCA8 contains no open reading frame but the most 5 exon is transcribed through the first exon of another gene KLHL1 which is transcribed in the opposite orientation This raises a possibility that the SCA8 transcript is an endogenous antisense RNA for KLHL1 KLHL1 encodes a cytoplasmic protein that may play a role in organizing the actin cytoskeleton of the brain cells Both SCA8 and KLHL1 are primarily expressed in specific brain tissues affected by SCA8 [77] Other gain-of-function mechanisms involving the mutant SCA8 transcript have not been investigated but by no means excluded

The major controversy in SCA8 stems from a lack of absolute specificity of the CTG repeat expansion for SCA8 which has raised a possibility that CTG expansions at the SCA8 locus represent a rare polymorphism rather than the disease-causing mutation [7879] Alleles greater than 100 CTG repeats at the SCA8 locus were also found in 12 (14 of 1120) of major psychosis patients and 07 (5 of 710) of normal control subjects who had no family history of ataxia [80]

SCA9 (vacant)

SCA10

The clinical phenotype of SCA10 is characterized by a combination of relatively pure cerebellar ataxia and epilepsy Ataxia is progressive and often leads to total disability Seizures are generalized motor seizures complex partial seizures or both Some patients show mild cognitive dysfunction sensory polyneuropathy andor soft corticospinal tract signs [81] Anticipation is conspicuous in some families but subtle or absent in others The disease has so far been confined to families of Mexican descent The SCA10 mutation is a very large expansion of the ATTCT pentanucleotide repeat located in intron 9 of the E46L (SCA10) gene on chromosome 22q13 [49] Normal alleles show 10 to 21 ATTCTs while affected individuals have 800ndash4500 repeats An inverse correlation exists between the size of the expanded allele and the age of onset The mechanism of the disease remains unknown

SCA11

SCA11 clinically defined as an ADCA-III has been mapped to chromosome 15q in a single British family [78]

SCA12

SCA12 is a rare ADCA characterized by adult onset ataxia upper body tremor hyperreflexia with bilateral extensor plantar responses paucity of movements and dementia [8283] The clinical picture includes oculomotor abnormalities (ie broken pursuit nystagmus slow saccades) The disease is slowly progressive and in the late stage psychiatric symptoms including depression anxiety or delusions may appear in some affected members Brain MRI shows cerebellar and cerebral cortical atrophy There is no evidence of anticipation The mutation of SCA12 is a CAG repeat expansion in the 5 untranslated region of the PPP2R2B gene on chromosome 5p31-p33 [84] Normal alleles have 17 to 28 CAG repeats while the pathologic alleles have 55 to 78 repeats The disease has been described in two kindreds one from US and the other from India [8587] It has been postulated that the expansion of the CAG repeat up-regulate PPP2R2B expression

SCA13

A French family presented with slowly progressive childhood-onset cerebellar gait ataxia dysarthria moderate mental retardation and mild motor developmental delays with in some cases nystagmus and pyramidal signs Brain MRI showed moderate cerebellar and pontine atrophy A genome wide search showed linkage to chromosome

19q133-q134 [86]

SCA14

A Japanese three-generation family with ADCA mapped to a locus on chromosome 19q134-qter [86] The family members with late onset (gt39 years old) exhibited pure cerebellar ataxia whereas those with an early onset (lt27 years old) showed intermittent axial myoclonus followed by ataxia Other neurological signs were sparse and neuroimaging studies revealed isolated cerebellar atrophy

SCA15 (vacant)

SCA16

This is a pure cerebellar ataxia with head tremor and thus a form of ADCA III [88] Although head tremor which is distinct from tittubation has been described in SCA2 SCA7 and SCA12 it is rare for all SCA types Age of onset ranges 20 to 66 years and anticipation was not apparent Brain MRI showed cerebellar atrophy without involving brainstem The SCA16 locus showed linkage to markers on chromosome 8q221-q241 [88]

SCA17

An expansion of CAG repeats of the TATA-binding protein (TBP) gene was initially reported in a Japanese patient with sporadic cerebellar ataxia and intellectual deterioration associated with de novo expansion The expanded allele consisted of impure CAG repeats encoding 63 glutamines and the de novo expansion involved partial duplication of the CAG repeat [89] In two German families four patients showed expanded CAG repeats in TBP gene coding for 50 to 55 polyglutamines while normal subjects had alleles ranging from 27 to 44 glutamines [90] Several additional Japanese families with phenotypes resembling Huntingtons disease or DRPLA also showed SCA17 CAG expansions [91]

Other SCAs

Anecdotally there are many ADCA families who are not linked to known genetic loci and who have no distinctive phenotype In one such French family SCAs 1 2 3 6 7 8 and 12 were excluded by mutation analysis and SCAs 4 5 10 11 13 14 by lod score less than 2 Affected members of this French family showed gait ataxia akinesia dysarthria hyporeflexia and anticipation [92] There are likely to be many similar families who have not yet been characterized or reported

DRPLA

DRPLA is a relatively frequent disease in Japan with an incidence of 02-07 per 100000 A few isolated families have been recognized worldwide [92] The DRPLA gene on the chromosome 12p was cloned in 1994 [9495] Early onset of the disease includes ataxia myoclonus epilepsy and progression to dementia later onset disease can present with cerebellar symptoms psychiatric symptoms seizures [9396] and choreoathetotic abnormal movements with a ldquoHuntington-likerdquo phenotype [97] Age of onset and severity correlate with the length of the CAG expansion The mutation in the DRPLA gene has also been found in the Haw River Syndrome which has some different clinical characteristics from DRPLA [98]

Episodic ataxia (EA)

In contrast to SCAs these rare diseases present with episodic ataxic attacks of variable frequency and duration with no symptoms between attacks Additional characteristic signs are associated with the different types of EA

EA type 1 (EA1)

EA1 is caused by mutations in a potassium channel gene KCNA1 on chromosome 12p [99] The onset is between childhood and adolescence Besides episodic ataxia clinical manifestations are myokymia around the eyes lips or fingers Brief attacks of ataxia and dysarthria lasting seconds are precipitated by exercise or startle

EA type 2 (EA2)

Clinical manifestations of EA2 consist of mild to severe intermittent cerebellar dysfunction associated with oculomotor abnormalities such as interictal nystagmus and diplopia and migraine Symptoms can be present for minutes to a few days Episodes are provoked by stress and exercise but not startle Like familial hemiplegic migraine (FHM) and spinocerebellar ataxia type 6 (SCA6) EA2 is associated with mutations in the gene encoding the -1A subunit of the calcium channel SCA6 is caused by a CAG repeat expansion [40] while point mutations in the CACNA1A gene cause EA2 and FHM [100] Missense mutations usually cause FHM and non-sense or splice site mutations cause EA2 [101] However this rule has many exceptions [102] and EA2 FHM and SCA6 may represent a clinical continuum of the distinct mutations in CACNA1A[103] Moreover an identical mutation can give various clinical expressions in a same family Paroxysmal symptoms could arise from reversible channel dysfunction while progressive neurodegeneration could reflect a toxic gain of function The latter appears to be a general phenomenon in polyglutamine diseases (see SCA 6) but it is not known how point mutations in CACNA1A are associated in some cases with neuronal degeneration [103] EA2 may respond to the treatment with acetazolamide [104105]

EA with paroxysmal choreoathetosis and spasticity

The onset of this disorder is at 2ndash15 years with ataxia dystonia and headaches [105] Episodes last for a few minutes with a daily to yearly frequency Spastic paraparesis can persist between the attacks Episodes are provoked by fatigue stress exercise and alcohol

AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET

Friedreichs ataxia

Friedreichs ataxia (FRDA) described in 1863 by Nicholaus Friedreich and characterized in detail by Harding [8] is the most frequent autosomal recessive ataxia It has an incidence in whites of 130000 [106] but has not been documented among Sub-Saharan Africans American Indians and peoples from China Japan and Southeast Asia [107108] FRDA is responsible for 30 to 40 percent of autosomal recessive ataxia among whites The disease is a progressive spinocerebellar degeneration with typical onset before the age of 25 years especially during childhood or puberty (7ndash14 y) [8] The degeneration of the posterior columns of the spinal cord afferent cerebellar pathways and selected nuclei of the cerebellum gives rise to an ataxic gait classically followed by dysarthria upper limb ataxia distal sensory loss decreased vibration and position sense and absence of reflexes Scoliosis and pes cavus also can develop The full picture of the disease often includes hypertrophic cardiomyopathy [109] impaired glucose tolerance or diabetes mellitus and occasionally hearing loss or optic atrophy [110] In early onset cases FRDA may need to be differentiated from adrenomyeloneuropathy by very long chain fatty acid (VLCFA) levels Refsums disease by serum phytanic acid levels and vitamin E deficiency by vitamin E levels In some cases dominant ataxias and Charcot-Marie-Tooth disease join in the differential diagnoses Neuropathological changes in FRDA include degeneration of the dorsal root ganglia Clarkes columns posterior columns corticospinalspinocerebellar tracts cerebellum pons and medulla [111] Nerve conduction studies show selective loss of sensory nerve action potentials

The FRDAX25 gene contains seven exons spanning 80 kb on chromosome 9q13 and encodes a 210 amino acid protein called frataxin [112129] Most FRDA patients have an expansion of the trinucleotide GAA in the first intron of the FRDAX25 gene [114] Normal alleles contain 6 to 28 GAA repeats while affected individuals have 60 to 1800 (Table 2) Point mutations in the FRDA gene (instead of the GAA expansion) are found in about two to four percent of the cases Compound heterozygous patients with one expanded GAA repeat allele and one point mutation are more likely to show variant clinical features such as optic atrophy or retained reflexes than patients carrying homozygous GAA expansions [115] Among patients with 2 alleles carrying expanded GAA repeats there is an inverse correlation between the size of the GAA expansion and the age of onset severity of the disease and the occurrence of cardiomyopathy and diabetes Patients with the ldquolate onsetrdquo (after 25 years old) variant (LOFA) and those with retained reflexes (FARR) are also caused by the FRDA gene mutation [5117] most commonly associated with modestly expanded alleles (ie lt400 repeats) [127] Genetic heterogeneity in FRDA has been proposed and a second locus (FRDA2) has recently been identified [118]

Table 2 Hereditary ataxia according to the age of onset

Age of onset Diagnostic clues pia Locusgene Diagnosis Early onset (connatal or childhood) Main Congenital Ataxia Syndromes

Jouberts syndrome abnormal eye movements AR Clinic Gillespies syndrome partial anyridia AR Clinic Behrs syndrome optic atrophy AR several Clinic Marinesco-Sjoumlgrens syndrome cataracts hypogonadism AR Clinic

Main Metabolic Ataxias Urea cycles disorders urinary organic acids AR several ClinicBiochemGenetAminoacidurias urinary amino acids AR several ClinicBiochemGenetDisorders of pyruvatelactate serum pyruvatelactate AR several ClinicBiochemGenet

Mitochondrial encephalomyopathies MELAS MERRF etc Mb several ClinicBiochemGenet

Peroxisomal disorders infantile Refsun syndrome AR several ClinicBiochemGenetDisorders of DNA repair

Ataxia telangiectasia skin sensitivity Icircplusmn-fetoprotein cancer AR 11q22-23ATM ClinicGenet

Xeroderma pigmentosum skin sensitivity cancer AR several ClinicGenet

Cockaynes syndrome skin sensitivity dysmorphology AR several ClinicGenet

Trichothiodystrophy skin sensitivity brittle hair AR several ClinicGenet

Intermediate onset (childhood or juvenile)

Friedreichs ataxia - FRDA sensorimotor loss cardiac skeletal AR 9q13frataxin ClinicGenet

Early onset ataxia with retained reflexes - EOARR

early onset retained reflexes AR several ClinicGenet

Isolated vitamin E deficiency - AVED

low serum levels of vitamin E AR 8q13TTP1 ClinicBiochemGenet

Spastic ataxia of Charlevoix-Saguenay - SACS

hypermyelation retinal-nerve fibers AR 13q11sacsin ClinicGenet

Recessive ataxia with ocular motor apraxia -AOA

ocular apraxia neuropathy AR 9q13HITZn-finger ClinicGenet

Progressive myoclonus ataxia - PMA

myoclonus ataxia seizures AR Clinic

Progressive myoclonus epilepsy - PMEc

Unverricht-Lundborg syndrome ARc 21q223cystatin B ClinicGenet

Abetalipoproteinemia abetalipoproteinemia AR 4q22-24MTP ClinicBiochemGenetHypobetalipoproteinemia hypobetalipoproteinemia AD 2p24 3p22 ClinicBiochem Niemman-Pick disease type C sphingomyelin lipidosis AR

18q11NPC1 (95)d ClinicBiochemGenet

Krabbes disease galactosylceramide lipidosis AR galactocerebrosidase ClinicBiochemGenet

Hexosaminidase deficiencies hexosaminidase deficit AR hexA and hexAB ClinicBiochemGenet

Late Onset (juvenile or adult) Autosomal dominant cerebellar ataxia - ADCA SCAs AD Several (see Table

1) ClinicGenet

Episodic ataxia EA-1 EA-2 and EPCA AD channelopaties ClinicGenet Von Hippel-Lindau syndrome

cerebellar hemangioblastomas AD 3p25VHL ClinicGenet

Cerebellar ataxia with hypogonadism hypogonadism ataxia AR Clinic

Mitochondrial multisystemic several ClinicBiochemGenet

[a] pattern of inheritance (ie AR autosomal recessive)

A fascinating concurrence of yeast and human genetics [119ndash124] led to the proposal that frataxin is involved in the homeostasis (probably the transport) of mitochondrial iron Accumulation of iron inside the mitochondria of FRDA cells could lead to increased oxidative stress by free radical production from hydrogen peroxide and hypersensitivity to the oxidative stress due to mitochondrial dysfunction Deficiencies found in mitochondrialcytoplasmic aconitase as well as in the respiratory chain complexes I II and III in FRDA patients [123125] are consistent with this hypothesis Moreover primary vitamin E deficiency (see later) a specific disease associated with a defect in a physiological free radical scavenger clinically resembles FRDA Interestingly all of the enzymes with defective activity in FRDA mitochondria have iron-sulfur (Fe-S) clusters at the active sites These moieties are highly sensitive to free radical damage An alternative or complementary hypothesis is that a primary activity of frataxin is related to the synthesis of the Fe-S cluster [112] In any case these findings led to the proposal that antioxidants could be useful for the treatment of FRDA Idebenone (a free-radical scavenger analogue of coenzyme Q10) may ameliorate andor to revert the cardiac hypertrophy in FRDA patients [126] This drug is currently being studied in clinical trials Although iron chelation by desferroxamine should decrease serum and cytoplasmic iron levels it may decrease aconitase activity which may be detrimental to the cellular function In addition whether chelation can alter mitochondrial iron levels without toxic side effects is unknown A recently developed mouse model of FRDA [113] raises a hope for providing a powerful means to explore many of these hypotheses and potential treatments

Other than the potential therapeutic effect of antioxidants on cardiomyopathy in FRDA the treatment remains supportive and symptomatic Physiotherapy and orthopedic management (prosthesis or surgery) are used either to preserve or to correct progressive deformations of the spine and feet It is important to provide appropriate management of cardiac functions glucose metabolism and secondary medical problems such as aspiration pneumonia

Early-onset cerebellar ataxia with retained reflexes

This disease was considered by Harding [128] to be a syndrome distinct from FRDA however genetic mapping of the early-onset cerebellar ataxia with retained reflexes (EOCARR) locus is necessary before it can be recognized as an independent genetic entity [127] Onset is before age 20 with a clinical picture similar to FRDA but with retained reflexes low incidence of sensory neuropathy less reduction of joint position sense and absence of skeletal abnormalities optic neuropathy cardiomyopathy or diabetes [127] Exclusion of FRDA by DNA testing is essential since some patients with the EOCARR phenotype have GAA expansions in the frataxin gene [127128] Moreover a branch of a recently described EOCARR family has the late onset form of FRDA while another branch has EOCARR phenotype [127] In EOCARR with very early onset differential diagnosis with ataxia telangiectasia mitochondrial disorders adrenoleukodystrophy and lysosomal storage diseases may be necessary

Ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency (AVED) is a rare treatable disorder with a phenotype that resembles FRDA In a patient with a clinical diagnosis of FRDA and a negative genetic result for FRDA serum vitamin E levels should be determined as patients with AVED have very low levels of vitamin E (lt5 gml) Age of onset is between childhood and young adulthood associated with slowly progressive gait and limb ataxia loss of deep tendon reflexes and vibratory and proprioceptive loss followed by progressive ophthalmoplegia dysarthria extensor plantar responses and muscle weakness The disorder is caused by a defect in the TTP1 gene [129] on chromosome 8q13 encoding the -tocopherol transfer protein [130] responsible for the transfer of -tocopherol to the circulating lipoproteins Early onset and severe forms of the disease are caused by truncating mutations or missense mutations in conserved amino acids [131] However DNA testing for the AVED mutations is not commercially available Early replacement therapy may prevent progression of the disease [132133]

Several diseases that lead to secondary vitamin E deficiency (ie by affecting the absorption andor transport of fat

[b] Mitochondrial diseases due to defective mitochondrial genes have maternal inheritance whereas mitochondrial diseases due to nuclear genes have ARAD

[c] Other clinical forms of PME (ie the neuronal ceroid lipofuscinoses Lafora disease type I sialidosis and MERRF) are associated with defects in various genes

[d] A causative second gene NPC2 has not been identified

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

Figure 4 MRI T2 images showings cervical cord atrophy thinning with reduced anteroposterior diameter Notice the hyperintense line in posterior portion of cord The thinned spinal cord is seen lying on the posterior wall of spinal canal with increased signal intensity in its posterior and lateral compartments The anterior subarachnoid space is enlarged The intramedullary signal changes reflect loss of myelinated fibers and gliosis

Pathophysiology of Friedreich ataxia

The major pathophysiologic finding in FA is a dying back phenomena of axons beginning in the periphery with ultimate loss of neurons and a secondary gliosis The primary sites of these changes are the spinal cord and spinal roots There is a loss of large myelinated axons in peripheral nerves which increases with age and disease duration Unmyelinated fibers in sensory roots and peripheral sensory nerves are spared

The posterior columns corticospinal ventral and lateral spinocerebellar tracts all show demyelination and depletion of large myelinated nerve fibers to differing extents This is accompanied by a fibrous gliosis that does not replace the bulk of the lost fibers Overall the spinal cord becomes thin and the anteroposterior (AP) and transverse diameters of the thoracic cord are reduced The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells The posterior column degeneration accounts for the loss of position and vibration sense and the sensory ataxia The loss of large neurons in the sensory ganglia causes extinction of tendon reflexes

Large neurons of the dorsal root ganglia especially lumbosacral and nerve cells in Clarkes column are reduced in number The posterior roots become thin The dentate nuclei exhibit mild to moderate neuronal loss and the middle and superior cerebellar peduncles are reduced in size There is patchy loss of Purkinje cells in the superior vermis of the cerebellum and of neurons in corresponding portions of the inferior olivary nuclei There are mild degenerative changes in the pontine and medullary nuclei and optic tracts The cerebellar ataxia is explained by loss of the lateral and ventral spinocerebellar tracts involvement of Clarkes column the dentate nucleus superior vermis and dentatorubral pathways

The corticospinal tracts are relatively spared down to the level of the cervicomedullary junction Beyond this point the corticospinal tracts are severely degenerated which becomes progressively more severe moving down the spinal cord This explains the common finding of bilateral extensor plantar responses and weakness late in the disease Loss of cells in the nuclei of cranial nerves VIII X and XII results in facial weakness speech and swallowing difficulty

Myocardial muscle fibers also show degeneration and are replaced by macrophages and fibroblasts Essentially chronic interstitial myocarditis occurs with hypertrophy of cardiac muscle fibers fibers become hypertrophied and lose their striations This is followed by swelling and vacuolation and finally interstitial fibrosis The nuclei appear hyperchromatic and occasionally vacuolated The cytoplasm appears granular with frequent lipofuscin depositions Kyphoscoliosis is likely secondary to spinal muscular imbalance

Histologic Findings in Friedreich ataxia

A cross-section through the lower cervical cord clearly shows loss of myelinated fibers of the dorsal columns and the corticospinal tracts (Weil stain) Milder involvement of spinocerebellar tracts is also present The affected tracts show compact fibrillary gliosis (hematoxylin and eosin [HampE]) but no breakdown products or macrophages reflecting the very slow rate of degeneration and death of fibers The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells (HampE) The posterior roots are nearly devoid of large myelinated fibers Within the thoracic spinal cord degeneration and loss of cells of the Clarke column is apparent

Figure 6 Friedreich Ataxia Spinal cord

Comment on the radiology of the previously reported case

The decreased anteroposterior diameter of the spinal cord at the upper cervical region confirms that atrophy of the upper cervical part of the spinal cord is a characteristic feature of Friedreichrsquos ataxia as opposed to other forms of corticocerebellar and cerebellar-brainstem atrophy [3-6] This had been indicated on the basis of subjective evaluation in two previous studies [201204]

No direct pathologic correlation of the intramedullary signal abnormalities is available However the sensitivity of MR imaging to degeneration of white matter tracts in the brain and spinal cord after stroke or in degenerative diseases of the CNS - that is manifested on the MRI T2 images as hyperintense lines- has been cited in several reports [211-214] Because of the substantial similarities between the intramedullary signal abnormality pattern that is found in the reported patient and the distribution of demyelination and gliosis of white matter tracts in the histopathologic pictures of the spinal cord in cases of Friedreichrsquos ataxia [200] we think it reasonable to assume that the MR appearance could reflect these pathologic findings Obviously the intramedullary signal abnormality pattern we found is not exclusive to Friedreichrsquos ataxia and can be observed in subacute combined degeneration tabes dorsalis wallerian degeneration and AIDS myelopathy In these conditions however associated clinical and laboratory findings usually allow the correct diagnosis

Detection of signal changes in the white matter tracts of the spinal cord of patients with Friedreichrsquos ataxia could be an index of severity or progression of the disease and in this respect it is more useful than cord atrophy The

Figure 5 Friedreich Ataxia

association between the extent of intramedullary signal changes and the chronicity and severity of disease was not examined in the reported patient Although this analysis could be informative it requires quantitation of the signal changes in the white matter tracts and evaluation of the thoracolumbar spine which were not done in the reported patient Noteworthy is the fact that we found intramedullary signal changes only in patients with Friedreichrsquos ataxia No such findings were seen in any of the patients with corticocerebellar or cerebellar-brainstem atrophy in the author experience Thus it appears that evaluation of the cervical spinal cord for intramedullary signal changes might be useful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

In a broad sense our results confirm that MR examination of the cervical spinal cord is more informative than examination of the brain in patients with Friedreichrsquos ataxia Although spinal cord atrophy and intramedullary signal changes theoretically could be searched for in the thoracic spinal cord of patients with Friedreichrsquosrsquo ataxia [200] focusing on the cervical spinal cord is recommended because it usually allows concurrent evaluation of the brainstem and the cerebellum This may help in the differential diagnosis with corticocerebellar and cerebellar-brainstem atrophies

In conclusion MR imaging of the cervical spinal cord can show thinning of the cord and intramedullary signal changes consistent with degeneration of white matter tracts in the lateral and posterior columns of patients with Friedreichrsquos ataxia These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

DIAGNOSIS FRIEDREICHS ATAXIA

DISCUSSION

Hereditary ataxias are a heterogeneous group of neurological disorders Outstanding contributions by Holmes [1] Greenfield [2] and Harding [3] established a syndromic framework for these diseases and remarkable progress in the field now permits a definitive diagnosis in 60 to 70 percent of hereditary ataxia patients Although an increasing number of genetic tests are becoming available for the known ataxia genes phenotypic variability and clinical overlap have hampered development of a useful clinical algorithm for the differential diagnosis of ataxic patients Furthermore some patients with hereditary ataxia may have no family history of ataxia The diagnosis of genetic ataxia in apparently sporadic cases is especially difficult as a variety of nongenetic causes could be underlying the manifestation of the ataxic syndrome Most of the genetic ataxias are adult-onset disorders for which there are no effective treatments and it is not yet possible to offer satisfactory estimates concerning age of onset or prognosis in potentially affected relatives The results of DNA testing however may have dramatic ethical social and legal impact on the life of test subjects and their families For these reasons careful genetic and psychological counseling is required for the patients who undergo genetic testing It should also be noted that some genetic ataxias are treatable and correct diagnosis for these disorders should not be missed

In this article the author reviews the clinical features and current genetic understanding of inherited ataxias The readers may also refer to recent reviews of hereditary ataxias [4] and dominant hereditary ataxias [67116] As ataxia commonly presents in patients without family history we will discuss the clinical approach to differential diagnosis of hereditary and non-hereditary conditions

AUTOSOMAL DOMINANT ATAXIA

Spinocerebellar ataxias

Autosomal dominant spinocerebellar ataxias (ADCA see Table 1) have been clinically classified into three syndromes (ADCA-I II and III) based on the presence of cerebellar ataxia in combination with other symptomatology [89] ADCA-I is defined by a cerebellar syndrome variably accompanied by ophthalmoplegia pyramidal and extrapyramidal signs dementia and other neurological disorders ADCAII is defined by a cerebellar syndrome associated with pigmentary retinopathy and ADCA-III is defined by pure ataxia without other neurologic features While this classification scheme is still useful more recent definition of diseases by specific genetic loci or based on individual families (defined by specific Spinocerebellar ataxias (SCA) loci) only roughly correlates with Hardings classification SCA 7 is the only genetically defined disorder in the ADCA-II group ADCA-I would

DIAGNOSIS

DISCUSSION

classically include SCAs 1 2 3 4 12 13 and 17 but each of these disorders may have purely cerebellar features early Most patients with SCA 5 6 8 10 11 14 and 16 would be classified with ADCA-III but others develop extracerebellar neurological abnormalities consistent with ADCA-I Thus the SCA terminology based on genetic analysis is more commonly presented today

Many of the SCAs (1 2 3 6 7 17 and dentatorubro-pallidoluysian atrophy (DRPLA)) are caused by an expansion of CAG repeats in their respective genes In these disorders the mutation is an expansion of a naturally occurring

Table 1 Autosomal dominant cerebellar ataxia (ADCA)

Disease Locus Type of mutationGene product

Normal alleles

Pathogenic alleles

Distribution (number of families)

of total SCA

Db

ADCA I SCA-1 6p22-p23 CAG expansionataxin-1 6-44 40-81 worldwide 5-15 C

SCA-2 12q23-241 CAG expansionataxin-2 14-31 34-59 Cuba worldwide 5-15 C

SCA-3MJD

14q243-q321 CAG expansionataxin-3 14-33 56-200 Portugal

worldwide 30-50 C

SCA-4 16q221 unknown USA Japan (7 families) N

SCA-12 5p31-p33 CAG expansion5 UTR of PPP2R2B 17-28 55-78 USA India (2

families) rare R

SCA-13 19q133-134 unknown France (1 family) rare R

SCA-17 6q27 Impure CAG expansionTBPa 27-44 47-63 Japan Germany rare R

ADCA II SCA-7 3p12-p13 CAG expansionataxin-7 7-19 37-300 worldwide C

SCA-8 13q21 CTG expansion3 UTR region of SCA8 15-91 107-127 C

ADCA III SCA-5 11cen unknown USA (1 family) rare N

SCA-6 19p131 CAG expansionCACNL1A4a 4-20 21-33 worldwide 5-10 C

SCA-10 22q13 ATTCT expansionintron 9 Hh-E4a 10-22 800-4500 Mexico rare C

SCA-11 15q14-q213 unknown England (1

family) rare N

SCA-14 19q134-qter unknown Japan (1 family) rare N

SCA-16 8q221-q241 unknown Japan rare N

Episodic Ataxia EA type 1 12p13

Missense mutationsCACNL1A4a worldwide R

EA type 2 19p13

Missense mutationsCACNL1A4a worldwide R

DRPLA

[b] D Diagnosis available=Commercially (C) Research (R) Non-available (N)

[a] TBP (TATA binding proteins) CACNL1A4 (1A-voltage-gated calcium channel subunit) Hh-E4 (human homologous of mouse E4 gene)

CAG repeat in the protein coding region of a specific protein This leads to an abnormal expanded series of glutamines being translated in that specific protein The expansion is unstable over generations leading to progressive lengthening of the repeat Disease results when the repeat reaches a specific pathologic range and further expansion leads to progressively earlier age of onset Thus in each of these diseases the CAG repeat size correlates inversely with the age of onset The common pathogenic mechanism of these diseases involves a gain of toxic function [10] and neuropathological studies in ldquopolyglutaminerdquo diseases reveal the presence of neuronal nuclear protein inclusion [1112] which contain the polyglutamine-containing protein specific interacting proteins and proteins from the ubiquitin-degradation pathway [10] These aggregates do not appear to be responsible for the disease in SCA1 [13] although their direct role in other ldquopolyglutaminerdquo diseases is unclear The pathogenicity of the mutant protein in these diseases may involve defective ldquoprotein clearancerdquo sequestration of transcription co-activators and co-repressors andor other gain of function mechanisms [14]

The mutations for SCA8 and SCA12 are expansions of a CAGCTG repeat in untranslated regions of their respective genes Whether the trinucleotide expansion found in SCA8 is a causative mutation or a polymorphism in linkage disequilibrium is still a matter of debate (see SCA8 below) Individuals with SCA10 have a large expansion of an intronic ATTCT pentanucleotide repeat The pathogenic mechanisms of these SCAs remain to be investigated SCAs4 5 11 13 14 and 16 have been mapped but their mutations have not been identified SCAs1 2 3 6 7 and 17 are more frequent than others SCAs and a few SCA types have been recognized only in a single family The incidence of the different types of SCA around the world is variable and known SCAs constitute about 60ndash80 of the families with ADCA (Table 1)

SCA1

The SCA1 gene is located on chromosome 6p linked to the HLA gene complex [15] SCA1 was cloned and the CAG repeat expansion identified in 1993 [16] The number of CAG repeats in normal and pathological alleles of SCA1 are shown in Table 1 The progression of SCA1 has a pattern common to most of the ADCA [17] typical onset with a cerebellar syndrome (ie broad-based gait limb ataxia progressive dysarthria) hand tremor and oculomotor signs including intermittent nystagmus slowing in saccadic velocity followed by limitation of up-gaze The bulbar and upper motor neurons signs may include lingual fasciculations noncerebellar dysphagia and dysarthria brisk deep tendon reflexes and increased tone (spasticity) Later in the disease this constellations of symptoms becomes more severe with coughing overt choking sensory loss mild peripheral neuropathy and extensor plantar responses In SCA1 extrapyramidal signs may be evident by the time the patient becomes wheelchair bounded The phenotype of the disease appears to be relatively homogeneous within and between families Variability observed in age of onset and progression appears to be attributable to the size of the CAG repeat expansion [1819] Bradykinesia and parkinsonism which may be prominent features in SCA3MJD have not been observed in SCA1 Cognitive decline does not appear to be severe in SCA1 Neuroimaging studies typically show atrophy of cerebellar cortex vermis and brainstem

SCA2

The SCA2 gene was mapped by linkage analysis of a homogeneous population of Holguin province (Cuba) to chromosome 12q24 [20] and later cloned independently by three groups [21ndash23] Clinical features of the disease include slow saccades kinetic or postural tremor and decrease of muscle tone and tendon reflexes Variable incidence of dystonia chorea and dementia has also been recognized Nonspecific cerebellar or pontocerebellar atrophy has been observed on MRI Nerve conduction studies show evidence of axonal sensory-motor neuropathy

SCA3MJD (Machado-Joseph disease)

Originally described in Portuguese families and named the ldquoAzorean diseaserdquo [24] SCA3 is now recognized worldwide The mutation in the SCA3 gene localized to 14q311 is an expanded CAG repeat in a novel protein designated ataxin-3 [25] Variable phenotypes are found in SCA3[2627] in addition to cerebellar ataxia and ophthalmoplegia early-onset disease can present with spasticity dystonia and an akinetic syndrome whereas late-onset SCA3 presents mainly with minimal extrapyramidal symptomatology The extrapyramidal signs are a characteristic but not exclusive feature of the SCA3 phenotype [27] There is an inverse correlation between the age of onset and the expanded CAG repeat length The severity of the disease as well as the presence of some symptoms (ie peripheral neuropathy) may depend on the length of the expansion with short and very large pathological alleles lacking neuropathy [28]

SCA4

A five-generation Utah kindred with an autosomal dominant late-onset spinocerebellar ataxia with the invariable presence of prominent axonal sensory neuropathy and normal eye movements demonstrated linkage to chromosome 16q221 [29] Six Japanese families with pure cerebellar ataxia without sensory neuropathy also showed linkage to this locus [3031]

SCA5

SCA5 was assigned to chromosome 11 in a single family descending from the grandparents of President Abraham Lincoln [32] In this family 56 individuals had cerebellar ataxia with onset at 10 to 68 years Anticipation is evident and progression of the disease is slow SCA5 does not affect life span probably because severe bulbar disease is generally absent A second apparently unrelated SCA5 family of French origin showed a similar phenotype with marked global cerebellar atrophy similar to SCA6 on MRI [33]

SCA6

SCA6 classically presents with pure cerebellar ataxia although patients with a prolonged disease course may show other clinical features including dystonic postures involuntary movements and abnormalities in tendon reflexes [34] Patients with SCA6 especially those with late onset disease may present without a family history The diagnosis of SCA6 should be considered in sporadic cases with horizontal and oblique gaze nystagmus and an abnormal vestibulo-ocular reflex without other ocular movement abnormalities or those with pure cerebellar atrophy [3435] Some phenotypic overlap with the allelic disease EA-2 (see the section of Episodic Ataxia) has been noted [3637] Brain MRI shows atrophy of the cerebellum and in some patients pons middle cerebellar peduncles and red nucleus [343839] The SCA6 mutation is a small CAG repeat expansion within the 1A-voltage-dependent calcium channel subunit (CACNL1A4) gene [40] The number of CAGs in mutant alleles ranges 20 to 30 while normal alleles are 4 to 17 CAGs (Table 1) [4041] An allele with 19 CAGs has been reported in a Japanese patient with ataxia [42] Although the age of onset inversely correlates with the expanded repeat size in different families the expanded repeat is usually stably transmitted within each family [414344] In rare cases however mild expansions have been reported [4546] Sisters homozygous for (CAG)2525 showed a similar age of onset but different progression rate suggesting pathogenic contribution of factors other than the repeat size [47] Homozygous cases suggested a gene dosage effect on the age of onset [3648ndash50] Anticipation in the absence of changes in the CAG repeat size has been described in French [51] Japanese [41] and Taiwanese kindreds

Although the expansion size of the CAG repeat falls into the normal ranges of other SCAs the polyglutamine tract in a densely packed membrane protein may allow the 1A subunits with small expansions to aggregate [5253] A key question is whether the SCA6 mutation causes disease by making the 1A subunit toxic or it does so by perturbing the gating of PQ-type channels [54] To reconcile these two different mechanisms it has been postulated that protein interactions altered by the expanded polyglutamine tract might cause gating abnormalities [55]

SCA7

SCA7 is characterized by progressive ataxia and pigmentary maculopathy with anticipation and is the only disease classified as an ADCA-II These features are accompanied by other clinical features including pyramidal and extrapyramidal signs ophthalmoplegia dementia hypoacusis hypotonia and auditory hallucinations [56] Slowing of voluntary and involuntary saccades is also an early sign of SCA7 [57] Specific juvenile and infantile forms of SCA7 have been defined Juvenile SCA7 occurs with maternal and paternal transmission whereas the infantile form occurs only with paternal transmission The infantile form shows severe hypotonia cerebral and cerebellar atrophy early visual loss congestive heart failure and patent ductus arteriosus [58] SCA7 is caused by an expansion of a CAG repeat in the SCA7 (ataxin-7) gene on chromosome 3p [5960] The normal range is 7 to 19 CAG repeats and pathogenic alleles range from 37 to approximately 306 repeats The expansion size correlates with the severity of the disease and inversely correlates with the age of onset [6162] Alleles with 28 to 36 repeats are intermediate alleles that are prone to further expansion accounting for de novo mutation cases [6364] Different disease-associated haplotypes segregated among SCA7 kindreds suggesting multiple origins of the mutation [63] Paternal transmission is underrepresented and when it does occur is associated with significant intergenerational expansion of the CAG repeat [65] The expanded CAG repeat in male germline is biased toward massive size increases potentially leading to putative embryonic lethality or dysfunctional sperm [66] The available data suggest that the mutant ataxin-7 protein is pathogenic due to a gain of toxic function by the polyglutamine expansion [67ndash70]

SCA8

SCA8 presents with slowly progressive ataxia with marked cerebellar atrophy [71] The disease is variably associated with pyramidal and cognitive dysfunctions [72] SCA8 patients have an expansion of a CTG repeat on chromosome 13q21 to the pathogenic range of 100 to 152 repeats while normal individuals have 15 to 91 CTGs [73] Affected individuals usually inherit an expanded allele from their mothers SCA8 alleles show an instability bias toward expansion with maternal transmission whereas paternal transmissions mostly result in smaller alleles which appear to be due to contraction of the expanded alleles to the normal range (lt100 CTGs) in the sperm [717475] Variable penetrance has been identified in SCA8 pedigrees [7176] There has been no evidence of correlation between the repeat size and the age of onset Haplotype analyses showed multiple origins for the SCA8 expansions [72]

The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract with the configuration (CTA)1-21(CTG)n in the 3 untranslated region of the SCA8 gene Many SCA patients have expanded alleles with interruptions by cryptic repeats (CCG CTA CTC CCA or CTT) which may have newly arisen or changed from generation to generation [74] SCA8 contains no open reading frame but the most 5 exon is transcribed through the first exon of another gene KLHL1 which is transcribed in the opposite orientation This raises a possibility that the SCA8 transcript is an endogenous antisense RNA for KLHL1 KLHL1 encodes a cytoplasmic protein that may play a role in organizing the actin cytoskeleton of the brain cells Both SCA8 and KLHL1 are primarily expressed in specific brain tissues affected by SCA8 [77] Other gain-of-function mechanisms involving the mutant SCA8 transcript have not been investigated but by no means excluded

The major controversy in SCA8 stems from a lack of absolute specificity of the CTG repeat expansion for SCA8 which has raised a possibility that CTG expansions at the SCA8 locus represent a rare polymorphism rather than the disease-causing mutation [7879] Alleles greater than 100 CTG repeats at the SCA8 locus were also found in 12 (14 of 1120) of major psychosis patients and 07 (5 of 710) of normal control subjects who had no family history of ataxia [80]

SCA9 (vacant)

SCA10

The clinical phenotype of SCA10 is characterized by a combination of relatively pure cerebellar ataxia and epilepsy Ataxia is progressive and often leads to total disability Seizures are generalized motor seizures complex partial seizures or both Some patients show mild cognitive dysfunction sensory polyneuropathy andor soft corticospinal tract signs [81] Anticipation is conspicuous in some families but subtle or absent in others The disease has so far been confined to families of Mexican descent The SCA10 mutation is a very large expansion of the ATTCT pentanucleotide repeat located in intron 9 of the E46L (SCA10) gene on chromosome 22q13 [49] Normal alleles show 10 to 21 ATTCTs while affected individuals have 800ndash4500 repeats An inverse correlation exists between the size of the expanded allele and the age of onset The mechanism of the disease remains unknown

SCA11

SCA11 clinically defined as an ADCA-III has been mapped to chromosome 15q in a single British family [78]

SCA12

SCA12 is a rare ADCA characterized by adult onset ataxia upper body tremor hyperreflexia with bilateral extensor plantar responses paucity of movements and dementia [8283] The clinical picture includes oculomotor abnormalities (ie broken pursuit nystagmus slow saccades) The disease is slowly progressive and in the late stage psychiatric symptoms including depression anxiety or delusions may appear in some affected members Brain MRI shows cerebellar and cerebral cortical atrophy There is no evidence of anticipation The mutation of SCA12 is a CAG repeat expansion in the 5 untranslated region of the PPP2R2B gene on chromosome 5p31-p33 [84] Normal alleles have 17 to 28 CAG repeats while the pathologic alleles have 55 to 78 repeats The disease has been described in two kindreds one from US and the other from India [8587] It has been postulated that the expansion of the CAG repeat up-regulate PPP2R2B expression

SCA13

A French family presented with slowly progressive childhood-onset cerebellar gait ataxia dysarthria moderate mental retardation and mild motor developmental delays with in some cases nystagmus and pyramidal signs Brain MRI showed moderate cerebellar and pontine atrophy A genome wide search showed linkage to chromosome

19q133-q134 [86]

SCA14

A Japanese three-generation family with ADCA mapped to a locus on chromosome 19q134-qter [86] The family members with late onset (gt39 years old) exhibited pure cerebellar ataxia whereas those with an early onset (lt27 years old) showed intermittent axial myoclonus followed by ataxia Other neurological signs were sparse and neuroimaging studies revealed isolated cerebellar atrophy

SCA15 (vacant)

SCA16

This is a pure cerebellar ataxia with head tremor and thus a form of ADCA III [88] Although head tremor which is distinct from tittubation has been described in SCA2 SCA7 and SCA12 it is rare for all SCA types Age of onset ranges 20 to 66 years and anticipation was not apparent Brain MRI showed cerebellar atrophy without involving brainstem The SCA16 locus showed linkage to markers on chromosome 8q221-q241 [88]

SCA17

An expansion of CAG repeats of the TATA-binding protein (TBP) gene was initially reported in a Japanese patient with sporadic cerebellar ataxia and intellectual deterioration associated with de novo expansion The expanded allele consisted of impure CAG repeats encoding 63 glutamines and the de novo expansion involved partial duplication of the CAG repeat [89] In two German families four patients showed expanded CAG repeats in TBP gene coding for 50 to 55 polyglutamines while normal subjects had alleles ranging from 27 to 44 glutamines [90] Several additional Japanese families with phenotypes resembling Huntingtons disease or DRPLA also showed SCA17 CAG expansions [91]

Other SCAs

Anecdotally there are many ADCA families who are not linked to known genetic loci and who have no distinctive phenotype In one such French family SCAs 1 2 3 6 7 8 and 12 were excluded by mutation analysis and SCAs 4 5 10 11 13 14 by lod score less than 2 Affected members of this French family showed gait ataxia akinesia dysarthria hyporeflexia and anticipation [92] There are likely to be many similar families who have not yet been characterized or reported

DRPLA

DRPLA is a relatively frequent disease in Japan with an incidence of 02-07 per 100000 A few isolated families have been recognized worldwide [92] The DRPLA gene on the chromosome 12p was cloned in 1994 [9495] Early onset of the disease includes ataxia myoclonus epilepsy and progression to dementia later onset disease can present with cerebellar symptoms psychiatric symptoms seizures [9396] and choreoathetotic abnormal movements with a ldquoHuntington-likerdquo phenotype [97] Age of onset and severity correlate with the length of the CAG expansion The mutation in the DRPLA gene has also been found in the Haw River Syndrome which has some different clinical characteristics from DRPLA [98]

Episodic ataxia (EA)

In contrast to SCAs these rare diseases present with episodic ataxic attacks of variable frequency and duration with no symptoms between attacks Additional characteristic signs are associated with the different types of EA

EA type 1 (EA1)

EA1 is caused by mutations in a potassium channel gene KCNA1 on chromosome 12p [99] The onset is between childhood and adolescence Besides episodic ataxia clinical manifestations are myokymia around the eyes lips or fingers Brief attacks of ataxia and dysarthria lasting seconds are precipitated by exercise or startle

EA type 2 (EA2)

Clinical manifestations of EA2 consist of mild to severe intermittent cerebellar dysfunction associated with oculomotor abnormalities such as interictal nystagmus and diplopia and migraine Symptoms can be present for minutes to a few days Episodes are provoked by stress and exercise but not startle Like familial hemiplegic migraine (FHM) and spinocerebellar ataxia type 6 (SCA6) EA2 is associated with mutations in the gene encoding the -1A subunit of the calcium channel SCA6 is caused by a CAG repeat expansion [40] while point mutations in the CACNA1A gene cause EA2 and FHM [100] Missense mutations usually cause FHM and non-sense or splice site mutations cause EA2 [101] However this rule has many exceptions [102] and EA2 FHM and SCA6 may represent a clinical continuum of the distinct mutations in CACNA1A[103] Moreover an identical mutation can give various clinical expressions in a same family Paroxysmal symptoms could arise from reversible channel dysfunction while progressive neurodegeneration could reflect a toxic gain of function The latter appears to be a general phenomenon in polyglutamine diseases (see SCA 6) but it is not known how point mutations in CACNA1A are associated in some cases with neuronal degeneration [103] EA2 may respond to the treatment with acetazolamide [104105]

EA with paroxysmal choreoathetosis and spasticity

The onset of this disorder is at 2ndash15 years with ataxia dystonia and headaches [105] Episodes last for a few minutes with a daily to yearly frequency Spastic paraparesis can persist between the attacks Episodes are provoked by fatigue stress exercise and alcohol

AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET

Friedreichs ataxia

Friedreichs ataxia (FRDA) described in 1863 by Nicholaus Friedreich and characterized in detail by Harding [8] is the most frequent autosomal recessive ataxia It has an incidence in whites of 130000 [106] but has not been documented among Sub-Saharan Africans American Indians and peoples from China Japan and Southeast Asia [107108] FRDA is responsible for 30 to 40 percent of autosomal recessive ataxia among whites The disease is a progressive spinocerebellar degeneration with typical onset before the age of 25 years especially during childhood or puberty (7ndash14 y) [8] The degeneration of the posterior columns of the spinal cord afferent cerebellar pathways and selected nuclei of the cerebellum gives rise to an ataxic gait classically followed by dysarthria upper limb ataxia distal sensory loss decreased vibration and position sense and absence of reflexes Scoliosis and pes cavus also can develop The full picture of the disease often includes hypertrophic cardiomyopathy [109] impaired glucose tolerance or diabetes mellitus and occasionally hearing loss or optic atrophy [110] In early onset cases FRDA may need to be differentiated from adrenomyeloneuropathy by very long chain fatty acid (VLCFA) levels Refsums disease by serum phytanic acid levels and vitamin E deficiency by vitamin E levels In some cases dominant ataxias and Charcot-Marie-Tooth disease join in the differential diagnoses Neuropathological changes in FRDA include degeneration of the dorsal root ganglia Clarkes columns posterior columns corticospinalspinocerebellar tracts cerebellum pons and medulla [111] Nerve conduction studies show selective loss of sensory nerve action potentials

The FRDAX25 gene contains seven exons spanning 80 kb on chromosome 9q13 and encodes a 210 amino acid protein called frataxin [112129] Most FRDA patients have an expansion of the trinucleotide GAA in the first intron of the FRDAX25 gene [114] Normal alleles contain 6 to 28 GAA repeats while affected individuals have 60 to 1800 (Table 2) Point mutations in the FRDA gene (instead of the GAA expansion) are found in about two to four percent of the cases Compound heterozygous patients with one expanded GAA repeat allele and one point mutation are more likely to show variant clinical features such as optic atrophy or retained reflexes than patients carrying homozygous GAA expansions [115] Among patients with 2 alleles carrying expanded GAA repeats there is an inverse correlation between the size of the GAA expansion and the age of onset severity of the disease and the occurrence of cardiomyopathy and diabetes Patients with the ldquolate onsetrdquo (after 25 years old) variant (LOFA) and those with retained reflexes (FARR) are also caused by the FRDA gene mutation [5117] most commonly associated with modestly expanded alleles (ie lt400 repeats) [127] Genetic heterogeneity in FRDA has been proposed and a second locus (FRDA2) has recently been identified [118]

Table 2 Hereditary ataxia according to the age of onset

Age of onset Diagnostic clues pia Locusgene Diagnosis Early onset (connatal or childhood) Main Congenital Ataxia Syndromes

Jouberts syndrome abnormal eye movements AR Clinic Gillespies syndrome partial anyridia AR Clinic Behrs syndrome optic atrophy AR several Clinic Marinesco-Sjoumlgrens syndrome cataracts hypogonadism AR Clinic

Main Metabolic Ataxias Urea cycles disorders urinary organic acids AR several ClinicBiochemGenetAminoacidurias urinary amino acids AR several ClinicBiochemGenetDisorders of pyruvatelactate serum pyruvatelactate AR several ClinicBiochemGenet

Mitochondrial encephalomyopathies MELAS MERRF etc Mb several ClinicBiochemGenet

Peroxisomal disorders infantile Refsun syndrome AR several ClinicBiochemGenetDisorders of DNA repair

Ataxia telangiectasia skin sensitivity Icircplusmn-fetoprotein cancer AR 11q22-23ATM ClinicGenet

Xeroderma pigmentosum skin sensitivity cancer AR several ClinicGenet

Cockaynes syndrome skin sensitivity dysmorphology AR several ClinicGenet

Trichothiodystrophy skin sensitivity brittle hair AR several ClinicGenet

Intermediate onset (childhood or juvenile)

Friedreichs ataxia - FRDA sensorimotor loss cardiac skeletal AR 9q13frataxin ClinicGenet

Early onset ataxia with retained reflexes - EOARR

early onset retained reflexes AR several ClinicGenet

Isolated vitamin E deficiency - AVED

low serum levels of vitamin E AR 8q13TTP1 ClinicBiochemGenet

Spastic ataxia of Charlevoix-Saguenay - SACS

hypermyelation retinal-nerve fibers AR 13q11sacsin ClinicGenet

Recessive ataxia with ocular motor apraxia -AOA

ocular apraxia neuropathy AR 9q13HITZn-finger ClinicGenet

Progressive myoclonus ataxia - PMA

myoclonus ataxia seizures AR Clinic

Progressive myoclonus epilepsy - PMEc

Unverricht-Lundborg syndrome ARc 21q223cystatin B ClinicGenet

Abetalipoproteinemia abetalipoproteinemia AR 4q22-24MTP ClinicBiochemGenetHypobetalipoproteinemia hypobetalipoproteinemia AD 2p24 3p22 ClinicBiochem Niemman-Pick disease type C sphingomyelin lipidosis AR

18q11NPC1 (95)d ClinicBiochemGenet

Krabbes disease galactosylceramide lipidosis AR galactocerebrosidase ClinicBiochemGenet

Hexosaminidase deficiencies hexosaminidase deficit AR hexA and hexAB ClinicBiochemGenet

Late Onset (juvenile or adult) Autosomal dominant cerebellar ataxia - ADCA SCAs AD Several (see Table

1) ClinicGenet

Episodic ataxia EA-1 EA-2 and EPCA AD channelopaties ClinicGenet Von Hippel-Lindau syndrome

cerebellar hemangioblastomas AD 3p25VHL ClinicGenet

Cerebellar ataxia with hypogonadism hypogonadism ataxia AR Clinic

Mitochondrial multisystemic several ClinicBiochemGenet

[a] pattern of inheritance (ie AR autosomal recessive)

A fascinating concurrence of yeast and human genetics [119ndash124] led to the proposal that frataxin is involved in the homeostasis (probably the transport) of mitochondrial iron Accumulation of iron inside the mitochondria of FRDA cells could lead to increased oxidative stress by free radical production from hydrogen peroxide and hypersensitivity to the oxidative stress due to mitochondrial dysfunction Deficiencies found in mitochondrialcytoplasmic aconitase as well as in the respiratory chain complexes I II and III in FRDA patients [123125] are consistent with this hypothesis Moreover primary vitamin E deficiency (see later) a specific disease associated with a defect in a physiological free radical scavenger clinically resembles FRDA Interestingly all of the enzymes with defective activity in FRDA mitochondria have iron-sulfur (Fe-S) clusters at the active sites These moieties are highly sensitive to free radical damage An alternative or complementary hypothesis is that a primary activity of frataxin is related to the synthesis of the Fe-S cluster [112] In any case these findings led to the proposal that antioxidants could be useful for the treatment of FRDA Idebenone (a free-radical scavenger analogue of coenzyme Q10) may ameliorate andor to revert the cardiac hypertrophy in FRDA patients [126] This drug is currently being studied in clinical trials Although iron chelation by desferroxamine should decrease serum and cytoplasmic iron levels it may decrease aconitase activity which may be detrimental to the cellular function In addition whether chelation can alter mitochondrial iron levels without toxic side effects is unknown A recently developed mouse model of FRDA [113] raises a hope for providing a powerful means to explore many of these hypotheses and potential treatments

Other than the potential therapeutic effect of antioxidants on cardiomyopathy in FRDA the treatment remains supportive and symptomatic Physiotherapy and orthopedic management (prosthesis or surgery) are used either to preserve or to correct progressive deformations of the spine and feet It is important to provide appropriate management of cardiac functions glucose metabolism and secondary medical problems such as aspiration pneumonia

Early-onset cerebellar ataxia with retained reflexes

This disease was considered by Harding [128] to be a syndrome distinct from FRDA however genetic mapping of the early-onset cerebellar ataxia with retained reflexes (EOCARR) locus is necessary before it can be recognized as an independent genetic entity [127] Onset is before age 20 with a clinical picture similar to FRDA but with retained reflexes low incidence of sensory neuropathy less reduction of joint position sense and absence of skeletal abnormalities optic neuropathy cardiomyopathy or diabetes [127] Exclusion of FRDA by DNA testing is essential since some patients with the EOCARR phenotype have GAA expansions in the frataxin gene [127128] Moreover a branch of a recently described EOCARR family has the late onset form of FRDA while another branch has EOCARR phenotype [127] In EOCARR with very early onset differential diagnosis with ataxia telangiectasia mitochondrial disorders adrenoleukodystrophy and lysosomal storage diseases may be necessary

Ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency (AVED) is a rare treatable disorder with a phenotype that resembles FRDA In a patient with a clinical diagnosis of FRDA and a negative genetic result for FRDA serum vitamin E levels should be determined as patients with AVED have very low levels of vitamin E (lt5 gml) Age of onset is between childhood and young adulthood associated with slowly progressive gait and limb ataxia loss of deep tendon reflexes and vibratory and proprioceptive loss followed by progressive ophthalmoplegia dysarthria extensor plantar responses and muscle weakness The disorder is caused by a defect in the TTP1 gene [129] on chromosome 8q13 encoding the -tocopherol transfer protein [130] responsible for the transfer of -tocopherol to the circulating lipoproteins Early onset and severe forms of the disease are caused by truncating mutations or missense mutations in conserved amino acids [131] However DNA testing for the AVED mutations is not commercially available Early replacement therapy may prevent progression of the disease [132133]

Several diseases that lead to secondary vitamin E deficiency (ie by affecting the absorption andor transport of fat

[b] Mitochondrial diseases due to defective mitochondrial genes have maternal inheritance whereas mitochondrial diseases due to nuclear genes have ARAD

[c] Other clinical forms of PME (ie the neuronal ceroid lipofuscinoses Lafora disease type I sialidosis and MERRF) are associated with defects in various genes

[d] A causative second gene NPC2 has not been identified

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

Histologic Findings in Friedreich ataxia

A cross-section through the lower cervical cord clearly shows loss of myelinated fibers of the dorsal columns and the corticospinal tracts (Weil stain) Milder involvement of spinocerebellar tracts is also present The affected tracts show compact fibrillary gliosis (hematoxylin and eosin [HampE]) but no breakdown products or macrophages reflecting the very slow rate of degeneration and death of fibers The dorsal spinal ganglia show shrinkage and eventual disappearance of neurons associated with proliferation of capsular cells (HampE) The posterior roots are nearly devoid of large myelinated fibers Within the thoracic spinal cord degeneration and loss of cells of the Clarke column is apparent

Figure 6 Friedreich Ataxia Spinal cord

Comment on the radiology of the previously reported case

The decreased anteroposterior diameter of the spinal cord at the upper cervical region confirms that atrophy of the upper cervical part of the spinal cord is a characteristic feature of Friedreichrsquos ataxia as opposed to other forms of corticocerebellar and cerebellar-brainstem atrophy [3-6] This had been indicated on the basis of subjective evaluation in two previous studies [201204]

No direct pathologic correlation of the intramedullary signal abnormalities is available However the sensitivity of MR imaging to degeneration of white matter tracts in the brain and spinal cord after stroke or in degenerative diseases of the CNS - that is manifested on the MRI T2 images as hyperintense lines- has been cited in several reports [211-214] Because of the substantial similarities between the intramedullary signal abnormality pattern that is found in the reported patient and the distribution of demyelination and gliosis of white matter tracts in the histopathologic pictures of the spinal cord in cases of Friedreichrsquos ataxia [200] we think it reasonable to assume that the MR appearance could reflect these pathologic findings Obviously the intramedullary signal abnormality pattern we found is not exclusive to Friedreichrsquos ataxia and can be observed in subacute combined degeneration tabes dorsalis wallerian degeneration and AIDS myelopathy In these conditions however associated clinical and laboratory findings usually allow the correct diagnosis

Detection of signal changes in the white matter tracts of the spinal cord of patients with Friedreichrsquos ataxia could be an index of severity or progression of the disease and in this respect it is more useful than cord atrophy The

Figure 5 Friedreich Ataxia

association between the extent of intramedullary signal changes and the chronicity and severity of disease was not examined in the reported patient Although this analysis could be informative it requires quantitation of the signal changes in the white matter tracts and evaluation of the thoracolumbar spine which were not done in the reported patient Noteworthy is the fact that we found intramedullary signal changes only in patients with Friedreichrsquos ataxia No such findings were seen in any of the patients with corticocerebellar or cerebellar-brainstem atrophy in the author experience Thus it appears that evaluation of the cervical spinal cord for intramedullary signal changes might be useful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

In a broad sense our results confirm that MR examination of the cervical spinal cord is more informative than examination of the brain in patients with Friedreichrsquos ataxia Although spinal cord atrophy and intramedullary signal changes theoretically could be searched for in the thoracic spinal cord of patients with Friedreichrsquosrsquo ataxia [200] focusing on the cervical spinal cord is recommended because it usually allows concurrent evaluation of the brainstem and the cerebellum This may help in the differential diagnosis with corticocerebellar and cerebellar-brainstem atrophies

In conclusion MR imaging of the cervical spinal cord can show thinning of the cord and intramedullary signal changes consistent with degeneration of white matter tracts in the lateral and posterior columns of patients with Friedreichrsquos ataxia These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

DIAGNOSIS FRIEDREICHS ATAXIA

DISCUSSION

Hereditary ataxias are a heterogeneous group of neurological disorders Outstanding contributions by Holmes [1] Greenfield [2] and Harding [3] established a syndromic framework for these diseases and remarkable progress in the field now permits a definitive diagnosis in 60 to 70 percent of hereditary ataxia patients Although an increasing number of genetic tests are becoming available for the known ataxia genes phenotypic variability and clinical overlap have hampered development of a useful clinical algorithm for the differential diagnosis of ataxic patients Furthermore some patients with hereditary ataxia may have no family history of ataxia The diagnosis of genetic ataxia in apparently sporadic cases is especially difficult as a variety of nongenetic causes could be underlying the manifestation of the ataxic syndrome Most of the genetic ataxias are adult-onset disorders for which there are no effective treatments and it is not yet possible to offer satisfactory estimates concerning age of onset or prognosis in potentially affected relatives The results of DNA testing however may have dramatic ethical social and legal impact on the life of test subjects and their families For these reasons careful genetic and psychological counseling is required for the patients who undergo genetic testing It should also be noted that some genetic ataxias are treatable and correct diagnosis for these disorders should not be missed

In this article the author reviews the clinical features and current genetic understanding of inherited ataxias The readers may also refer to recent reviews of hereditary ataxias [4] and dominant hereditary ataxias [67116] As ataxia commonly presents in patients without family history we will discuss the clinical approach to differential diagnosis of hereditary and non-hereditary conditions

AUTOSOMAL DOMINANT ATAXIA

Spinocerebellar ataxias

Autosomal dominant spinocerebellar ataxias (ADCA see Table 1) have been clinically classified into three syndromes (ADCA-I II and III) based on the presence of cerebellar ataxia in combination with other symptomatology [89] ADCA-I is defined by a cerebellar syndrome variably accompanied by ophthalmoplegia pyramidal and extrapyramidal signs dementia and other neurological disorders ADCAII is defined by a cerebellar syndrome associated with pigmentary retinopathy and ADCA-III is defined by pure ataxia without other neurologic features While this classification scheme is still useful more recent definition of diseases by specific genetic loci or based on individual families (defined by specific Spinocerebellar ataxias (SCA) loci) only roughly correlates with Hardings classification SCA 7 is the only genetically defined disorder in the ADCA-II group ADCA-I would

DIAGNOSIS

DISCUSSION

classically include SCAs 1 2 3 4 12 13 and 17 but each of these disorders may have purely cerebellar features early Most patients with SCA 5 6 8 10 11 14 and 16 would be classified with ADCA-III but others develop extracerebellar neurological abnormalities consistent with ADCA-I Thus the SCA terminology based on genetic analysis is more commonly presented today

Many of the SCAs (1 2 3 6 7 17 and dentatorubro-pallidoluysian atrophy (DRPLA)) are caused by an expansion of CAG repeats in their respective genes In these disorders the mutation is an expansion of a naturally occurring

Table 1 Autosomal dominant cerebellar ataxia (ADCA)

Disease Locus Type of mutationGene product

Normal alleles

Pathogenic alleles

Distribution (number of families)

of total SCA

Db

ADCA I SCA-1 6p22-p23 CAG expansionataxin-1 6-44 40-81 worldwide 5-15 C

SCA-2 12q23-241 CAG expansionataxin-2 14-31 34-59 Cuba worldwide 5-15 C

SCA-3MJD

14q243-q321 CAG expansionataxin-3 14-33 56-200 Portugal

worldwide 30-50 C

SCA-4 16q221 unknown USA Japan (7 families) N

SCA-12 5p31-p33 CAG expansion5 UTR of PPP2R2B 17-28 55-78 USA India (2

families) rare R

SCA-13 19q133-134 unknown France (1 family) rare R

SCA-17 6q27 Impure CAG expansionTBPa 27-44 47-63 Japan Germany rare R

ADCA II SCA-7 3p12-p13 CAG expansionataxin-7 7-19 37-300 worldwide C

SCA-8 13q21 CTG expansion3 UTR region of SCA8 15-91 107-127 C

ADCA III SCA-5 11cen unknown USA (1 family) rare N

SCA-6 19p131 CAG expansionCACNL1A4a 4-20 21-33 worldwide 5-10 C

SCA-10 22q13 ATTCT expansionintron 9 Hh-E4a 10-22 800-4500 Mexico rare C

SCA-11 15q14-q213 unknown England (1

family) rare N

SCA-14 19q134-qter unknown Japan (1 family) rare N

SCA-16 8q221-q241 unknown Japan rare N

Episodic Ataxia EA type 1 12p13

Missense mutationsCACNL1A4a worldwide R

EA type 2 19p13

Missense mutationsCACNL1A4a worldwide R

DRPLA

[b] D Diagnosis available=Commercially (C) Research (R) Non-available (N)

[a] TBP (TATA binding proteins) CACNL1A4 (1A-voltage-gated calcium channel subunit) Hh-E4 (human homologous of mouse E4 gene)

CAG repeat in the protein coding region of a specific protein This leads to an abnormal expanded series of glutamines being translated in that specific protein The expansion is unstable over generations leading to progressive lengthening of the repeat Disease results when the repeat reaches a specific pathologic range and further expansion leads to progressively earlier age of onset Thus in each of these diseases the CAG repeat size correlates inversely with the age of onset The common pathogenic mechanism of these diseases involves a gain of toxic function [10] and neuropathological studies in ldquopolyglutaminerdquo diseases reveal the presence of neuronal nuclear protein inclusion [1112] which contain the polyglutamine-containing protein specific interacting proteins and proteins from the ubiquitin-degradation pathway [10] These aggregates do not appear to be responsible for the disease in SCA1 [13] although their direct role in other ldquopolyglutaminerdquo diseases is unclear The pathogenicity of the mutant protein in these diseases may involve defective ldquoprotein clearancerdquo sequestration of transcription co-activators and co-repressors andor other gain of function mechanisms [14]

The mutations for SCA8 and SCA12 are expansions of a CAGCTG repeat in untranslated regions of their respective genes Whether the trinucleotide expansion found in SCA8 is a causative mutation or a polymorphism in linkage disequilibrium is still a matter of debate (see SCA8 below) Individuals with SCA10 have a large expansion of an intronic ATTCT pentanucleotide repeat The pathogenic mechanisms of these SCAs remain to be investigated SCAs4 5 11 13 14 and 16 have been mapped but their mutations have not been identified SCAs1 2 3 6 7 and 17 are more frequent than others SCAs and a few SCA types have been recognized only in a single family The incidence of the different types of SCA around the world is variable and known SCAs constitute about 60ndash80 of the families with ADCA (Table 1)

SCA1

The SCA1 gene is located on chromosome 6p linked to the HLA gene complex [15] SCA1 was cloned and the CAG repeat expansion identified in 1993 [16] The number of CAG repeats in normal and pathological alleles of SCA1 are shown in Table 1 The progression of SCA1 has a pattern common to most of the ADCA [17] typical onset with a cerebellar syndrome (ie broad-based gait limb ataxia progressive dysarthria) hand tremor and oculomotor signs including intermittent nystagmus slowing in saccadic velocity followed by limitation of up-gaze The bulbar and upper motor neurons signs may include lingual fasciculations noncerebellar dysphagia and dysarthria brisk deep tendon reflexes and increased tone (spasticity) Later in the disease this constellations of symptoms becomes more severe with coughing overt choking sensory loss mild peripheral neuropathy and extensor plantar responses In SCA1 extrapyramidal signs may be evident by the time the patient becomes wheelchair bounded The phenotype of the disease appears to be relatively homogeneous within and between families Variability observed in age of onset and progression appears to be attributable to the size of the CAG repeat expansion [1819] Bradykinesia and parkinsonism which may be prominent features in SCA3MJD have not been observed in SCA1 Cognitive decline does not appear to be severe in SCA1 Neuroimaging studies typically show atrophy of cerebellar cortex vermis and brainstem

SCA2

The SCA2 gene was mapped by linkage analysis of a homogeneous population of Holguin province (Cuba) to chromosome 12q24 [20] and later cloned independently by three groups [21ndash23] Clinical features of the disease include slow saccades kinetic or postural tremor and decrease of muscle tone and tendon reflexes Variable incidence of dystonia chorea and dementia has also been recognized Nonspecific cerebellar or pontocerebellar atrophy has been observed on MRI Nerve conduction studies show evidence of axonal sensory-motor neuropathy

SCA3MJD (Machado-Joseph disease)

Originally described in Portuguese families and named the ldquoAzorean diseaserdquo [24] SCA3 is now recognized worldwide The mutation in the SCA3 gene localized to 14q311 is an expanded CAG repeat in a novel protein designated ataxin-3 [25] Variable phenotypes are found in SCA3[2627] in addition to cerebellar ataxia and ophthalmoplegia early-onset disease can present with spasticity dystonia and an akinetic syndrome whereas late-onset SCA3 presents mainly with minimal extrapyramidal symptomatology The extrapyramidal signs are a characteristic but not exclusive feature of the SCA3 phenotype [27] There is an inverse correlation between the age of onset and the expanded CAG repeat length The severity of the disease as well as the presence of some symptoms (ie peripheral neuropathy) may depend on the length of the expansion with short and very large pathological alleles lacking neuropathy [28]

SCA4

A five-generation Utah kindred with an autosomal dominant late-onset spinocerebellar ataxia with the invariable presence of prominent axonal sensory neuropathy and normal eye movements demonstrated linkage to chromosome 16q221 [29] Six Japanese families with pure cerebellar ataxia without sensory neuropathy also showed linkage to this locus [3031]

SCA5

SCA5 was assigned to chromosome 11 in a single family descending from the grandparents of President Abraham Lincoln [32] In this family 56 individuals had cerebellar ataxia with onset at 10 to 68 years Anticipation is evident and progression of the disease is slow SCA5 does not affect life span probably because severe bulbar disease is generally absent A second apparently unrelated SCA5 family of French origin showed a similar phenotype with marked global cerebellar atrophy similar to SCA6 on MRI [33]

SCA6

SCA6 classically presents with pure cerebellar ataxia although patients with a prolonged disease course may show other clinical features including dystonic postures involuntary movements and abnormalities in tendon reflexes [34] Patients with SCA6 especially those with late onset disease may present without a family history The diagnosis of SCA6 should be considered in sporadic cases with horizontal and oblique gaze nystagmus and an abnormal vestibulo-ocular reflex without other ocular movement abnormalities or those with pure cerebellar atrophy [3435] Some phenotypic overlap with the allelic disease EA-2 (see the section of Episodic Ataxia) has been noted [3637] Brain MRI shows atrophy of the cerebellum and in some patients pons middle cerebellar peduncles and red nucleus [343839] The SCA6 mutation is a small CAG repeat expansion within the 1A-voltage-dependent calcium channel subunit (CACNL1A4) gene [40] The number of CAGs in mutant alleles ranges 20 to 30 while normal alleles are 4 to 17 CAGs (Table 1) [4041] An allele with 19 CAGs has been reported in a Japanese patient with ataxia [42] Although the age of onset inversely correlates with the expanded repeat size in different families the expanded repeat is usually stably transmitted within each family [414344] In rare cases however mild expansions have been reported [4546] Sisters homozygous for (CAG)2525 showed a similar age of onset but different progression rate suggesting pathogenic contribution of factors other than the repeat size [47] Homozygous cases suggested a gene dosage effect on the age of onset [3648ndash50] Anticipation in the absence of changes in the CAG repeat size has been described in French [51] Japanese [41] and Taiwanese kindreds

Although the expansion size of the CAG repeat falls into the normal ranges of other SCAs the polyglutamine tract in a densely packed membrane protein may allow the 1A subunits with small expansions to aggregate [5253] A key question is whether the SCA6 mutation causes disease by making the 1A subunit toxic or it does so by perturbing the gating of PQ-type channels [54] To reconcile these two different mechanisms it has been postulated that protein interactions altered by the expanded polyglutamine tract might cause gating abnormalities [55]

SCA7

SCA7 is characterized by progressive ataxia and pigmentary maculopathy with anticipation and is the only disease classified as an ADCA-II These features are accompanied by other clinical features including pyramidal and extrapyramidal signs ophthalmoplegia dementia hypoacusis hypotonia and auditory hallucinations [56] Slowing of voluntary and involuntary saccades is also an early sign of SCA7 [57] Specific juvenile and infantile forms of SCA7 have been defined Juvenile SCA7 occurs with maternal and paternal transmission whereas the infantile form occurs only with paternal transmission The infantile form shows severe hypotonia cerebral and cerebellar atrophy early visual loss congestive heart failure and patent ductus arteriosus [58] SCA7 is caused by an expansion of a CAG repeat in the SCA7 (ataxin-7) gene on chromosome 3p [5960] The normal range is 7 to 19 CAG repeats and pathogenic alleles range from 37 to approximately 306 repeats The expansion size correlates with the severity of the disease and inversely correlates with the age of onset [6162] Alleles with 28 to 36 repeats are intermediate alleles that are prone to further expansion accounting for de novo mutation cases [6364] Different disease-associated haplotypes segregated among SCA7 kindreds suggesting multiple origins of the mutation [63] Paternal transmission is underrepresented and when it does occur is associated with significant intergenerational expansion of the CAG repeat [65] The expanded CAG repeat in male germline is biased toward massive size increases potentially leading to putative embryonic lethality or dysfunctional sperm [66] The available data suggest that the mutant ataxin-7 protein is pathogenic due to a gain of toxic function by the polyglutamine expansion [67ndash70]

SCA8

SCA8 presents with slowly progressive ataxia with marked cerebellar atrophy [71] The disease is variably associated with pyramidal and cognitive dysfunctions [72] SCA8 patients have an expansion of a CTG repeat on chromosome 13q21 to the pathogenic range of 100 to 152 repeats while normal individuals have 15 to 91 CTGs [73] Affected individuals usually inherit an expanded allele from their mothers SCA8 alleles show an instability bias toward expansion with maternal transmission whereas paternal transmissions mostly result in smaller alleles which appear to be due to contraction of the expanded alleles to the normal range (lt100 CTGs) in the sperm [717475] Variable penetrance has been identified in SCA8 pedigrees [7176] There has been no evidence of correlation between the repeat size and the age of onset Haplotype analyses showed multiple origins for the SCA8 expansions [72]

The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract with the configuration (CTA)1-21(CTG)n in the 3 untranslated region of the SCA8 gene Many SCA patients have expanded alleles with interruptions by cryptic repeats (CCG CTA CTC CCA or CTT) which may have newly arisen or changed from generation to generation [74] SCA8 contains no open reading frame but the most 5 exon is transcribed through the first exon of another gene KLHL1 which is transcribed in the opposite orientation This raises a possibility that the SCA8 transcript is an endogenous antisense RNA for KLHL1 KLHL1 encodes a cytoplasmic protein that may play a role in organizing the actin cytoskeleton of the brain cells Both SCA8 and KLHL1 are primarily expressed in specific brain tissues affected by SCA8 [77] Other gain-of-function mechanisms involving the mutant SCA8 transcript have not been investigated but by no means excluded

The major controversy in SCA8 stems from a lack of absolute specificity of the CTG repeat expansion for SCA8 which has raised a possibility that CTG expansions at the SCA8 locus represent a rare polymorphism rather than the disease-causing mutation [7879] Alleles greater than 100 CTG repeats at the SCA8 locus were also found in 12 (14 of 1120) of major psychosis patients and 07 (5 of 710) of normal control subjects who had no family history of ataxia [80]

SCA9 (vacant)

SCA10

The clinical phenotype of SCA10 is characterized by a combination of relatively pure cerebellar ataxia and epilepsy Ataxia is progressive and often leads to total disability Seizures are generalized motor seizures complex partial seizures or both Some patients show mild cognitive dysfunction sensory polyneuropathy andor soft corticospinal tract signs [81] Anticipation is conspicuous in some families but subtle or absent in others The disease has so far been confined to families of Mexican descent The SCA10 mutation is a very large expansion of the ATTCT pentanucleotide repeat located in intron 9 of the E46L (SCA10) gene on chromosome 22q13 [49] Normal alleles show 10 to 21 ATTCTs while affected individuals have 800ndash4500 repeats An inverse correlation exists between the size of the expanded allele and the age of onset The mechanism of the disease remains unknown

SCA11

SCA11 clinically defined as an ADCA-III has been mapped to chromosome 15q in a single British family [78]

SCA12

SCA12 is a rare ADCA characterized by adult onset ataxia upper body tremor hyperreflexia with bilateral extensor plantar responses paucity of movements and dementia [8283] The clinical picture includes oculomotor abnormalities (ie broken pursuit nystagmus slow saccades) The disease is slowly progressive and in the late stage psychiatric symptoms including depression anxiety or delusions may appear in some affected members Brain MRI shows cerebellar and cerebral cortical atrophy There is no evidence of anticipation The mutation of SCA12 is a CAG repeat expansion in the 5 untranslated region of the PPP2R2B gene on chromosome 5p31-p33 [84] Normal alleles have 17 to 28 CAG repeats while the pathologic alleles have 55 to 78 repeats The disease has been described in two kindreds one from US and the other from India [8587] It has been postulated that the expansion of the CAG repeat up-regulate PPP2R2B expression

SCA13

A French family presented with slowly progressive childhood-onset cerebellar gait ataxia dysarthria moderate mental retardation and mild motor developmental delays with in some cases nystagmus and pyramidal signs Brain MRI showed moderate cerebellar and pontine atrophy A genome wide search showed linkage to chromosome

19q133-q134 [86]

SCA14

A Japanese three-generation family with ADCA mapped to a locus on chromosome 19q134-qter [86] The family members with late onset (gt39 years old) exhibited pure cerebellar ataxia whereas those with an early onset (lt27 years old) showed intermittent axial myoclonus followed by ataxia Other neurological signs were sparse and neuroimaging studies revealed isolated cerebellar atrophy

SCA15 (vacant)

SCA16

This is a pure cerebellar ataxia with head tremor and thus a form of ADCA III [88] Although head tremor which is distinct from tittubation has been described in SCA2 SCA7 and SCA12 it is rare for all SCA types Age of onset ranges 20 to 66 years and anticipation was not apparent Brain MRI showed cerebellar atrophy without involving brainstem The SCA16 locus showed linkage to markers on chromosome 8q221-q241 [88]

SCA17

An expansion of CAG repeats of the TATA-binding protein (TBP) gene was initially reported in a Japanese patient with sporadic cerebellar ataxia and intellectual deterioration associated with de novo expansion The expanded allele consisted of impure CAG repeats encoding 63 glutamines and the de novo expansion involved partial duplication of the CAG repeat [89] In two German families four patients showed expanded CAG repeats in TBP gene coding for 50 to 55 polyglutamines while normal subjects had alleles ranging from 27 to 44 glutamines [90] Several additional Japanese families with phenotypes resembling Huntingtons disease or DRPLA also showed SCA17 CAG expansions [91]

Other SCAs

Anecdotally there are many ADCA families who are not linked to known genetic loci and who have no distinctive phenotype In one such French family SCAs 1 2 3 6 7 8 and 12 were excluded by mutation analysis and SCAs 4 5 10 11 13 14 by lod score less than 2 Affected members of this French family showed gait ataxia akinesia dysarthria hyporeflexia and anticipation [92] There are likely to be many similar families who have not yet been characterized or reported

DRPLA

DRPLA is a relatively frequent disease in Japan with an incidence of 02-07 per 100000 A few isolated families have been recognized worldwide [92] The DRPLA gene on the chromosome 12p was cloned in 1994 [9495] Early onset of the disease includes ataxia myoclonus epilepsy and progression to dementia later onset disease can present with cerebellar symptoms psychiatric symptoms seizures [9396] and choreoathetotic abnormal movements with a ldquoHuntington-likerdquo phenotype [97] Age of onset and severity correlate with the length of the CAG expansion The mutation in the DRPLA gene has also been found in the Haw River Syndrome which has some different clinical characteristics from DRPLA [98]

Episodic ataxia (EA)

In contrast to SCAs these rare diseases present with episodic ataxic attacks of variable frequency and duration with no symptoms between attacks Additional characteristic signs are associated with the different types of EA

EA type 1 (EA1)

EA1 is caused by mutations in a potassium channel gene KCNA1 on chromosome 12p [99] The onset is between childhood and adolescence Besides episodic ataxia clinical manifestations are myokymia around the eyes lips or fingers Brief attacks of ataxia and dysarthria lasting seconds are precipitated by exercise or startle

EA type 2 (EA2)

Clinical manifestations of EA2 consist of mild to severe intermittent cerebellar dysfunction associated with oculomotor abnormalities such as interictal nystagmus and diplopia and migraine Symptoms can be present for minutes to a few days Episodes are provoked by stress and exercise but not startle Like familial hemiplegic migraine (FHM) and spinocerebellar ataxia type 6 (SCA6) EA2 is associated with mutations in the gene encoding the -1A subunit of the calcium channel SCA6 is caused by a CAG repeat expansion [40] while point mutations in the CACNA1A gene cause EA2 and FHM [100] Missense mutations usually cause FHM and non-sense or splice site mutations cause EA2 [101] However this rule has many exceptions [102] and EA2 FHM and SCA6 may represent a clinical continuum of the distinct mutations in CACNA1A[103] Moreover an identical mutation can give various clinical expressions in a same family Paroxysmal symptoms could arise from reversible channel dysfunction while progressive neurodegeneration could reflect a toxic gain of function The latter appears to be a general phenomenon in polyglutamine diseases (see SCA 6) but it is not known how point mutations in CACNA1A are associated in some cases with neuronal degeneration [103] EA2 may respond to the treatment with acetazolamide [104105]

EA with paroxysmal choreoathetosis and spasticity

The onset of this disorder is at 2ndash15 years with ataxia dystonia and headaches [105] Episodes last for a few minutes with a daily to yearly frequency Spastic paraparesis can persist between the attacks Episodes are provoked by fatigue stress exercise and alcohol

AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET

Friedreichs ataxia

Friedreichs ataxia (FRDA) described in 1863 by Nicholaus Friedreich and characterized in detail by Harding [8] is the most frequent autosomal recessive ataxia It has an incidence in whites of 130000 [106] but has not been documented among Sub-Saharan Africans American Indians and peoples from China Japan and Southeast Asia [107108] FRDA is responsible for 30 to 40 percent of autosomal recessive ataxia among whites The disease is a progressive spinocerebellar degeneration with typical onset before the age of 25 years especially during childhood or puberty (7ndash14 y) [8] The degeneration of the posterior columns of the spinal cord afferent cerebellar pathways and selected nuclei of the cerebellum gives rise to an ataxic gait classically followed by dysarthria upper limb ataxia distal sensory loss decreased vibration and position sense and absence of reflexes Scoliosis and pes cavus also can develop The full picture of the disease often includes hypertrophic cardiomyopathy [109] impaired glucose tolerance or diabetes mellitus and occasionally hearing loss or optic atrophy [110] In early onset cases FRDA may need to be differentiated from adrenomyeloneuropathy by very long chain fatty acid (VLCFA) levels Refsums disease by serum phytanic acid levels and vitamin E deficiency by vitamin E levels In some cases dominant ataxias and Charcot-Marie-Tooth disease join in the differential diagnoses Neuropathological changes in FRDA include degeneration of the dorsal root ganglia Clarkes columns posterior columns corticospinalspinocerebellar tracts cerebellum pons and medulla [111] Nerve conduction studies show selective loss of sensory nerve action potentials

The FRDAX25 gene contains seven exons spanning 80 kb on chromosome 9q13 and encodes a 210 amino acid protein called frataxin [112129] Most FRDA patients have an expansion of the trinucleotide GAA in the first intron of the FRDAX25 gene [114] Normal alleles contain 6 to 28 GAA repeats while affected individuals have 60 to 1800 (Table 2) Point mutations in the FRDA gene (instead of the GAA expansion) are found in about two to four percent of the cases Compound heterozygous patients with one expanded GAA repeat allele and one point mutation are more likely to show variant clinical features such as optic atrophy or retained reflexes than patients carrying homozygous GAA expansions [115] Among patients with 2 alleles carrying expanded GAA repeats there is an inverse correlation between the size of the GAA expansion and the age of onset severity of the disease and the occurrence of cardiomyopathy and diabetes Patients with the ldquolate onsetrdquo (after 25 years old) variant (LOFA) and those with retained reflexes (FARR) are also caused by the FRDA gene mutation [5117] most commonly associated with modestly expanded alleles (ie lt400 repeats) [127] Genetic heterogeneity in FRDA has been proposed and a second locus (FRDA2) has recently been identified [118]

Table 2 Hereditary ataxia according to the age of onset

Age of onset Diagnostic clues pia Locusgene Diagnosis Early onset (connatal or childhood) Main Congenital Ataxia Syndromes

Jouberts syndrome abnormal eye movements AR Clinic Gillespies syndrome partial anyridia AR Clinic Behrs syndrome optic atrophy AR several Clinic Marinesco-Sjoumlgrens syndrome cataracts hypogonadism AR Clinic

Main Metabolic Ataxias Urea cycles disorders urinary organic acids AR several ClinicBiochemGenetAminoacidurias urinary amino acids AR several ClinicBiochemGenetDisorders of pyruvatelactate serum pyruvatelactate AR several ClinicBiochemGenet

Mitochondrial encephalomyopathies MELAS MERRF etc Mb several ClinicBiochemGenet

Peroxisomal disorders infantile Refsun syndrome AR several ClinicBiochemGenetDisorders of DNA repair

Ataxia telangiectasia skin sensitivity Icircplusmn-fetoprotein cancer AR 11q22-23ATM ClinicGenet

Xeroderma pigmentosum skin sensitivity cancer AR several ClinicGenet

Cockaynes syndrome skin sensitivity dysmorphology AR several ClinicGenet

Trichothiodystrophy skin sensitivity brittle hair AR several ClinicGenet

Intermediate onset (childhood or juvenile)

Friedreichs ataxia - FRDA sensorimotor loss cardiac skeletal AR 9q13frataxin ClinicGenet

Early onset ataxia with retained reflexes - EOARR

early onset retained reflexes AR several ClinicGenet

Isolated vitamin E deficiency - AVED

low serum levels of vitamin E AR 8q13TTP1 ClinicBiochemGenet

Spastic ataxia of Charlevoix-Saguenay - SACS

hypermyelation retinal-nerve fibers AR 13q11sacsin ClinicGenet

Recessive ataxia with ocular motor apraxia -AOA

ocular apraxia neuropathy AR 9q13HITZn-finger ClinicGenet

Progressive myoclonus ataxia - PMA

myoclonus ataxia seizures AR Clinic

Progressive myoclonus epilepsy - PMEc

Unverricht-Lundborg syndrome ARc 21q223cystatin B ClinicGenet

Abetalipoproteinemia abetalipoproteinemia AR 4q22-24MTP ClinicBiochemGenetHypobetalipoproteinemia hypobetalipoproteinemia AD 2p24 3p22 ClinicBiochem Niemman-Pick disease type C sphingomyelin lipidosis AR

18q11NPC1 (95)d ClinicBiochemGenet

Krabbes disease galactosylceramide lipidosis AR galactocerebrosidase ClinicBiochemGenet

Hexosaminidase deficiencies hexosaminidase deficit AR hexA and hexAB ClinicBiochemGenet

Late Onset (juvenile or adult) Autosomal dominant cerebellar ataxia - ADCA SCAs AD Several (see Table

1) ClinicGenet

Episodic ataxia EA-1 EA-2 and EPCA AD channelopaties ClinicGenet Von Hippel-Lindau syndrome

cerebellar hemangioblastomas AD 3p25VHL ClinicGenet

Cerebellar ataxia with hypogonadism hypogonadism ataxia AR Clinic

Mitochondrial multisystemic several ClinicBiochemGenet

[a] pattern of inheritance (ie AR autosomal recessive)

A fascinating concurrence of yeast and human genetics [119ndash124] led to the proposal that frataxin is involved in the homeostasis (probably the transport) of mitochondrial iron Accumulation of iron inside the mitochondria of FRDA cells could lead to increased oxidative stress by free radical production from hydrogen peroxide and hypersensitivity to the oxidative stress due to mitochondrial dysfunction Deficiencies found in mitochondrialcytoplasmic aconitase as well as in the respiratory chain complexes I II and III in FRDA patients [123125] are consistent with this hypothesis Moreover primary vitamin E deficiency (see later) a specific disease associated with a defect in a physiological free radical scavenger clinically resembles FRDA Interestingly all of the enzymes with defective activity in FRDA mitochondria have iron-sulfur (Fe-S) clusters at the active sites These moieties are highly sensitive to free radical damage An alternative or complementary hypothesis is that a primary activity of frataxin is related to the synthesis of the Fe-S cluster [112] In any case these findings led to the proposal that antioxidants could be useful for the treatment of FRDA Idebenone (a free-radical scavenger analogue of coenzyme Q10) may ameliorate andor to revert the cardiac hypertrophy in FRDA patients [126] This drug is currently being studied in clinical trials Although iron chelation by desferroxamine should decrease serum and cytoplasmic iron levels it may decrease aconitase activity which may be detrimental to the cellular function In addition whether chelation can alter mitochondrial iron levels without toxic side effects is unknown A recently developed mouse model of FRDA [113] raises a hope for providing a powerful means to explore many of these hypotheses and potential treatments

Other than the potential therapeutic effect of antioxidants on cardiomyopathy in FRDA the treatment remains supportive and symptomatic Physiotherapy and orthopedic management (prosthesis or surgery) are used either to preserve or to correct progressive deformations of the spine and feet It is important to provide appropriate management of cardiac functions glucose metabolism and secondary medical problems such as aspiration pneumonia

Early-onset cerebellar ataxia with retained reflexes

This disease was considered by Harding [128] to be a syndrome distinct from FRDA however genetic mapping of the early-onset cerebellar ataxia with retained reflexes (EOCARR) locus is necessary before it can be recognized as an independent genetic entity [127] Onset is before age 20 with a clinical picture similar to FRDA but with retained reflexes low incidence of sensory neuropathy less reduction of joint position sense and absence of skeletal abnormalities optic neuropathy cardiomyopathy or diabetes [127] Exclusion of FRDA by DNA testing is essential since some patients with the EOCARR phenotype have GAA expansions in the frataxin gene [127128] Moreover a branch of a recently described EOCARR family has the late onset form of FRDA while another branch has EOCARR phenotype [127] In EOCARR with very early onset differential diagnosis with ataxia telangiectasia mitochondrial disorders adrenoleukodystrophy and lysosomal storage diseases may be necessary

Ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency (AVED) is a rare treatable disorder with a phenotype that resembles FRDA In a patient with a clinical diagnosis of FRDA and a negative genetic result for FRDA serum vitamin E levels should be determined as patients with AVED have very low levels of vitamin E (lt5 gml) Age of onset is between childhood and young adulthood associated with slowly progressive gait and limb ataxia loss of deep tendon reflexes and vibratory and proprioceptive loss followed by progressive ophthalmoplegia dysarthria extensor plantar responses and muscle weakness The disorder is caused by a defect in the TTP1 gene [129] on chromosome 8q13 encoding the -tocopherol transfer protein [130] responsible for the transfer of -tocopherol to the circulating lipoproteins Early onset and severe forms of the disease are caused by truncating mutations or missense mutations in conserved amino acids [131] However DNA testing for the AVED mutations is not commercially available Early replacement therapy may prevent progression of the disease [132133]

Several diseases that lead to secondary vitamin E deficiency (ie by affecting the absorption andor transport of fat

[b] Mitochondrial diseases due to defective mitochondrial genes have maternal inheritance whereas mitochondrial diseases due to nuclear genes have ARAD

[c] Other clinical forms of PME (ie the neuronal ceroid lipofuscinoses Lafora disease type I sialidosis and MERRF) are associated with defects in various genes

[d] A causative second gene NPC2 has not been identified

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

association between the extent of intramedullary signal changes and the chronicity and severity of disease was not examined in the reported patient Although this analysis could be informative it requires quantitation of the signal changes in the white matter tracts and evaluation of the thoracolumbar spine which were not done in the reported patient Noteworthy is the fact that we found intramedullary signal changes only in patients with Friedreichrsquos ataxia No such findings were seen in any of the patients with corticocerebellar or cerebellar-brainstem atrophy in the author experience Thus it appears that evaluation of the cervical spinal cord for intramedullary signal changes might be useful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

In a broad sense our results confirm that MR examination of the cervical spinal cord is more informative than examination of the brain in patients with Friedreichrsquos ataxia Although spinal cord atrophy and intramedullary signal changes theoretically could be searched for in the thoracic spinal cord of patients with Friedreichrsquosrsquo ataxia [200] focusing on the cervical spinal cord is recommended because it usually allows concurrent evaluation of the brainstem and the cerebellum This may help in the differential diagnosis with corticocerebellar and cerebellar-brainstem atrophies

In conclusion MR imaging of the cervical spinal cord can show thinning of the cord and intramedullary signal changes consistent with degeneration of white matter tracts in the lateral and posterior columns of patients with Friedreichrsquos ataxia These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

DIAGNOSIS FRIEDREICHS ATAXIA

DISCUSSION

Hereditary ataxias are a heterogeneous group of neurological disorders Outstanding contributions by Holmes [1] Greenfield [2] and Harding [3] established a syndromic framework for these diseases and remarkable progress in the field now permits a definitive diagnosis in 60 to 70 percent of hereditary ataxia patients Although an increasing number of genetic tests are becoming available for the known ataxia genes phenotypic variability and clinical overlap have hampered development of a useful clinical algorithm for the differential diagnosis of ataxic patients Furthermore some patients with hereditary ataxia may have no family history of ataxia The diagnosis of genetic ataxia in apparently sporadic cases is especially difficult as a variety of nongenetic causes could be underlying the manifestation of the ataxic syndrome Most of the genetic ataxias are adult-onset disorders for which there are no effective treatments and it is not yet possible to offer satisfactory estimates concerning age of onset or prognosis in potentially affected relatives The results of DNA testing however may have dramatic ethical social and legal impact on the life of test subjects and their families For these reasons careful genetic and psychological counseling is required for the patients who undergo genetic testing It should also be noted that some genetic ataxias are treatable and correct diagnosis for these disorders should not be missed

In this article the author reviews the clinical features and current genetic understanding of inherited ataxias The readers may also refer to recent reviews of hereditary ataxias [4] and dominant hereditary ataxias [67116] As ataxia commonly presents in patients without family history we will discuss the clinical approach to differential diagnosis of hereditary and non-hereditary conditions

AUTOSOMAL DOMINANT ATAXIA

Spinocerebellar ataxias

Autosomal dominant spinocerebellar ataxias (ADCA see Table 1) have been clinically classified into three syndromes (ADCA-I II and III) based on the presence of cerebellar ataxia in combination with other symptomatology [89] ADCA-I is defined by a cerebellar syndrome variably accompanied by ophthalmoplegia pyramidal and extrapyramidal signs dementia and other neurological disorders ADCAII is defined by a cerebellar syndrome associated with pigmentary retinopathy and ADCA-III is defined by pure ataxia without other neurologic features While this classification scheme is still useful more recent definition of diseases by specific genetic loci or based on individual families (defined by specific Spinocerebellar ataxias (SCA) loci) only roughly correlates with Hardings classification SCA 7 is the only genetically defined disorder in the ADCA-II group ADCA-I would

DIAGNOSIS

DISCUSSION

classically include SCAs 1 2 3 4 12 13 and 17 but each of these disorders may have purely cerebellar features early Most patients with SCA 5 6 8 10 11 14 and 16 would be classified with ADCA-III but others develop extracerebellar neurological abnormalities consistent with ADCA-I Thus the SCA terminology based on genetic analysis is more commonly presented today

Many of the SCAs (1 2 3 6 7 17 and dentatorubro-pallidoluysian atrophy (DRPLA)) are caused by an expansion of CAG repeats in their respective genes In these disorders the mutation is an expansion of a naturally occurring

Table 1 Autosomal dominant cerebellar ataxia (ADCA)

Disease Locus Type of mutationGene product

Normal alleles

Pathogenic alleles

Distribution (number of families)

of total SCA

Db

ADCA I SCA-1 6p22-p23 CAG expansionataxin-1 6-44 40-81 worldwide 5-15 C

SCA-2 12q23-241 CAG expansionataxin-2 14-31 34-59 Cuba worldwide 5-15 C

SCA-3MJD

14q243-q321 CAG expansionataxin-3 14-33 56-200 Portugal

worldwide 30-50 C

SCA-4 16q221 unknown USA Japan (7 families) N

SCA-12 5p31-p33 CAG expansion5 UTR of PPP2R2B 17-28 55-78 USA India (2

families) rare R

SCA-13 19q133-134 unknown France (1 family) rare R

SCA-17 6q27 Impure CAG expansionTBPa 27-44 47-63 Japan Germany rare R

ADCA II SCA-7 3p12-p13 CAG expansionataxin-7 7-19 37-300 worldwide C

SCA-8 13q21 CTG expansion3 UTR region of SCA8 15-91 107-127 C

ADCA III SCA-5 11cen unknown USA (1 family) rare N

SCA-6 19p131 CAG expansionCACNL1A4a 4-20 21-33 worldwide 5-10 C

SCA-10 22q13 ATTCT expansionintron 9 Hh-E4a 10-22 800-4500 Mexico rare C

SCA-11 15q14-q213 unknown England (1

family) rare N

SCA-14 19q134-qter unknown Japan (1 family) rare N

SCA-16 8q221-q241 unknown Japan rare N

Episodic Ataxia EA type 1 12p13

Missense mutationsCACNL1A4a worldwide R

EA type 2 19p13

Missense mutationsCACNL1A4a worldwide R

DRPLA

[b] D Diagnosis available=Commercially (C) Research (R) Non-available (N)

[a] TBP (TATA binding proteins) CACNL1A4 (1A-voltage-gated calcium channel subunit) Hh-E4 (human homologous of mouse E4 gene)

CAG repeat in the protein coding region of a specific protein This leads to an abnormal expanded series of glutamines being translated in that specific protein The expansion is unstable over generations leading to progressive lengthening of the repeat Disease results when the repeat reaches a specific pathologic range and further expansion leads to progressively earlier age of onset Thus in each of these diseases the CAG repeat size correlates inversely with the age of onset The common pathogenic mechanism of these diseases involves a gain of toxic function [10] and neuropathological studies in ldquopolyglutaminerdquo diseases reveal the presence of neuronal nuclear protein inclusion [1112] which contain the polyglutamine-containing protein specific interacting proteins and proteins from the ubiquitin-degradation pathway [10] These aggregates do not appear to be responsible for the disease in SCA1 [13] although their direct role in other ldquopolyglutaminerdquo diseases is unclear The pathogenicity of the mutant protein in these diseases may involve defective ldquoprotein clearancerdquo sequestration of transcription co-activators and co-repressors andor other gain of function mechanisms [14]

The mutations for SCA8 and SCA12 are expansions of a CAGCTG repeat in untranslated regions of their respective genes Whether the trinucleotide expansion found in SCA8 is a causative mutation or a polymorphism in linkage disequilibrium is still a matter of debate (see SCA8 below) Individuals with SCA10 have a large expansion of an intronic ATTCT pentanucleotide repeat The pathogenic mechanisms of these SCAs remain to be investigated SCAs4 5 11 13 14 and 16 have been mapped but their mutations have not been identified SCAs1 2 3 6 7 and 17 are more frequent than others SCAs and a few SCA types have been recognized only in a single family The incidence of the different types of SCA around the world is variable and known SCAs constitute about 60ndash80 of the families with ADCA (Table 1)

SCA1

The SCA1 gene is located on chromosome 6p linked to the HLA gene complex [15] SCA1 was cloned and the CAG repeat expansion identified in 1993 [16] The number of CAG repeats in normal and pathological alleles of SCA1 are shown in Table 1 The progression of SCA1 has a pattern common to most of the ADCA [17] typical onset with a cerebellar syndrome (ie broad-based gait limb ataxia progressive dysarthria) hand tremor and oculomotor signs including intermittent nystagmus slowing in saccadic velocity followed by limitation of up-gaze The bulbar and upper motor neurons signs may include lingual fasciculations noncerebellar dysphagia and dysarthria brisk deep tendon reflexes and increased tone (spasticity) Later in the disease this constellations of symptoms becomes more severe with coughing overt choking sensory loss mild peripheral neuropathy and extensor plantar responses In SCA1 extrapyramidal signs may be evident by the time the patient becomes wheelchair bounded The phenotype of the disease appears to be relatively homogeneous within and between families Variability observed in age of onset and progression appears to be attributable to the size of the CAG repeat expansion [1819] Bradykinesia and parkinsonism which may be prominent features in SCA3MJD have not been observed in SCA1 Cognitive decline does not appear to be severe in SCA1 Neuroimaging studies typically show atrophy of cerebellar cortex vermis and brainstem

SCA2

The SCA2 gene was mapped by linkage analysis of a homogeneous population of Holguin province (Cuba) to chromosome 12q24 [20] and later cloned independently by three groups [21ndash23] Clinical features of the disease include slow saccades kinetic or postural tremor and decrease of muscle tone and tendon reflexes Variable incidence of dystonia chorea and dementia has also been recognized Nonspecific cerebellar or pontocerebellar atrophy has been observed on MRI Nerve conduction studies show evidence of axonal sensory-motor neuropathy

SCA3MJD (Machado-Joseph disease)

Originally described in Portuguese families and named the ldquoAzorean diseaserdquo [24] SCA3 is now recognized worldwide The mutation in the SCA3 gene localized to 14q311 is an expanded CAG repeat in a novel protein designated ataxin-3 [25] Variable phenotypes are found in SCA3[2627] in addition to cerebellar ataxia and ophthalmoplegia early-onset disease can present with spasticity dystonia and an akinetic syndrome whereas late-onset SCA3 presents mainly with minimal extrapyramidal symptomatology The extrapyramidal signs are a characteristic but not exclusive feature of the SCA3 phenotype [27] There is an inverse correlation between the age of onset and the expanded CAG repeat length The severity of the disease as well as the presence of some symptoms (ie peripheral neuropathy) may depend on the length of the expansion with short and very large pathological alleles lacking neuropathy [28]

SCA4

A five-generation Utah kindred with an autosomal dominant late-onset spinocerebellar ataxia with the invariable presence of prominent axonal sensory neuropathy and normal eye movements demonstrated linkage to chromosome 16q221 [29] Six Japanese families with pure cerebellar ataxia without sensory neuropathy also showed linkage to this locus [3031]

SCA5

SCA5 was assigned to chromosome 11 in a single family descending from the grandparents of President Abraham Lincoln [32] In this family 56 individuals had cerebellar ataxia with onset at 10 to 68 years Anticipation is evident and progression of the disease is slow SCA5 does not affect life span probably because severe bulbar disease is generally absent A second apparently unrelated SCA5 family of French origin showed a similar phenotype with marked global cerebellar atrophy similar to SCA6 on MRI [33]

SCA6

SCA6 classically presents with pure cerebellar ataxia although patients with a prolonged disease course may show other clinical features including dystonic postures involuntary movements and abnormalities in tendon reflexes [34] Patients with SCA6 especially those with late onset disease may present without a family history The diagnosis of SCA6 should be considered in sporadic cases with horizontal and oblique gaze nystagmus and an abnormal vestibulo-ocular reflex without other ocular movement abnormalities or those with pure cerebellar atrophy [3435] Some phenotypic overlap with the allelic disease EA-2 (see the section of Episodic Ataxia) has been noted [3637] Brain MRI shows atrophy of the cerebellum and in some patients pons middle cerebellar peduncles and red nucleus [343839] The SCA6 mutation is a small CAG repeat expansion within the 1A-voltage-dependent calcium channel subunit (CACNL1A4) gene [40] The number of CAGs in mutant alleles ranges 20 to 30 while normal alleles are 4 to 17 CAGs (Table 1) [4041] An allele with 19 CAGs has been reported in a Japanese patient with ataxia [42] Although the age of onset inversely correlates with the expanded repeat size in different families the expanded repeat is usually stably transmitted within each family [414344] In rare cases however mild expansions have been reported [4546] Sisters homozygous for (CAG)2525 showed a similar age of onset but different progression rate suggesting pathogenic contribution of factors other than the repeat size [47] Homozygous cases suggested a gene dosage effect on the age of onset [3648ndash50] Anticipation in the absence of changes in the CAG repeat size has been described in French [51] Japanese [41] and Taiwanese kindreds

Although the expansion size of the CAG repeat falls into the normal ranges of other SCAs the polyglutamine tract in a densely packed membrane protein may allow the 1A subunits with small expansions to aggregate [5253] A key question is whether the SCA6 mutation causes disease by making the 1A subunit toxic or it does so by perturbing the gating of PQ-type channels [54] To reconcile these two different mechanisms it has been postulated that protein interactions altered by the expanded polyglutamine tract might cause gating abnormalities [55]

SCA7

SCA7 is characterized by progressive ataxia and pigmentary maculopathy with anticipation and is the only disease classified as an ADCA-II These features are accompanied by other clinical features including pyramidal and extrapyramidal signs ophthalmoplegia dementia hypoacusis hypotonia and auditory hallucinations [56] Slowing of voluntary and involuntary saccades is also an early sign of SCA7 [57] Specific juvenile and infantile forms of SCA7 have been defined Juvenile SCA7 occurs with maternal and paternal transmission whereas the infantile form occurs only with paternal transmission The infantile form shows severe hypotonia cerebral and cerebellar atrophy early visual loss congestive heart failure and patent ductus arteriosus [58] SCA7 is caused by an expansion of a CAG repeat in the SCA7 (ataxin-7) gene on chromosome 3p [5960] The normal range is 7 to 19 CAG repeats and pathogenic alleles range from 37 to approximately 306 repeats The expansion size correlates with the severity of the disease and inversely correlates with the age of onset [6162] Alleles with 28 to 36 repeats are intermediate alleles that are prone to further expansion accounting for de novo mutation cases [6364] Different disease-associated haplotypes segregated among SCA7 kindreds suggesting multiple origins of the mutation [63] Paternal transmission is underrepresented and when it does occur is associated with significant intergenerational expansion of the CAG repeat [65] The expanded CAG repeat in male germline is biased toward massive size increases potentially leading to putative embryonic lethality or dysfunctional sperm [66] The available data suggest that the mutant ataxin-7 protein is pathogenic due to a gain of toxic function by the polyglutamine expansion [67ndash70]

SCA8

SCA8 presents with slowly progressive ataxia with marked cerebellar atrophy [71] The disease is variably associated with pyramidal and cognitive dysfunctions [72] SCA8 patients have an expansion of a CTG repeat on chromosome 13q21 to the pathogenic range of 100 to 152 repeats while normal individuals have 15 to 91 CTGs [73] Affected individuals usually inherit an expanded allele from their mothers SCA8 alleles show an instability bias toward expansion with maternal transmission whereas paternal transmissions mostly result in smaller alleles which appear to be due to contraction of the expanded alleles to the normal range (lt100 CTGs) in the sperm [717475] Variable penetrance has been identified in SCA8 pedigrees [7176] There has been no evidence of correlation between the repeat size and the age of onset Haplotype analyses showed multiple origins for the SCA8 expansions [72]

The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract with the configuration (CTA)1-21(CTG)n in the 3 untranslated region of the SCA8 gene Many SCA patients have expanded alleles with interruptions by cryptic repeats (CCG CTA CTC CCA or CTT) which may have newly arisen or changed from generation to generation [74] SCA8 contains no open reading frame but the most 5 exon is transcribed through the first exon of another gene KLHL1 which is transcribed in the opposite orientation This raises a possibility that the SCA8 transcript is an endogenous antisense RNA for KLHL1 KLHL1 encodes a cytoplasmic protein that may play a role in organizing the actin cytoskeleton of the brain cells Both SCA8 and KLHL1 are primarily expressed in specific brain tissues affected by SCA8 [77] Other gain-of-function mechanisms involving the mutant SCA8 transcript have not been investigated but by no means excluded

The major controversy in SCA8 stems from a lack of absolute specificity of the CTG repeat expansion for SCA8 which has raised a possibility that CTG expansions at the SCA8 locus represent a rare polymorphism rather than the disease-causing mutation [7879] Alleles greater than 100 CTG repeats at the SCA8 locus were also found in 12 (14 of 1120) of major psychosis patients and 07 (5 of 710) of normal control subjects who had no family history of ataxia [80]

SCA9 (vacant)

SCA10

The clinical phenotype of SCA10 is characterized by a combination of relatively pure cerebellar ataxia and epilepsy Ataxia is progressive and often leads to total disability Seizures are generalized motor seizures complex partial seizures or both Some patients show mild cognitive dysfunction sensory polyneuropathy andor soft corticospinal tract signs [81] Anticipation is conspicuous in some families but subtle or absent in others The disease has so far been confined to families of Mexican descent The SCA10 mutation is a very large expansion of the ATTCT pentanucleotide repeat located in intron 9 of the E46L (SCA10) gene on chromosome 22q13 [49] Normal alleles show 10 to 21 ATTCTs while affected individuals have 800ndash4500 repeats An inverse correlation exists between the size of the expanded allele and the age of onset The mechanism of the disease remains unknown

SCA11

SCA11 clinically defined as an ADCA-III has been mapped to chromosome 15q in a single British family [78]

SCA12

SCA12 is a rare ADCA characterized by adult onset ataxia upper body tremor hyperreflexia with bilateral extensor plantar responses paucity of movements and dementia [8283] The clinical picture includes oculomotor abnormalities (ie broken pursuit nystagmus slow saccades) The disease is slowly progressive and in the late stage psychiatric symptoms including depression anxiety or delusions may appear in some affected members Brain MRI shows cerebellar and cerebral cortical atrophy There is no evidence of anticipation The mutation of SCA12 is a CAG repeat expansion in the 5 untranslated region of the PPP2R2B gene on chromosome 5p31-p33 [84] Normal alleles have 17 to 28 CAG repeats while the pathologic alleles have 55 to 78 repeats The disease has been described in two kindreds one from US and the other from India [8587] It has been postulated that the expansion of the CAG repeat up-regulate PPP2R2B expression

SCA13

A French family presented with slowly progressive childhood-onset cerebellar gait ataxia dysarthria moderate mental retardation and mild motor developmental delays with in some cases nystagmus and pyramidal signs Brain MRI showed moderate cerebellar and pontine atrophy A genome wide search showed linkage to chromosome

19q133-q134 [86]

SCA14

A Japanese three-generation family with ADCA mapped to a locus on chromosome 19q134-qter [86] The family members with late onset (gt39 years old) exhibited pure cerebellar ataxia whereas those with an early onset (lt27 years old) showed intermittent axial myoclonus followed by ataxia Other neurological signs were sparse and neuroimaging studies revealed isolated cerebellar atrophy

SCA15 (vacant)

SCA16

This is a pure cerebellar ataxia with head tremor and thus a form of ADCA III [88] Although head tremor which is distinct from tittubation has been described in SCA2 SCA7 and SCA12 it is rare for all SCA types Age of onset ranges 20 to 66 years and anticipation was not apparent Brain MRI showed cerebellar atrophy without involving brainstem The SCA16 locus showed linkage to markers on chromosome 8q221-q241 [88]

SCA17

An expansion of CAG repeats of the TATA-binding protein (TBP) gene was initially reported in a Japanese patient with sporadic cerebellar ataxia and intellectual deterioration associated with de novo expansion The expanded allele consisted of impure CAG repeats encoding 63 glutamines and the de novo expansion involved partial duplication of the CAG repeat [89] In two German families four patients showed expanded CAG repeats in TBP gene coding for 50 to 55 polyglutamines while normal subjects had alleles ranging from 27 to 44 glutamines [90] Several additional Japanese families with phenotypes resembling Huntingtons disease or DRPLA also showed SCA17 CAG expansions [91]

Other SCAs

Anecdotally there are many ADCA families who are not linked to known genetic loci and who have no distinctive phenotype In one such French family SCAs 1 2 3 6 7 8 and 12 were excluded by mutation analysis and SCAs 4 5 10 11 13 14 by lod score less than 2 Affected members of this French family showed gait ataxia akinesia dysarthria hyporeflexia and anticipation [92] There are likely to be many similar families who have not yet been characterized or reported

DRPLA

DRPLA is a relatively frequent disease in Japan with an incidence of 02-07 per 100000 A few isolated families have been recognized worldwide [92] The DRPLA gene on the chromosome 12p was cloned in 1994 [9495] Early onset of the disease includes ataxia myoclonus epilepsy and progression to dementia later onset disease can present with cerebellar symptoms psychiatric symptoms seizures [9396] and choreoathetotic abnormal movements with a ldquoHuntington-likerdquo phenotype [97] Age of onset and severity correlate with the length of the CAG expansion The mutation in the DRPLA gene has also been found in the Haw River Syndrome which has some different clinical characteristics from DRPLA [98]

Episodic ataxia (EA)

In contrast to SCAs these rare diseases present with episodic ataxic attacks of variable frequency and duration with no symptoms between attacks Additional characteristic signs are associated with the different types of EA

EA type 1 (EA1)

EA1 is caused by mutations in a potassium channel gene KCNA1 on chromosome 12p [99] The onset is between childhood and adolescence Besides episodic ataxia clinical manifestations are myokymia around the eyes lips or fingers Brief attacks of ataxia and dysarthria lasting seconds are precipitated by exercise or startle

EA type 2 (EA2)

Clinical manifestations of EA2 consist of mild to severe intermittent cerebellar dysfunction associated with oculomotor abnormalities such as interictal nystagmus and diplopia and migraine Symptoms can be present for minutes to a few days Episodes are provoked by stress and exercise but not startle Like familial hemiplegic migraine (FHM) and spinocerebellar ataxia type 6 (SCA6) EA2 is associated with mutations in the gene encoding the -1A subunit of the calcium channel SCA6 is caused by a CAG repeat expansion [40] while point mutations in the CACNA1A gene cause EA2 and FHM [100] Missense mutations usually cause FHM and non-sense or splice site mutations cause EA2 [101] However this rule has many exceptions [102] and EA2 FHM and SCA6 may represent a clinical continuum of the distinct mutations in CACNA1A[103] Moreover an identical mutation can give various clinical expressions in a same family Paroxysmal symptoms could arise from reversible channel dysfunction while progressive neurodegeneration could reflect a toxic gain of function The latter appears to be a general phenomenon in polyglutamine diseases (see SCA 6) but it is not known how point mutations in CACNA1A are associated in some cases with neuronal degeneration [103] EA2 may respond to the treatment with acetazolamide [104105]

EA with paroxysmal choreoathetosis and spasticity

The onset of this disorder is at 2ndash15 years with ataxia dystonia and headaches [105] Episodes last for a few minutes with a daily to yearly frequency Spastic paraparesis can persist between the attacks Episodes are provoked by fatigue stress exercise and alcohol

AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET

Friedreichs ataxia

Friedreichs ataxia (FRDA) described in 1863 by Nicholaus Friedreich and characterized in detail by Harding [8] is the most frequent autosomal recessive ataxia It has an incidence in whites of 130000 [106] but has not been documented among Sub-Saharan Africans American Indians and peoples from China Japan and Southeast Asia [107108] FRDA is responsible for 30 to 40 percent of autosomal recessive ataxia among whites The disease is a progressive spinocerebellar degeneration with typical onset before the age of 25 years especially during childhood or puberty (7ndash14 y) [8] The degeneration of the posterior columns of the spinal cord afferent cerebellar pathways and selected nuclei of the cerebellum gives rise to an ataxic gait classically followed by dysarthria upper limb ataxia distal sensory loss decreased vibration and position sense and absence of reflexes Scoliosis and pes cavus also can develop The full picture of the disease often includes hypertrophic cardiomyopathy [109] impaired glucose tolerance or diabetes mellitus and occasionally hearing loss or optic atrophy [110] In early onset cases FRDA may need to be differentiated from adrenomyeloneuropathy by very long chain fatty acid (VLCFA) levels Refsums disease by serum phytanic acid levels and vitamin E deficiency by vitamin E levels In some cases dominant ataxias and Charcot-Marie-Tooth disease join in the differential diagnoses Neuropathological changes in FRDA include degeneration of the dorsal root ganglia Clarkes columns posterior columns corticospinalspinocerebellar tracts cerebellum pons and medulla [111] Nerve conduction studies show selective loss of sensory nerve action potentials

The FRDAX25 gene contains seven exons spanning 80 kb on chromosome 9q13 and encodes a 210 amino acid protein called frataxin [112129] Most FRDA patients have an expansion of the trinucleotide GAA in the first intron of the FRDAX25 gene [114] Normal alleles contain 6 to 28 GAA repeats while affected individuals have 60 to 1800 (Table 2) Point mutations in the FRDA gene (instead of the GAA expansion) are found in about two to four percent of the cases Compound heterozygous patients with one expanded GAA repeat allele and one point mutation are more likely to show variant clinical features such as optic atrophy or retained reflexes than patients carrying homozygous GAA expansions [115] Among patients with 2 alleles carrying expanded GAA repeats there is an inverse correlation between the size of the GAA expansion and the age of onset severity of the disease and the occurrence of cardiomyopathy and diabetes Patients with the ldquolate onsetrdquo (after 25 years old) variant (LOFA) and those with retained reflexes (FARR) are also caused by the FRDA gene mutation [5117] most commonly associated with modestly expanded alleles (ie lt400 repeats) [127] Genetic heterogeneity in FRDA has been proposed and a second locus (FRDA2) has recently been identified [118]

Table 2 Hereditary ataxia according to the age of onset

Age of onset Diagnostic clues pia Locusgene Diagnosis Early onset (connatal or childhood) Main Congenital Ataxia Syndromes

Jouberts syndrome abnormal eye movements AR Clinic Gillespies syndrome partial anyridia AR Clinic Behrs syndrome optic atrophy AR several Clinic Marinesco-Sjoumlgrens syndrome cataracts hypogonadism AR Clinic

Main Metabolic Ataxias Urea cycles disorders urinary organic acids AR several ClinicBiochemGenetAminoacidurias urinary amino acids AR several ClinicBiochemGenetDisorders of pyruvatelactate serum pyruvatelactate AR several ClinicBiochemGenet

Mitochondrial encephalomyopathies MELAS MERRF etc Mb several ClinicBiochemGenet

Peroxisomal disorders infantile Refsun syndrome AR several ClinicBiochemGenetDisorders of DNA repair

Ataxia telangiectasia skin sensitivity Icircplusmn-fetoprotein cancer AR 11q22-23ATM ClinicGenet

Xeroderma pigmentosum skin sensitivity cancer AR several ClinicGenet

Cockaynes syndrome skin sensitivity dysmorphology AR several ClinicGenet

Trichothiodystrophy skin sensitivity brittle hair AR several ClinicGenet

Intermediate onset (childhood or juvenile)

Friedreichs ataxia - FRDA sensorimotor loss cardiac skeletal AR 9q13frataxin ClinicGenet

Early onset ataxia with retained reflexes - EOARR

early onset retained reflexes AR several ClinicGenet

Isolated vitamin E deficiency - AVED

low serum levels of vitamin E AR 8q13TTP1 ClinicBiochemGenet

Spastic ataxia of Charlevoix-Saguenay - SACS

hypermyelation retinal-nerve fibers AR 13q11sacsin ClinicGenet

Recessive ataxia with ocular motor apraxia -AOA

ocular apraxia neuropathy AR 9q13HITZn-finger ClinicGenet

Progressive myoclonus ataxia - PMA

myoclonus ataxia seizures AR Clinic

Progressive myoclonus epilepsy - PMEc

Unverricht-Lundborg syndrome ARc 21q223cystatin B ClinicGenet

Abetalipoproteinemia abetalipoproteinemia AR 4q22-24MTP ClinicBiochemGenetHypobetalipoproteinemia hypobetalipoproteinemia AD 2p24 3p22 ClinicBiochem Niemman-Pick disease type C sphingomyelin lipidosis AR

18q11NPC1 (95)d ClinicBiochemGenet

Krabbes disease galactosylceramide lipidosis AR galactocerebrosidase ClinicBiochemGenet

Hexosaminidase deficiencies hexosaminidase deficit AR hexA and hexAB ClinicBiochemGenet

Late Onset (juvenile or adult) Autosomal dominant cerebellar ataxia - ADCA SCAs AD Several (see Table

1) ClinicGenet

Episodic ataxia EA-1 EA-2 and EPCA AD channelopaties ClinicGenet Von Hippel-Lindau syndrome

cerebellar hemangioblastomas AD 3p25VHL ClinicGenet

Cerebellar ataxia with hypogonadism hypogonadism ataxia AR Clinic

Mitochondrial multisystemic several ClinicBiochemGenet

[a] pattern of inheritance (ie AR autosomal recessive)

A fascinating concurrence of yeast and human genetics [119ndash124] led to the proposal that frataxin is involved in the homeostasis (probably the transport) of mitochondrial iron Accumulation of iron inside the mitochondria of FRDA cells could lead to increased oxidative stress by free radical production from hydrogen peroxide and hypersensitivity to the oxidative stress due to mitochondrial dysfunction Deficiencies found in mitochondrialcytoplasmic aconitase as well as in the respiratory chain complexes I II and III in FRDA patients [123125] are consistent with this hypothesis Moreover primary vitamin E deficiency (see later) a specific disease associated with a defect in a physiological free radical scavenger clinically resembles FRDA Interestingly all of the enzymes with defective activity in FRDA mitochondria have iron-sulfur (Fe-S) clusters at the active sites These moieties are highly sensitive to free radical damage An alternative or complementary hypothesis is that a primary activity of frataxin is related to the synthesis of the Fe-S cluster [112] In any case these findings led to the proposal that antioxidants could be useful for the treatment of FRDA Idebenone (a free-radical scavenger analogue of coenzyme Q10) may ameliorate andor to revert the cardiac hypertrophy in FRDA patients [126] This drug is currently being studied in clinical trials Although iron chelation by desferroxamine should decrease serum and cytoplasmic iron levels it may decrease aconitase activity which may be detrimental to the cellular function In addition whether chelation can alter mitochondrial iron levels without toxic side effects is unknown A recently developed mouse model of FRDA [113] raises a hope for providing a powerful means to explore many of these hypotheses and potential treatments

Other than the potential therapeutic effect of antioxidants on cardiomyopathy in FRDA the treatment remains supportive and symptomatic Physiotherapy and orthopedic management (prosthesis or surgery) are used either to preserve or to correct progressive deformations of the spine and feet It is important to provide appropriate management of cardiac functions glucose metabolism and secondary medical problems such as aspiration pneumonia

Early-onset cerebellar ataxia with retained reflexes

This disease was considered by Harding [128] to be a syndrome distinct from FRDA however genetic mapping of the early-onset cerebellar ataxia with retained reflexes (EOCARR) locus is necessary before it can be recognized as an independent genetic entity [127] Onset is before age 20 with a clinical picture similar to FRDA but with retained reflexes low incidence of sensory neuropathy less reduction of joint position sense and absence of skeletal abnormalities optic neuropathy cardiomyopathy or diabetes [127] Exclusion of FRDA by DNA testing is essential since some patients with the EOCARR phenotype have GAA expansions in the frataxin gene [127128] Moreover a branch of a recently described EOCARR family has the late onset form of FRDA while another branch has EOCARR phenotype [127] In EOCARR with very early onset differential diagnosis with ataxia telangiectasia mitochondrial disorders adrenoleukodystrophy and lysosomal storage diseases may be necessary

Ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency (AVED) is a rare treatable disorder with a phenotype that resembles FRDA In a patient with a clinical diagnosis of FRDA and a negative genetic result for FRDA serum vitamin E levels should be determined as patients with AVED have very low levels of vitamin E (lt5 gml) Age of onset is between childhood and young adulthood associated with slowly progressive gait and limb ataxia loss of deep tendon reflexes and vibratory and proprioceptive loss followed by progressive ophthalmoplegia dysarthria extensor plantar responses and muscle weakness The disorder is caused by a defect in the TTP1 gene [129] on chromosome 8q13 encoding the -tocopherol transfer protein [130] responsible for the transfer of -tocopherol to the circulating lipoproteins Early onset and severe forms of the disease are caused by truncating mutations or missense mutations in conserved amino acids [131] However DNA testing for the AVED mutations is not commercially available Early replacement therapy may prevent progression of the disease [132133]

Several diseases that lead to secondary vitamin E deficiency (ie by affecting the absorption andor transport of fat

[b] Mitochondrial diseases due to defective mitochondrial genes have maternal inheritance whereas mitochondrial diseases due to nuclear genes have ARAD

[c] Other clinical forms of PME (ie the neuronal ceroid lipofuscinoses Lafora disease type I sialidosis and MERRF) are associated with defects in various genes

[d] A causative second gene NPC2 has not been identified

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

classically include SCAs 1 2 3 4 12 13 and 17 but each of these disorders may have purely cerebellar features early Most patients with SCA 5 6 8 10 11 14 and 16 would be classified with ADCA-III but others develop extracerebellar neurological abnormalities consistent with ADCA-I Thus the SCA terminology based on genetic analysis is more commonly presented today

Many of the SCAs (1 2 3 6 7 17 and dentatorubro-pallidoluysian atrophy (DRPLA)) are caused by an expansion of CAG repeats in their respective genes In these disorders the mutation is an expansion of a naturally occurring

Table 1 Autosomal dominant cerebellar ataxia (ADCA)

Disease Locus Type of mutationGene product

Normal alleles

Pathogenic alleles

Distribution (number of families)

of total SCA

Db

ADCA I SCA-1 6p22-p23 CAG expansionataxin-1 6-44 40-81 worldwide 5-15 C

SCA-2 12q23-241 CAG expansionataxin-2 14-31 34-59 Cuba worldwide 5-15 C

SCA-3MJD

14q243-q321 CAG expansionataxin-3 14-33 56-200 Portugal

worldwide 30-50 C

SCA-4 16q221 unknown USA Japan (7 families) N

SCA-12 5p31-p33 CAG expansion5 UTR of PPP2R2B 17-28 55-78 USA India (2

families) rare R

SCA-13 19q133-134 unknown France (1 family) rare R

SCA-17 6q27 Impure CAG expansionTBPa 27-44 47-63 Japan Germany rare R

ADCA II SCA-7 3p12-p13 CAG expansionataxin-7 7-19 37-300 worldwide C

SCA-8 13q21 CTG expansion3 UTR region of SCA8 15-91 107-127 C

ADCA III SCA-5 11cen unknown USA (1 family) rare N

SCA-6 19p131 CAG expansionCACNL1A4a 4-20 21-33 worldwide 5-10 C

SCA-10 22q13 ATTCT expansionintron 9 Hh-E4a 10-22 800-4500 Mexico rare C

SCA-11 15q14-q213 unknown England (1

family) rare N

SCA-14 19q134-qter unknown Japan (1 family) rare N

SCA-16 8q221-q241 unknown Japan rare N

Episodic Ataxia EA type 1 12p13

Missense mutationsCACNL1A4a worldwide R

EA type 2 19p13

Missense mutationsCACNL1A4a worldwide R

DRPLA

[b] D Diagnosis available=Commercially (C) Research (R) Non-available (N)

[a] TBP (TATA binding proteins) CACNL1A4 (1A-voltage-gated calcium channel subunit) Hh-E4 (human homologous of mouse E4 gene)

CAG repeat in the protein coding region of a specific protein This leads to an abnormal expanded series of glutamines being translated in that specific protein The expansion is unstable over generations leading to progressive lengthening of the repeat Disease results when the repeat reaches a specific pathologic range and further expansion leads to progressively earlier age of onset Thus in each of these diseases the CAG repeat size correlates inversely with the age of onset The common pathogenic mechanism of these diseases involves a gain of toxic function [10] and neuropathological studies in ldquopolyglutaminerdquo diseases reveal the presence of neuronal nuclear protein inclusion [1112] which contain the polyglutamine-containing protein specific interacting proteins and proteins from the ubiquitin-degradation pathway [10] These aggregates do not appear to be responsible for the disease in SCA1 [13] although their direct role in other ldquopolyglutaminerdquo diseases is unclear The pathogenicity of the mutant protein in these diseases may involve defective ldquoprotein clearancerdquo sequestration of transcription co-activators and co-repressors andor other gain of function mechanisms [14]

The mutations for SCA8 and SCA12 are expansions of a CAGCTG repeat in untranslated regions of their respective genes Whether the trinucleotide expansion found in SCA8 is a causative mutation or a polymorphism in linkage disequilibrium is still a matter of debate (see SCA8 below) Individuals with SCA10 have a large expansion of an intronic ATTCT pentanucleotide repeat The pathogenic mechanisms of these SCAs remain to be investigated SCAs4 5 11 13 14 and 16 have been mapped but their mutations have not been identified SCAs1 2 3 6 7 and 17 are more frequent than others SCAs and a few SCA types have been recognized only in a single family The incidence of the different types of SCA around the world is variable and known SCAs constitute about 60ndash80 of the families with ADCA (Table 1)

SCA1

The SCA1 gene is located on chromosome 6p linked to the HLA gene complex [15] SCA1 was cloned and the CAG repeat expansion identified in 1993 [16] The number of CAG repeats in normal and pathological alleles of SCA1 are shown in Table 1 The progression of SCA1 has a pattern common to most of the ADCA [17] typical onset with a cerebellar syndrome (ie broad-based gait limb ataxia progressive dysarthria) hand tremor and oculomotor signs including intermittent nystagmus slowing in saccadic velocity followed by limitation of up-gaze The bulbar and upper motor neurons signs may include lingual fasciculations noncerebellar dysphagia and dysarthria brisk deep tendon reflexes and increased tone (spasticity) Later in the disease this constellations of symptoms becomes more severe with coughing overt choking sensory loss mild peripheral neuropathy and extensor plantar responses In SCA1 extrapyramidal signs may be evident by the time the patient becomes wheelchair bounded The phenotype of the disease appears to be relatively homogeneous within and between families Variability observed in age of onset and progression appears to be attributable to the size of the CAG repeat expansion [1819] Bradykinesia and parkinsonism which may be prominent features in SCA3MJD have not been observed in SCA1 Cognitive decline does not appear to be severe in SCA1 Neuroimaging studies typically show atrophy of cerebellar cortex vermis and brainstem

SCA2

The SCA2 gene was mapped by linkage analysis of a homogeneous population of Holguin province (Cuba) to chromosome 12q24 [20] and later cloned independently by three groups [21ndash23] Clinical features of the disease include slow saccades kinetic or postural tremor and decrease of muscle tone and tendon reflexes Variable incidence of dystonia chorea and dementia has also been recognized Nonspecific cerebellar or pontocerebellar atrophy has been observed on MRI Nerve conduction studies show evidence of axonal sensory-motor neuropathy

SCA3MJD (Machado-Joseph disease)

Originally described in Portuguese families and named the ldquoAzorean diseaserdquo [24] SCA3 is now recognized worldwide The mutation in the SCA3 gene localized to 14q311 is an expanded CAG repeat in a novel protein designated ataxin-3 [25] Variable phenotypes are found in SCA3[2627] in addition to cerebellar ataxia and ophthalmoplegia early-onset disease can present with spasticity dystonia and an akinetic syndrome whereas late-onset SCA3 presents mainly with minimal extrapyramidal symptomatology The extrapyramidal signs are a characteristic but not exclusive feature of the SCA3 phenotype [27] There is an inverse correlation between the age of onset and the expanded CAG repeat length The severity of the disease as well as the presence of some symptoms (ie peripheral neuropathy) may depend on the length of the expansion with short and very large pathological alleles lacking neuropathy [28]

SCA4

A five-generation Utah kindred with an autosomal dominant late-onset spinocerebellar ataxia with the invariable presence of prominent axonal sensory neuropathy and normal eye movements demonstrated linkage to chromosome 16q221 [29] Six Japanese families with pure cerebellar ataxia without sensory neuropathy also showed linkage to this locus [3031]

SCA5

SCA5 was assigned to chromosome 11 in a single family descending from the grandparents of President Abraham Lincoln [32] In this family 56 individuals had cerebellar ataxia with onset at 10 to 68 years Anticipation is evident and progression of the disease is slow SCA5 does not affect life span probably because severe bulbar disease is generally absent A second apparently unrelated SCA5 family of French origin showed a similar phenotype with marked global cerebellar atrophy similar to SCA6 on MRI [33]

SCA6

SCA6 classically presents with pure cerebellar ataxia although patients with a prolonged disease course may show other clinical features including dystonic postures involuntary movements and abnormalities in tendon reflexes [34] Patients with SCA6 especially those with late onset disease may present without a family history The diagnosis of SCA6 should be considered in sporadic cases with horizontal and oblique gaze nystagmus and an abnormal vestibulo-ocular reflex without other ocular movement abnormalities or those with pure cerebellar atrophy [3435] Some phenotypic overlap with the allelic disease EA-2 (see the section of Episodic Ataxia) has been noted [3637] Brain MRI shows atrophy of the cerebellum and in some patients pons middle cerebellar peduncles and red nucleus [343839] The SCA6 mutation is a small CAG repeat expansion within the 1A-voltage-dependent calcium channel subunit (CACNL1A4) gene [40] The number of CAGs in mutant alleles ranges 20 to 30 while normal alleles are 4 to 17 CAGs (Table 1) [4041] An allele with 19 CAGs has been reported in a Japanese patient with ataxia [42] Although the age of onset inversely correlates with the expanded repeat size in different families the expanded repeat is usually stably transmitted within each family [414344] In rare cases however mild expansions have been reported [4546] Sisters homozygous for (CAG)2525 showed a similar age of onset but different progression rate suggesting pathogenic contribution of factors other than the repeat size [47] Homozygous cases suggested a gene dosage effect on the age of onset [3648ndash50] Anticipation in the absence of changes in the CAG repeat size has been described in French [51] Japanese [41] and Taiwanese kindreds

Although the expansion size of the CAG repeat falls into the normal ranges of other SCAs the polyglutamine tract in a densely packed membrane protein may allow the 1A subunits with small expansions to aggregate [5253] A key question is whether the SCA6 mutation causes disease by making the 1A subunit toxic or it does so by perturbing the gating of PQ-type channels [54] To reconcile these two different mechanisms it has been postulated that protein interactions altered by the expanded polyglutamine tract might cause gating abnormalities [55]

SCA7

SCA7 is characterized by progressive ataxia and pigmentary maculopathy with anticipation and is the only disease classified as an ADCA-II These features are accompanied by other clinical features including pyramidal and extrapyramidal signs ophthalmoplegia dementia hypoacusis hypotonia and auditory hallucinations [56] Slowing of voluntary and involuntary saccades is also an early sign of SCA7 [57] Specific juvenile and infantile forms of SCA7 have been defined Juvenile SCA7 occurs with maternal and paternal transmission whereas the infantile form occurs only with paternal transmission The infantile form shows severe hypotonia cerebral and cerebellar atrophy early visual loss congestive heart failure and patent ductus arteriosus [58] SCA7 is caused by an expansion of a CAG repeat in the SCA7 (ataxin-7) gene on chromosome 3p [5960] The normal range is 7 to 19 CAG repeats and pathogenic alleles range from 37 to approximately 306 repeats The expansion size correlates with the severity of the disease and inversely correlates with the age of onset [6162] Alleles with 28 to 36 repeats are intermediate alleles that are prone to further expansion accounting for de novo mutation cases [6364] Different disease-associated haplotypes segregated among SCA7 kindreds suggesting multiple origins of the mutation [63] Paternal transmission is underrepresented and when it does occur is associated with significant intergenerational expansion of the CAG repeat [65] The expanded CAG repeat in male germline is biased toward massive size increases potentially leading to putative embryonic lethality or dysfunctional sperm [66] The available data suggest that the mutant ataxin-7 protein is pathogenic due to a gain of toxic function by the polyglutamine expansion [67ndash70]

SCA8

SCA8 presents with slowly progressive ataxia with marked cerebellar atrophy [71] The disease is variably associated with pyramidal and cognitive dysfunctions [72] SCA8 patients have an expansion of a CTG repeat on chromosome 13q21 to the pathogenic range of 100 to 152 repeats while normal individuals have 15 to 91 CTGs [73] Affected individuals usually inherit an expanded allele from their mothers SCA8 alleles show an instability bias toward expansion with maternal transmission whereas paternal transmissions mostly result in smaller alleles which appear to be due to contraction of the expanded alleles to the normal range (lt100 CTGs) in the sperm [717475] Variable penetrance has been identified in SCA8 pedigrees [7176] There has been no evidence of correlation between the repeat size and the age of onset Haplotype analyses showed multiple origins for the SCA8 expansions [72]

The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract with the configuration (CTA)1-21(CTG)n in the 3 untranslated region of the SCA8 gene Many SCA patients have expanded alleles with interruptions by cryptic repeats (CCG CTA CTC CCA or CTT) which may have newly arisen or changed from generation to generation [74] SCA8 contains no open reading frame but the most 5 exon is transcribed through the first exon of another gene KLHL1 which is transcribed in the opposite orientation This raises a possibility that the SCA8 transcript is an endogenous antisense RNA for KLHL1 KLHL1 encodes a cytoplasmic protein that may play a role in organizing the actin cytoskeleton of the brain cells Both SCA8 and KLHL1 are primarily expressed in specific brain tissues affected by SCA8 [77] Other gain-of-function mechanisms involving the mutant SCA8 transcript have not been investigated but by no means excluded

The major controversy in SCA8 stems from a lack of absolute specificity of the CTG repeat expansion for SCA8 which has raised a possibility that CTG expansions at the SCA8 locus represent a rare polymorphism rather than the disease-causing mutation [7879] Alleles greater than 100 CTG repeats at the SCA8 locus were also found in 12 (14 of 1120) of major psychosis patients and 07 (5 of 710) of normal control subjects who had no family history of ataxia [80]

SCA9 (vacant)

SCA10

The clinical phenotype of SCA10 is characterized by a combination of relatively pure cerebellar ataxia and epilepsy Ataxia is progressive and often leads to total disability Seizures are generalized motor seizures complex partial seizures or both Some patients show mild cognitive dysfunction sensory polyneuropathy andor soft corticospinal tract signs [81] Anticipation is conspicuous in some families but subtle or absent in others The disease has so far been confined to families of Mexican descent The SCA10 mutation is a very large expansion of the ATTCT pentanucleotide repeat located in intron 9 of the E46L (SCA10) gene on chromosome 22q13 [49] Normal alleles show 10 to 21 ATTCTs while affected individuals have 800ndash4500 repeats An inverse correlation exists between the size of the expanded allele and the age of onset The mechanism of the disease remains unknown

SCA11

SCA11 clinically defined as an ADCA-III has been mapped to chromosome 15q in a single British family [78]

SCA12

SCA12 is a rare ADCA characterized by adult onset ataxia upper body tremor hyperreflexia with bilateral extensor plantar responses paucity of movements and dementia [8283] The clinical picture includes oculomotor abnormalities (ie broken pursuit nystagmus slow saccades) The disease is slowly progressive and in the late stage psychiatric symptoms including depression anxiety or delusions may appear in some affected members Brain MRI shows cerebellar and cerebral cortical atrophy There is no evidence of anticipation The mutation of SCA12 is a CAG repeat expansion in the 5 untranslated region of the PPP2R2B gene on chromosome 5p31-p33 [84] Normal alleles have 17 to 28 CAG repeats while the pathologic alleles have 55 to 78 repeats The disease has been described in two kindreds one from US and the other from India [8587] It has been postulated that the expansion of the CAG repeat up-regulate PPP2R2B expression

SCA13

A French family presented with slowly progressive childhood-onset cerebellar gait ataxia dysarthria moderate mental retardation and mild motor developmental delays with in some cases nystagmus and pyramidal signs Brain MRI showed moderate cerebellar and pontine atrophy A genome wide search showed linkage to chromosome

19q133-q134 [86]

SCA14

A Japanese three-generation family with ADCA mapped to a locus on chromosome 19q134-qter [86] The family members with late onset (gt39 years old) exhibited pure cerebellar ataxia whereas those with an early onset (lt27 years old) showed intermittent axial myoclonus followed by ataxia Other neurological signs were sparse and neuroimaging studies revealed isolated cerebellar atrophy

SCA15 (vacant)

SCA16

This is a pure cerebellar ataxia with head tremor and thus a form of ADCA III [88] Although head tremor which is distinct from tittubation has been described in SCA2 SCA7 and SCA12 it is rare for all SCA types Age of onset ranges 20 to 66 years and anticipation was not apparent Brain MRI showed cerebellar atrophy without involving brainstem The SCA16 locus showed linkage to markers on chromosome 8q221-q241 [88]

SCA17

An expansion of CAG repeats of the TATA-binding protein (TBP) gene was initially reported in a Japanese patient with sporadic cerebellar ataxia and intellectual deterioration associated with de novo expansion The expanded allele consisted of impure CAG repeats encoding 63 glutamines and the de novo expansion involved partial duplication of the CAG repeat [89] In two German families four patients showed expanded CAG repeats in TBP gene coding for 50 to 55 polyglutamines while normal subjects had alleles ranging from 27 to 44 glutamines [90] Several additional Japanese families with phenotypes resembling Huntingtons disease or DRPLA also showed SCA17 CAG expansions [91]

Other SCAs

Anecdotally there are many ADCA families who are not linked to known genetic loci and who have no distinctive phenotype In one such French family SCAs 1 2 3 6 7 8 and 12 were excluded by mutation analysis and SCAs 4 5 10 11 13 14 by lod score less than 2 Affected members of this French family showed gait ataxia akinesia dysarthria hyporeflexia and anticipation [92] There are likely to be many similar families who have not yet been characterized or reported

DRPLA

DRPLA is a relatively frequent disease in Japan with an incidence of 02-07 per 100000 A few isolated families have been recognized worldwide [92] The DRPLA gene on the chromosome 12p was cloned in 1994 [9495] Early onset of the disease includes ataxia myoclonus epilepsy and progression to dementia later onset disease can present with cerebellar symptoms psychiatric symptoms seizures [9396] and choreoathetotic abnormal movements with a ldquoHuntington-likerdquo phenotype [97] Age of onset and severity correlate with the length of the CAG expansion The mutation in the DRPLA gene has also been found in the Haw River Syndrome which has some different clinical characteristics from DRPLA [98]

Episodic ataxia (EA)

In contrast to SCAs these rare diseases present with episodic ataxic attacks of variable frequency and duration with no symptoms between attacks Additional characteristic signs are associated with the different types of EA

EA type 1 (EA1)

EA1 is caused by mutations in a potassium channel gene KCNA1 on chromosome 12p [99] The onset is between childhood and adolescence Besides episodic ataxia clinical manifestations are myokymia around the eyes lips or fingers Brief attacks of ataxia and dysarthria lasting seconds are precipitated by exercise or startle

EA type 2 (EA2)

Clinical manifestations of EA2 consist of mild to severe intermittent cerebellar dysfunction associated with oculomotor abnormalities such as interictal nystagmus and diplopia and migraine Symptoms can be present for minutes to a few days Episodes are provoked by stress and exercise but not startle Like familial hemiplegic migraine (FHM) and spinocerebellar ataxia type 6 (SCA6) EA2 is associated with mutations in the gene encoding the -1A subunit of the calcium channel SCA6 is caused by a CAG repeat expansion [40] while point mutations in the CACNA1A gene cause EA2 and FHM [100] Missense mutations usually cause FHM and non-sense or splice site mutations cause EA2 [101] However this rule has many exceptions [102] and EA2 FHM and SCA6 may represent a clinical continuum of the distinct mutations in CACNA1A[103] Moreover an identical mutation can give various clinical expressions in a same family Paroxysmal symptoms could arise from reversible channel dysfunction while progressive neurodegeneration could reflect a toxic gain of function The latter appears to be a general phenomenon in polyglutamine diseases (see SCA 6) but it is not known how point mutations in CACNA1A are associated in some cases with neuronal degeneration [103] EA2 may respond to the treatment with acetazolamide [104105]

EA with paroxysmal choreoathetosis and spasticity

The onset of this disorder is at 2ndash15 years with ataxia dystonia and headaches [105] Episodes last for a few minutes with a daily to yearly frequency Spastic paraparesis can persist between the attacks Episodes are provoked by fatigue stress exercise and alcohol

AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET

Friedreichs ataxia

Friedreichs ataxia (FRDA) described in 1863 by Nicholaus Friedreich and characterized in detail by Harding [8] is the most frequent autosomal recessive ataxia It has an incidence in whites of 130000 [106] but has not been documented among Sub-Saharan Africans American Indians and peoples from China Japan and Southeast Asia [107108] FRDA is responsible for 30 to 40 percent of autosomal recessive ataxia among whites The disease is a progressive spinocerebellar degeneration with typical onset before the age of 25 years especially during childhood or puberty (7ndash14 y) [8] The degeneration of the posterior columns of the spinal cord afferent cerebellar pathways and selected nuclei of the cerebellum gives rise to an ataxic gait classically followed by dysarthria upper limb ataxia distal sensory loss decreased vibration and position sense and absence of reflexes Scoliosis and pes cavus also can develop The full picture of the disease often includes hypertrophic cardiomyopathy [109] impaired glucose tolerance or diabetes mellitus and occasionally hearing loss or optic atrophy [110] In early onset cases FRDA may need to be differentiated from adrenomyeloneuropathy by very long chain fatty acid (VLCFA) levels Refsums disease by serum phytanic acid levels and vitamin E deficiency by vitamin E levels In some cases dominant ataxias and Charcot-Marie-Tooth disease join in the differential diagnoses Neuropathological changes in FRDA include degeneration of the dorsal root ganglia Clarkes columns posterior columns corticospinalspinocerebellar tracts cerebellum pons and medulla [111] Nerve conduction studies show selective loss of sensory nerve action potentials

The FRDAX25 gene contains seven exons spanning 80 kb on chromosome 9q13 and encodes a 210 amino acid protein called frataxin [112129] Most FRDA patients have an expansion of the trinucleotide GAA in the first intron of the FRDAX25 gene [114] Normal alleles contain 6 to 28 GAA repeats while affected individuals have 60 to 1800 (Table 2) Point mutations in the FRDA gene (instead of the GAA expansion) are found in about two to four percent of the cases Compound heterozygous patients with one expanded GAA repeat allele and one point mutation are more likely to show variant clinical features such as optic atrophy or retained reflexes than patients carrying homozygous GAA expansions [115] Among patients with 2 alleles carrying expanded GAA repeats there is an inverse correlation between the size of the GAA expansion and the age of onset severity of the disease and the occurrence of cardiomyopathy and diabetes Patients with the ldquolate onsetrdquo (after 25 years old) variant (LOFA) and those with retained reflexes (FARR) are also caused by the FRDA gene mutation [5117] most commonly associated with modestly expanded alleles (ie lt400 repeats) [127] Genetic heterogeneity in FRDA has been proposed and a second locus (FRDA2) has recently been identified [118]

Table 2 Hereditary ataxia according to the age of onset

Age of onset Diagnostic clues pia Locusgene Diagnosis Early onset (connatal or childhood) Main Congenital Ataxia Syndromes

Jouberts syndrome abnormal eye movements AR Clinic Gillespies syndrome partial anyridia AR Clinic Behrs syndrome optic atrophy AR several Clinic Marinesco-Sjoumlgrens syndrome cataracts hypogonadism AR Clinic

Main Metabolic Ataxias Urea cycles disorders urinary organic acids AR several ClinicBiochemGenetAminoacidurias urinary amino acids AR several ClinicBiochemGenetDisorders of pyruvatelactate serum pyruvatelactate AR several ClinicBiochemGenet

Mitochondrial encephalomyopathies MELAS MERRF etc Mb several ClinicBiochemGenet

Peroxisomal disorders infantile Refsun syndrome AR several ClinicBiochemGenetDisorders of DNA repair

Ataxia telangiectasia skin sensitivity Icircplusmn-fetoprotein cancer AR 11q22-23ATM ClinicGenet

Xeroderma pigmentosum skin sensitivity cancer AR several ClinicGenet

Cockaynes syndrome skin sensitivity dysmorphology AR several ClinicGenet

Trichothiodystrophy skin sensitivity brittle hair AR several ClinicGenet

Intermediate onset (childhood or juvenile)

Friedreichs ataxia - FRDA sensorimotor loss cardiac skeletal AR 9q13frataxin ClinicGenet

Early onset ataxia with retained reflexes - EOARR

early onset retained reflexes AR several ClinicGenet

Isolated vitamin E deficiency - AVED

low serum levels of vitamin E AR 8q13TTP1 ClinicBiochemGenet

Spastic ataxia of Charlevoix-Saguenay - SACS

hypermyelation retinal-nerve fibers AR 13q11sacsin ClinicGenet

Recessive ataxia with ocular motor apraxia -AOA

ocular apraxia neuropathy AR 9q13HITZn-finger ClinicGenet

Progressive myoclonus ataxia - PMA

myoclonus ataxia seizures AR Clinic

Progressive myoclonus epilepsy - PMEc

Unverricht-Lundborg syndrome ARc 21q223cystatin B ClinicGenet

Abetalipoproteinemia abetalipoproteinemia AR 4q22-24MTP ClinicBiochemGenetHypobetalipoproteinemia hypobetalipoproteinemia AD 2p24 3p22 ClinicBiochem Niemman-Pick disease type C sphingomyelin lipidosis AR

18q11NPC1 (95)d ClinicBiochemGenet

Krabbes disease galactosylceramide lipidosis AR galactocerebrosidase ClinicBiochemGenet

Hexosaminidase deficiencies hexosaminidase deficit AR hexA and hexAB ClinicBiochemGenet

Late Onset (juvenile or adult) Autosomal dominant cerebellar ataxia - ADCA SCAs AD Several (see Table

1) ClinicGenet

Episodic ataxia EA-1 EA-2 and EPCA AD channelopaties ClinicGenet Von Hippel-Lindau syndrome

cerebellar hemangioblastomas AD 3p25VHL ClinicGenet

Cerebellar ataxia with hypogonadism hypogonadism ataxia AR Clinic

Mitochondrial multisystemic several ClinicBiochemGenet

[a] pattern of inheritance (ie AR autosomal recessive)

A fascinating concurrence of yeast and human genetics [119ndash124] led to the proposal that frataxin is involved in the homeostasis (probably the transport) of mitochondrial iron Accumulation of iron inside the mitochondria of FRDA cells could lead to increased oxidative stress by free radical production from hydrogen peroxide and hypersensitivity to the oxidative stress due to mitochondrial dysfunction Deficiencies found in mitochondrialcytoplasmic aconitase as well as in the respiratory chain complexes I II and III in FRDA patients [123125] are consistent with this hypothesis Moreover primary vitamin E deficiency (see later) a specific disease associated with a defect in a physiological free radical scavenger clinically resembles FRDA Interestingly all of the enzymes with defective activity in FRDA mitochondria have iron-sulfur (Fe-S) clusters at the active sites These moieties are highly sensitive to free radical damage An alternative or complementary hypothesis is that a primary activity of frataxin is related to the synthesis of the Fe-S cluster [112] In any case these findings led to the proposal that antioxidants could be useful for the treatment of FRDA Idebenone (a free-radical scavenger analogue of coenzyme Q10) may ameliorate andor to revert the cardiac hypertrophy in FRDA patients [126] This drug is currently being studied in clinical trials Although iron chelation by desferroxamine should decrease serum and cytoplasmic iron levels it may decrease aconitase activity which may be detrimental to the cellular function In addition whether chelation can alter mitochondrial iron levels without toxic side effects is unknown A recently developed mouse model of FRDA [113] raises a hope for providing a powerful means to explore many of these hypotheses and potential treatments

Other than the potential therapeutic effect of antioxidants on cardiomyopathy in FRDA the treatment remains supportive and symptomatic Physiotherapy and orthopedic management (prosthesis or surgery) are used either to preserve or to correct progressive deformations of the spine and feet It is important to provide appropriate management of cardiac functions glucose metabolism and secondary medical problems such as aspiration pneumonia

Early-onset cerebellar ataxia with retained reflexes

This disease was considered by Harding [128] to be a syndrome distinct from FRDA however genetic mapping of the early-onset cerebellar ataxia with retained reflexes (EOCARR) locus is necessary before it can be recognized as an independent genetic entity [127] Onset is before age 20 with a clinical picture similar to FRDA but with retained reflexes low incidence of sensory neuropathy less reduction of joint position sense and absence of skeletal abnormalities optic neuropathy cardiomyopathy or diabetes [127] Exclusion of FRDA by DNA testing is essential since some patients with the EOCARR phenotype have GAA expansions in the frataxin gene [127128] Moreover a branch of a recently described EOCARR family has the late onset form of FRDA while another branch has EOCARR phenotype [127] In EOCARR with very early onset differential diagnosis with ataxia telangiectasia mitochondrial disorders adrenoleukodystrophy and lysosomal storage diseases may be necessary

Ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency (AVED) is a rare treatable disorder with a phenotype that resembles FRDA In a patient with a clinical diagnosis of FRDA and a negative genetic result for FRDA serum vitamin E levels should be determined as patients with AVED have very low levels of vitamin E (lt5 gml) Age of onset is between childhood and young adulthood associated with slowly progressive gait and limb ataxia loss of deep tendon reflexes and vibratory and proprioceptive loss followed by progressive ophthalmoplegia dysarthria extensor plantar responses and muscle weakness The disorder is caused by a defect in the TTP1 gene [129] on chromosome 8q13 encoding the -tocopherol transfer protein [130] responsible for the transfer of -tocopherol to the circulating lipoproteins Early onset and severe forms of the disease are caused by truncating mutations or missense mutations in conserved amino acids [131] However DNA testing for the AVED mutations is not commercially available Early replacement therapy may prevent progression of the disease [132133]

Several diseases that lead to secondary vitamin E deficiency (ie by affecting the absorption andor transport of fat

[b] Mitochondrial diseases due to defective mitochondrial genes have maternal inheritance whereas mitochondrial diseases due to nuclear genes have ARAD

[c] Other clinical forms of PME (ie the neuronal ceroid lipofuscinoses Lafora disease type I sialidosis and MERRF) are associated with defects in various genes

[d] A causative second gene NPC2 has not been identified

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

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SUMMARY

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References

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[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

CAG repeat in the protein coding region of a specific protein This leads to an abnormal expanded series of glutamines being translated in that specific protein The expansion is unstable over generations leading to progressive lengthening of the repeat Disease results when the repeat reaches a specific pathologic range and further expansion leads to progressively earlier age of onset Thus in each of these diseases the CAG repeat size correlates inversely with the age of onset The common pathogenic mechanism of these diseases involves a gain of toxic function [10] and neuropathological studies in ldquopolyglutaminerdquo diseases reveal the presence of neuronal nuclear protein inclusion [1112] which contain the polyglutamine-containing protein specific interacting proteins and proteins from the ubiquitin-degradation pathway [10] These aggregates do not appear to be responsible for the disease in SCA1 [13] although their direct role in other ldquopolyglutaminerdquo diseases is unclear The pathogenicity of the mutant protein in these diseases may involve defective ldquoprotein clearancerdquo sequestration of transcription co-activators and co-repressors andor other gain of function mechanisms [14]

The mutations for SCA8 and SCA12 are expansions of a CAGCTG repeat in untranslated regions of their respective genes Whether the trinucleotide expansion found in SCA8 is a causative mutation or a polymorphism in linkage disequilibrium is still a matter of debate (see SCA8 below) Individuals with SCA10 have a large expansion of an intronic ATTCT pentanucleotide repeat The pathogenic mechanisms of these SCAs remain to be investigated SCAs4 5 11 13 14 and 16 have been mapped but their mutations have not been identified SCAs1 2 3 6 7 and 17 are more frequent than others SCAs and a few SCA types have been recognized only in a single family The incidence of the different types of SCA around the world is variable and known SCAs constitute about 60ndash80 of the families with ADCA (Table 1)

SCA1

The SCA1 gene is located on chromosome 6p linked to the HLA gene complex [15] SCA1 was cloned and the CAG repeat expansion identified in 1993 [16] The number of CAG repeats in normal and pathological alleles of SCA1 are shown in Table 1 The progression of SCA1 has a pattern common to most of the ADCA [17] typical onset with a cerebellar syndrome (ie broad-based gait limb ataxia progressive dysarthria) hand tremor and oculomotor signs including intermittent nystagmus slowing in saccadic velocity followed by limitation of up-gaze The bulbar and upper motor neurons signs may include lingual fasciculations noncerebellar dysphagia and dysarthria brisk deep tendon reflexes and increased tone (spasticity) Later in the disease this constellations of symptoms becomes more severe with coughing overt choking sensory loss mild peripheral neuropathy and extensor plantar responses In SCA1 extrapyramidal signs may be evident by the time the patient becomes wheelchair bounded The phenotype of the disease appears to be relatively homogeneous within and between families Variability observed in age of onset and progression appears to be attributable to the size of the CAG repeat expansion [1819] Bradykinesia and parkinsonism which may be prominent features in SCA3MJD have not been observed in SCA1 Cognitive decline does not appear to be severe in SCA1 Neuroimaging studies typically show atrophy of cerebellar cortex vermis and brainstem

SCA2

The SCA2 gene was mapped by linkage analysis of a homogeneous population of Holguin province (Cuba) to chromosome 12q24 [20] and later cloned independently by three groups [21ndash23] Clinical features of the disease include slow saccades kinetic or postural tremor and decrease of muscle tone and tendon reflexes Variable incidence of dystonia chorea and dementia has also been recognized Nonspecific cerebellar or pontocerebellar atrophy has been observed on MRI Nerve conduction studies show evidence of axonal sensory-motor neuropathy

SCA3MJD (Machado-Joseph disease)

Originally described in Portuguese families and named the ldquoAzorean diseaserdquo [24] SCA3 is now recognized worldwide The mutation in the SCA3 gene localized to 14q311 is an expanded CAG repeat in a novel protein designated ataxin-3 [25] Variable phenotypes are found in SCA3[2627] in addition to cerebellar ataxia and ophthalmoplegia early-onset disease can present with spasticity dystonia and an akinetic syndrome whereas late-onset SCA3 presents mainly with minimal extrapyramidal symptomatology The extrapyramidal signs are a characteristic but not exclusive feature of the SCA3 phenotype [27] There is an inverse correlation between the age of onset and the expanded CAG repeat length The severity of the disease as well as the presence of some symptoms (ie peripheral neuropathy) may depend on the length of the expansion with short and very large pathological alleles lacking neuropathy [28]

SCA4

A five-generation Utah kindred with an autosomal dominant late-onset spinocerebellar ataxia with the invariable presence of prominent axonal sensory neuropathy and normal eye movements demonstrated linkage to chromosome 16q221 [29] Six Japanese families with pure cerebellar ataxia without sensory neuropathy also showed linkage to this locus [3031]

SCA5

SCA5 was assigned to chromosome 11 in a single family descending from the grandparents of President Abraham Lincoln [32] In this family 56 individuals had cerebellar ataxia with onset at 10 to 68 years Anticipation is evident and progression of the disease is slow SCA5 does not affect life span probably because severe bulbar disease is generally absent A second apparently unrelated SCA5 family of French origin showed a similar phenotype with marked global cerebellar atrophy similar to SCA6 on MRI [33]

SCA6

SCA6 classically presents with pure cerebellar ataxia although patients with a prolonged disease course may show other clinical features including dystonic postures involuntary movements and abnormalities in tendon reflexes [34] Patients with SCA6 especially those with late onset disease may present without a family history The diagnosis of SCA6 should be considered in sporadic cases with horizontal and oblique gaze nystagmus and an abnormal vestibulo-ocular reflex without other ocular movement abnormalities or those with pure cerebellar atrophy [3435] Some phenotypic overlap with the allelic disease EA-2 (see the section of Episodic Ataxia) has been noted [3637] Brain MRI shows atrophy of the cerebellum and in some patients pons middle cerebellar peduncles and red nucleus [343839] The SCA6 mutation is a small CAG repeat expansion within the 1A-voltage-dependent calcium channel subunit (CACNL1A4) gene [40] The number of CAGs in mutant alleles ranges 20 to 30 while normal alleles are 4 to 17 CAGs (Table 1) [4041] An allele with 19 CAGs has been reported in a Japanese patient with ataxia [42] Although the age of onset inversely correlates with the expanded repeat size in different families the expanded repeat is usually stably transmitted within each family [414344] In rare cases however mild expansions have been reported [4546] Sisters homozygous for (CAG)2525 showed a similar age of onset but different progression rate suggesting pathogenic contribution of factors other than the repeat size [47] Homozygous cases suggested a gene dosage effect on the age of onset [3648ndash50] Anticipation in the absence of changes in the CAG repeat size has been described in French [51] Japanese [41] and Taiwanese kindreds

Although the expansion size of the CAG repeat falls into the normal ranges of other SCAs the polyglutamine tract in a densely packed membrane protein may allow the 1A subunits with small expansions to aggregate [5253] A key question is whether the SCA6 mutation causes disease by making the 1A subunit toxic or it does so by perturbing the gating of PQ-type channels [54] To reconcile these two different mechanisms it has been postulated that protein interactions altered by the expanded polyglutamine tract might cause gating abnormalities [55]

SCA7

SCA7 is characterized by progressive ataxia and pigmentary maculopathy with anticipation and is the only disease classified as an ADCA-II These features are accompanied by other clinical features including pyramidal and extrapyramidal signs ophthalmoplegia dementia hypoacusis hypotonia and auditory hallucinations [56] Slowing of voluntary and involuntary saccades is also an early sign of SCA7 [57] Specific juvenile and infantile forms of SCA7 have been defined Juvenile SCA7 occurs with maternal and paternal transmission whereas the infantile form occurs only with paternal transmission The infantile form shows severe hypotonia cerebral and cerebellar atrophy early visual loss congestive heart failure and patent ductus arteriosus [58] SCA7 is caused by an expansion of a CAG repeat in the SCA7 (ataxin-7) gene on chromosome 3p [5960] The normal range is 7 to 19 CAG repeats and pathogenic alleles range from 37 to approximately 306 repeats The expansion size correlates with the severity of the disease and inversely correlates with the age of onset [6162] Alleles with 28 to 36 repeats are intermediate alleles that are prone to further expansion accounting for de novo mutation cases [6364] Different disease-associated haplotypes segregated among SCA7 kindreds suggesting multiple origins of the mutation [63] Paternal transmission is underrepresented and when it does occur is associated with significant intergenerational expansion of the CAG repeat [65] The expanded CAG repeat in male germline is biased toward massive size increases potentially leading to putative embryonic lethality or dysfunctional sperm [66] The available data suggest that the mutant ataxin-7 protein is pathogenic due to a gain of toxic function by the polyglutamine expansion [67ndash70]

SCA8

SCA8 presents with slowly progressive ataxia with marked cerebellar atrophy [71] The disease is variably associated with pyramidal and cognitive dysfunctions [72] SCA8 patients have an expansion of a CTG repeat on chromosome 13q21 to the pathogenic range of 100 to 152 repeats while normal individuals have 15 to 91 CTGs [73] Affected individuals usually inherit an expanded allele from their mothers SCA8 alleles show an instability bias toward expansion with maternal transmission whereas paternal transmissions mostly result in smaller alleles which appear to be due to contraction of the expanded alleles to the normal range (lt100 CTGs) in the sperm [717475] Variable penetrance has been identified in SCA8 pedigrees [7176] There has been no evidence of correlation between the repeat size and the age of onset Haplotype analyses showed multiple origins for the SCA8 expansions [72]

The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract with the configuration (CTA)1-21(CTG)n in the 3 untranslated region of the SCA8 gene Many SCA patients have expanded alleles with interruptions by cryptic repeats (CCG CTA CTC CCA or CTT) which may have newly arisen or changed from generation to generation [74] SCA8 contains no open reading frame but the most 5 exon is transcribed through the first exon of another gene KLHL1 which is transcribed in the opposite orientation This raises a possibility that the SCA8 transcript is an endogenous antisense RNA for KLHL1 KLHL1 encodes a cytoplasmic protein that may play a role in organizing the actin cytoskeleton of the brain cells Both SCA8 and KLHL1 are primarily expressed in specific brain tissues affected by SCA8 [77] Other gain-of-function mechanisms involving the mutant SCA8 transcript have not been investigated but by no means excluded

The major controversy in SCA8 stems from a lack of absolute specificity of the CTG repeat expansion for SCA8 which has raised a possibility that CTG expansions at the SCA8 locus represent a rare polymorphism rather than the disease-causing mutation [7879] Alleles greater than 100 CTG repeats at the SCA8 locus were also found in 12 (14 of 1120) of major psychosis patients and 07 (5 of 710) of normal control subjects who had no family history of ataxia [80]

SCA9 (vacant)

SCA10

The clinical phenotype of SCA10 is characterized by a combination of relatively pure cerebellar ataxia and epilepsy Ataxia is progressive and often leads to total disability Seizures are generalized motor seizures complex partial seizures or both Some patients show mild cognitive dysfunction sensory polyneuropathy andor soft corticospinal tract signs [81] Anticipation is conspicuous in some families but subtle or absent in others The disease has so far been confined to families of Mexican descent The SCA10 mutation is a very large expansion of the ATTCT pentanucleotide repeat located in intron 9 of the E46L (SCA10) gene on chromosome 22q13 [49] Normal alleles show 10 to 21 ATTCTs while affected individuals have 800ndash4500 repeats An inverse correlation exists between the size of the expanded allele and the age of onset The mechanism of the disease remains unknown

SCA11

SCA11 clinically defined as an ADCA-III has been mapped to chromosome 15q in a single British family [78]

SCA12

SCA12 is a rare ADCA characterized by adult onset ataxia upper body tremor hyperreflexia with bilateral extensor plantar responses paucity of movements and dementia [8283] The clinical picture includes oculomotor abnormalities (ie broken pursuit nystagmus slow saccades) The disease is slowly progressive and in the late stage psychiatric symptoms including depression anxiety or delusions may appear in some affected members Brain MRI shows cerebellar and cerebral cortical atrophy There is no evidence of anticipation The mutation of SCA12 is a CAG repeat expansion in the 5 untranslated region of the PPP2R2B gene on chromosome 5p31-p33 [84] Normal alleles have 17 to 28 CAG repeats while the pathologic alleles have 55 to 78 repeats The disease has been described in two kindreds one from US and the other from India [8587] It has been postulated that the expansion of the CAG repeat up-regulate PPP2R2B expression

SCA13

A French family presented with slowly progressive childhood-onset cerebellar gait ataxia dysarthria moderate mental retardation and mild motor developmental delays with in some cases nystagmus and pyramidal signs Brain MRI showed moderate cerebellar and pontine atrophy A genome wide search showed linkage to chromosome

19q133-q134 [86]

SCA14

A Japanese three-generation family with ADCA mapped to a locus on chromosome 19q134-qter [86] The family members with late onset (gt39 years old) exhibited pure cerebellar ataxia whereas those with an early onset (lt27 years old) showed intermittent axial myoclonus followed by ataxia Other neurological signs were sparse and neuroimaging studies revealed isolated cerebellar atrophy

SCA15 (vacant)

SCA16

This is a pure cerebellar ataxia with head tremor and thus a form of ADCA III [88] Although head tremor which is distinct from tittubation has been described in SCA2 SCA7 and SCA12 it is rare for all SCA types Age of onset ranges 20 to 66 years and anticipation was not apparent Brain MRI showed cerebellar atrophy without involving brainstem The SCA16 locus showed linkage to markers on chromosome 8q221-q241 [88]

SCA17

An expansion of CAG repeats of the TATA-binding protein (TBP) gene was initially reported in a Japanese patient with sporadic cerebellar ataxia and intellectual deterioration associated with de novo expansion The expanded allele consisted of impure CAG repeats encoding 63 glutamines and the de novo expansion involved partial duplication of the CAG repeat [89] In two German families four patients showed expanded CAG repeats in TBP gene coding for 50 to 55 polyglutamines while normal subjects had alleles ranging from 27 to 44 glutamines [90] Several additional Japanese families with phenotypes resembling Huntingtons disease or DRPLA also showed SCA17 CAG expansions [91]

Other SCAs

Anecdotally there are many ADCA families who are not linked to known genetic loci and who have no distinctive phenotype In one such French family SCAs 1 2 3 6 7 8 and 12 were excluded by mutation analysis and SCAs 4 5 10 11 13 14 by lod score less than 2 Affected members of this French family showed gait ataxia akinesia dysarthria hyporeflexia and anticipation [92] There are likely to be many similar families who have not yet been characterized or reported

DRPLA

DRPLA is a relatively frequent disease in Japan with an incidence of 02-07 per 100000 A few isolated families have been recognized worldwide [92] The DRPLA gene on the chromosome 12p was cloned in 1994 [9495] Early onset of the disease includes ataxia myoclonus epilepsy and progression to dementia later onset disease can present with cerebellar symptoms psychiatric symptoms seizures [9396] and choreoathetotic abnormal movements with a ldquoHuntington-likerdquo phenotype [97] Age of onset and severity correlate with the length of the CAG expansion The mutation in the DRPLA gene has also been found in the Haw River Syndrome which has some different clinical characteristics from DRPLA [98]

Episodic ataxia (EA)

In contrast to SCAs these rare diseases present with episodic ataxic attacks of variable frequency and duration with no symptoms between attacks Additional characteristic signs are associated with the different types of EA

EA type 1 (EA1)

EA1 is caused by mutations in a potassium channel gene KCNA1 on chromosome 12p [99] The onset is between childhood and adolescence Besides episodic ataxia clinical manifestations are myokymia around the eyes lips or fingers Brief attacks of ataxia and dysarthria lasting seconds are precipitated by exercise or startle

EA type 2 (EA2)

Clinical manifestations of EA2 consist of mild to severe intermittent cerebellar dysfunction associated with oculomotor abnormalities such as interictal nystagmus and diplopia and migraine Symptoms can be present for minutes to a few days Episodes are provoked by stress and exercise but not startle Like familial hemiplegic migraine (FHM) and spinocerebellar ataxia type 6 (SCA6) EA2 is associated with mutations in the gene encoding the -1A subunit of the calcium channel SCA6 is caused by a CAG repeat expansion [40] while point mutations in the CACNA1A gene cause EA2 and FHM [100] Missense mutations usually cause FHM and non-sense or splice site mutations cause EA2 [101] However this rule has many exceptions [102] and EA2 FHM and SCA6 may represent a clinical continuum of the distinct mutations in CACNA1A[103] Moreover an identical mutation can give various clinical expressions in a same family Paroxysmal symptoms could arise from reversible channel dysfunction while progressive neurodegeneration could reflect a toxic gain of function The latter appears to be a general phenomenon in polyglutamine diseases (see SCA 6) but it is not known how point mutations in CACNA1A are associated in some cases with neuronal degeneration [103] EA2 may respond to the treatment with acetazolamide [104105]

EA with paroxysmal choreoathetosis and spasticity

The onset of this disorder is at 2ndash15 years with ataxia dystonia and headaches [105] Episodes last for a few minutes with a daily to yearly frequency Spastic paraparesis can persist between the attacks Episodes are provoked by fatigue stress exercise and alcohol

AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET

Friedreichs ataxia

Friedreichs ataxia (FRDA) described in 1863 by Nicholaus Friedreich and characterized in detail by Harding [8] is the most frequent autosomal recessive ataxia It has an incidence in whites of 130000 [106] but has not been documented among Sub-Saharan Africans American Indians and peoples from China Japan and Southeast Asia [107108] FRDA is responsible for 30 to 40 percent of autosomal recessive ataxia among whites The disease is a progressive spinocerebellar degeneration with typical onset before the age of 25 years especially during childhood or puberty (7ndash14 y) [8] The degeneration of the posterior columns of the spinal cord afferent cerebellar pathways and selected nuclei of the cerebellum gives rise to an ataxic gait classically followed by dysarthria upper limb ataxia distal sensory loss decreased vibration and position sense and absence of reflexes Scoliosis and pes cavus also can develop The full picture of the disease often includes hypertrophic cardiomyopathy [109] impaired glucose tolerance or diabetes mellitus and occasionally hearing loss or optic atrophy [110] In early onset cases FRDA may need to be differentiated from adrenomyeloneuropathy by very long chain fatty acid (VLCFA) levels Refsums disease by serum phytanic acid levels and vitamin E deficiency by vitamin E levels In some cases dominant ataxias and Charcot-Marie-Tooth disease join in the differential diagnoses Neuropathological changes in FRDA include degeneration of the dorsal root ganglia Clarkes columns posterior columns corticospinalspinocerebellar tracts cerebellum pons and medulla [111] Nerve conduction studies show selective loss of sensory nerve action potentials

The FRDAX25 gene contains seven exons spanning 80 kb on chromosome 9q13 and encodes a 210 amino acid protein called frataxin [112129] Most FRDA patients have an expansion of the trinucleotide GAA in the first intron of the FRDAX25 gene [114] Normal alleles contain 6 to 28 GAA repeats while affected individuals have 60 to 1800 (Table 2) Point mutations in the FRDA gene (instead of the GAA expansion) are found in about two to four percent of the cases Compound heterozygous patients with one expanded GAA repeat allele and one point mutation are more likely to show variant clinical features such as optic atrophy or retained reflexes than patients carrying homozygous GAA expansions [115] Among patients with 2 alleles carrying expanded GAA repeats there is an inverse correlation between the size of the GAA expansion and the age of onset severity of the disease and the occurrence of cardiomyopathy and diabetes Patients with the ldquolate onsetrdquo (after 25 years old) variant (LOFA) and those with retained reflexes (FARR) are also caused by the FRDA gene mutation [5117] most commonly associated with modestly expanded alleles (ie lt400 repeats) [127] Genetic heterogeneity in FRDA has been proposed and a second locus (FRDA2) has recently been identified [118]

Table 2 Hereditary ataxia according to the age of onset

Age of onset Diagnostic clues pia Locusgene Diagnosis Early onset (connatal or childhood) Main Congenital Ataxia Syndromes

Jouberts syndrome abnormal eye movements AR Clinic Gillespies syndrome partial anyridia AR Clinic Behrs syndrome optic atrophy AR several Clinic Marinesco-Sjoumlgrens syndrome cataracts hypogonadism AR Clinic

Main Metabolic Ataxias Urea cycles disorders urinary organic acids AR several ClinicBiochemGenetAminoacidurias urinary amino acids AR several ClinicBiochemGenetDisorders of pyruvatelactate serum pyruvatelactate AR several ClinicBiochemGenet

Mitochondrial encephalomyopathies MELAS MERRF etc Mb several ClinicBiochemGenet

Peroxisomal disorders infantile Refsun syndrome AR several ClinicBiochemGenetDisorders of DNA repair

Ataxia telangiectasia skin sensitivity Icircplusmn-fetoprotein cancer AR 11q22-23ATM ClinicGenet

Xeroderma pigmentosum skin sensitivity cancer AR several ClinicGenet

Cockaynes syndrome skin sensitivity dysmorphology AR several ClinicGenet

Trichothiodystrophy skin sensitivity brittle hair AR several ClinicGenet

Intermediate onset (childhood or juvenile)

Friedreichs ataxia - FRDA sensorimotor loss cardiac skeletal AR 9q13frataxin ClinicGenet

Early onset ataxia with retained reflexes - EOARR

early onset retained reflexes AR several ClinicGenet

Isolated vitamin E deficiency - AVED

low serum levels of vitamin E AR 8q13TTP1 ClinicBiochemGenet

Spastic ataxia of Charlevoix-Saguenay - SACS

hypermyelation retinal-nerve fibers AR 13q11sacsin ClinicGenet

Recessive ataxia with ocular motor apraxia -AOA

ocular apraxia neuropathy AR 9q13HITZn-finger ClinicGenet

Progressive myoclonus ataxia - PMA

myoclonus ataxia seizures AR Clinic

Progressive myoclonus epilepsy - PMEc

Unverricht-Lundborg syndrome ARc 21q223cystatin B ClinicGenet

Abetalipoproteinemia abetalipoproteinemia AR 4q22-24MTP ClinicBiochemGenetHypobetalipoproteinemia hypobetalipoproteinemia AD 2p24 3p22 ClinicBiochem Niemman-Pick disease type C sphingomyelin lipidosis AR

18q11NPC1 (95)d ClinicBiochemGenet

Krabbes disease galactosylceramide lipidosis AR galactocerebrosidase ClinicBiochemGenet

Hexosaminidase deficiencies hexosaminidase deficit AR hexA and hexAB ClinicBiochemGenet

Late Onset (juvenile or adult) Autosomal dominant cerebellar ataxia - ADCA SCAs AD Several (see Table

1) ClinicGenet

Episodic ataxia EA-1 EA-2 and EPCA AD channelopaties ClinicGenet Von Hippel-Lindau syndrome

cerebellar hemangioblastomas AD 3p25VHL ClinicGenet

Cerebellar ataxia with hypogonadism hypogonadism ataxia AR Clinic

Mitochondrial multisystemic several ClinicBiochemGenet

[a] pattern of inheritance (ie AR autosomal recessive)

A fascinating concurrence of yeast and human genetics [119ndash124] led to the proposal that frataxin is involved in the homeostasis (probably the transport) of mitochondrial iron Accumulation of iron inside the mitochondria of FRDA cells could lead to increased oxidative stress by free radical production from hydrogen peroxide and hypersensitivity to the oxidative stress due to mitochondrial dysfunction Deficiencies found in mitochondrialcytoplasmic aconitase as well as in the respiratory chain complexes I II and III in FRDA patients [123125] are consistent with this hypothesis Moreover primary vitamin E deficiency (see later) a specific disease associated with a defect in a physiological free radical scavenger clinically resembles FRDA Interestingly all of the enzymes with defective activity in FRDA mitochondria have iron-sulfur (Fe-S) clusters at the active sites These moieties are highly sensitive to free radical damage An alternative or complementary hypothesis is that a primary activity of frataxin is related to the synthesis of the Fe-S cluster [112] In any case these findings led to the proposal that antioxidants could be useful for the treatment of FRDA Idebenone (a free-radical scavenger analogue of coenzyme Q10) may ameliorate andor to revert the cardiac hypertrophy in FRDA patients [126] This drug is currently being studied in clinical trials Although iron chelation by desferroxamine should decrease serum and cytoplasmic iron levels it may decrease aconitase activity which may be detrimental to the cellular function In addition whether chelation can alter mitochondrial iron levels without toxic side effects is unknown A recently developed mouse model of FRDA [113] raises a hope for providing a powerful means to explore many of these hypotheses and potential treatments

Other than the potential therapeutic effect of antioxidants on cardiomyopathy in FRDA the treatment remains supportive and symptomatic Physiotherapy and orthopedic management (prosthesis or surgery) are used either to preserve or to correct progressive deformations of the spine and feet It is important to provide appropriate management of cardiac functions glucose metabolism and secondary medical problems such as aspiration pneumonia

Early-onset cerebellar ataxia with retained reflexes

This disease was considered by Harding [128] to be a syndrome distinct from FRDA however genetic mapping of the early-onset cerebellar ataxia with retained reflexes (EOCARR) locus is necessary before it can be recognized as an independent genetic entity [127] Onset is before age 20 with a clinical picture similar to FRDA but with retained reflexes low incidence of sensory neuropathy less reduction of joint position sense and absence of skeletal abnormalities optic neuropathy cardiomyopathy or diabetes [127] Exclusion of FRDA by DNA testing is essential since some patients with the EOCARR phenotype have GAA expansions in the frataxin gene [127128] Moreover a branch of a recently described EOCARR family has the late onset form of FRDA while another branch has EOCARR phenotype [127] In EOCARR with very early onset differential diagnosis with ataxia telangiectasia mitochondrial disorders adrenoleukodystrophy and lysosomal storage diseases may be necessary

Ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency (AVED) is a rare treatable disorder with a phenotype that resembles FRDA In a patient with a clinical diagnosis of FRDA and a negative genetic result for FRDA serum vitamin E levels should be determined as patients with AVED have very low levels of vitamin E (lt5 gml) Age of onset is between childhood and young adulthood associated with slowly progressive gait and limb ataxia loss of deep tendon reflexes and vibratory and proprioceptive loss followed by progressive ophthalmoplegia dysarthria extensor plantar responses and muscle weakness The disorder is caused by a defect in the TTP1 gene [129] on chromosome 8q13 encoding the -tocopherol transfer protein [130] responsible for the transfer of -tocopherol to the circulating lipoproteins Early onset and severe forms of the disease are caused by truncating mutations or missense mutations in conserved amino acids [131] However DNA testing for the AVED mutations is not commercially available Early replacement therapy may prevent progression of the disease [132133]

Several diseases that lead to secondary vitamin E deficiency (ie by affecting the absorption andor transport of fat

[b] Mitochondrial diseases due to defective mitochondrial genes have maternal inheritance whereas mitochondrial diseases due to nuclear genes have ARAD

[c] Other clinical forms of PME (ie the neuronal ceroid lipofuscinoses Lafora disease type I sialidosis and MERRF) are associated with defects in various genes

[d] A causative second gene NPC2 has not been identified

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

A five-generation Utah kindred with an autosomal dominant late-onset spinocerebellar ataxia with the invariable presence of prominent axonal sensory neuropathy and normal eye movements demonstrated linkage to chromosome 16q221 [29] Six Japanese families with pure cerebellar ataxia without sensory neuropathy also showed linkage to this locus [3031]

SCA5

SCA5 was assigned to chromosome 11 in a single family descending from the grandparents of President Abraham Lincoln [32] In this family 56 individuals had cerebellar ataxia with onset at 10 to 68 years Anticipation is evident and progression of the disease is slow SCA5 does not affect life span probably because severe bulbar disease is generally absent A second apparently unrelated SCA5 family of French origin showed a similar phenotype with marked global cerebellar atrophy similar to SCA6 on MRI [33]

SCA6

SCA6 classically presents with pure cerebellar ataxia although patients with a prolonged disease course may show other clinical features including dystonic postures involuntary movements and abnormalities in tendon reflexes [34] Patients with SCA6 especially those with late onset disease may present without a family history The diagnosis of SCA6 should be considered in sporadic cases with horizontal and oblique gaze nystagmus and an abnormal vestibulo-ocular reflex without other ocular movement abnormalities or those with pure cerebellar atrophy [3435] Some phenotypic overlap with the allelic disease EA-2 (see the section of Episodic Ataxia) has been noted [3637] Brain MRI shows atrophy of the cerebellum and in some patients pons middle cerebellar peduncles and red nucleus [343839] The SCA6 mutation is a small CAG repeat expansion within the 1A-voltage-dependent calcium channel subunit (CACNL1A4) gene [40] The number of CAGs in mutant alleles ranges 20 to 30 while normal alleles are 4 to 17 CAGs (Table 1) [4041] An allele with 19 CAGs has been reported in a Japanese patient with ataxia [42] Although the age of onset inversely correlates with the expanded repeat size in different families the expanded repeat is usually stably transmitted within each family [414344] In rare cases however mild expansions have been reported [4546] Sisters homozygous for (CAG)2525 showed a similar age of onset but different progression rate suggesting pathogenic contribution of factors other than the repeat size [47] Homozygous cases suggested a gene dosage effect on the age of onset [3648ndash50] Anticipation in the absence of changes in the CAG repeat size has been described in French [51] Japanese [41] and Taiwanese kindreds

Although the expansion size of the CAG repeat falls into the normal ranges of other SCAs the polyglutamine tract in a densely packed membrane protein may allow the 1A subunits with small expansions to aggregate [5253] A key question is whether the SCA6 mutation causes disease by making the 1A subunit toxic or it does so by perturbing the gating of PQ-type channels [54] To reconcile these two different mechanisms it has been postulated that protein interactions altered by the expanded polyglutamine tract might cause gating abnormalities [55]

SCA7

SCA7 is characterized by progressive ataxia and pigmentary maculopathy with anticipation and is the only disease classified as an ADCA-II These features are accompanied by other clinical features including pyramidal and extrapyramidal signs ophthalmoplegia dementia hypoacusis hypotonia and auditory hallucinations [56] Slowing of voluntary and involuntary saccades is also an early sign of SCA7 [57] Specific juvenile and infantile forms of SCA7 have been defined Juvenile SCA7 occurs with maternal and paternal transmission whereas the infantile form occurs only with paternal transmission The infantile form shows severe hypotonia cerebral and cerebellar atrophy early visual loss congestive heart failure and patent ductus arteriosus [58] SCA7 is caused by an expansion of a CAG repeat in the SCA7 (ataxin-7) gene on chromosome 3p [5960] The normal range is 7 to 19 CAG repeats and pathogenic alleles range from 37 to approximately 306 repeats The expansion size correlates with the severity of the disease and inversely correlates with the age of onset [6162] Alleles with 28 to 36 repeats are intermediate alleles that are prone to further expansion accounting for de novo mutation cases [6364] Different disease-associated haplotypes segregated among SCA7 kindreds suggesting multiple origins of the mutation [63] Paternal transmission is underrepresented and when it does occur is associated with significant intergenerational expansion of the CAG repeat [65] The expanded CAG repeat in male germline is biased toward massive size increases potentially leading to putative embryonic lethality or dysfunctional sperm [66] The available data suggest that the mutant ataxin-7 protein is pathogenic due to a gain of toxic function by the polyglutamine expansion [67ndash70]

SCA8

SCA8 presents with slowly progressive ataxia with marked cerebellar atrophy [71] The disease is variably associated with pyramidal and cognitive dysfunctions [72] SCA8 patients have an expansion of a CTG repeat on chromosome 13q21 to the pathogenic range of 100 to 152 repeats while normal individuals have 15 to 91 CTGs [73] Affected individuals usually inherit an expanded allele from their mothers SCA8 alleles show an instability bias toward expansion with maternal transmission whereas paternal transmissions mostly result in smaller alleles which appear to be due to contraction of the expanded alleles to the normal range (lt100 CTGs) in the sperm [717475] Variable penetrance has been identified in SCA8 pedigrees [7176] There has been no evidence of correlation between the repeat size and the age of onset Haplotype analyses showed multiple origins for the SCA8 expansions [72]

The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract with the configuration (CTA)1-21(CTG)n in the 3 untranslated region of the SCA8 gene Many SCA patients have expanded alleles with interruptions by cryptic repeats (CCG CTA CTC CCA or CTT) which may have newly arisen or changed from generation to generation [74] SCA8 contains no open reading frame but the most 5 exon is transcribed through the first exon of another gene KLHL1 which is transcribed in the opposite orientation This raises a possibility that the SCA8 transcript is an endogenous antisense RNA for KLHL1 KLHL1 encodes a cytoplasmic protein that may play a role in organizing the actin cytoskeleton of the brain cells Both SCA8 and KLHL1 are primarily expressed in specific brain tissues affected by SCA8 [77] Other gain-of-function mechanisms involving the mutant SCA8 transcript have not been investigated but by no means excluded

The major controversy in SCA8 stems from a lack of absolute specificity of the CTG repeat expansion for SCA8 which has raised a possibility that CTG expansions at the SCA8 locus represent a rare polymorphism rather than the disease-causing mutation [7879] Alleles greater than 100 CTG repeats at the SCA8 locus were also found in 12 (14 of 1120) of major psychosis patients and 07 (5 of 710) of normal control subjects who had no family history of ataxia [80]

SCA9 (vacant)

SCA10

The clinical phenotype of SCA10 is characterized by a combination of relatively pure cerebellar ataxia and epilepsy Ataxia is progressive and often leads to total disability Seizures are generalized motor seizures complex partial seizures or both Some patients show mild cognitive dysfunction sensory polyneuropathy andor soft corticospinal tract signs [81] Anticipation is conspicuous in some families but subtle or absent in others The disease has so far been confined to families of Mexican descent The SCA10 mutation is a very large expansion of the ATTCT pentanucleotide repeat located in intron 9 of the E46L (SCA10) gene on chromosome 22q13 [49] Normal alleles show 10 to 21 ATTCTs while affected individuals have 800ndash4500 repeats An inverse correlation exists between the size of the expanded allele and the age of onset The mechanism of the disease remains unknown

SCA11

SCA11 clinically defined as an ADCA-III has been mapped to chromosome 15q in a single British family [78]

SCA12

SCA12 is a rare ADCA characterized by adult onset ataxia upper body tremor hyperreflexia with bilateral extensor plantar responses paucity of movements and dementia [8283] The clinical picture includes oculomotor abnormalities (ie broken pursuit nystagmus slow saccades) The disease is slowly progressive and in the late stage psychiatric symptoms including depression anxiety or delusions may appear in some affected members Brain MRI shows cerebellar and cerebral cortical atrophy There is no evidence of anticipation The mutation of SCA12 is a CAG repeat expansion in the 5 untranslated region of the PPP2R2B gene on chromosome 5p31-p33 [84] Normal alleles have 17 to 28 CAG repeats while the pathologic alleles have 55 to 78 repeats The disease has been described in two kindreds one from US and the other from India [8587] It has been postulated that the expansion of the CAG repeat up-regulate PPP2R2B expression

SCA13

A French family presented with slowly progressive childhood-onset cerebellar gait ataxia dysarthria moderate mental retardation and mild motor developmental delays with in some cases nystagmus and pyramidal signs Brain MRI showed moderate cerebellar and pontine atrophy A genome wide search showed linkage to chromosome

19q133-q134 [86]

SCA14

A Japanese three-generation family with ADCA mapped to a locus on chromosome 19q134-qter [86] The family members with late onset (gt39 years old) exhibited pure cerebellar ataxia whereas those with an early onset (lt27 years old) showed intermittent axial myoclonus followed by ataxia Other neurological signs were sparse and neuroimaging studies revealed isolated cerebellar atrophy

SCA15 (vacant)

SCA16

This is a pure cerebellar ataxia with head tremor and thus a form of ADCA III [88] Although head tremor which is distinct from tittubation has been described in SCA2 SCA7 and SCA12 it is rare for all SCA types Age of onset ranges 20 to 66 years and anticipation was not apparent Brain MRI showed cerebellar atrophy without involving brainstem The SCA16 locus showed linkage to markers on chromosome 8q221-q241 [88]

SCA17

An expansion of CAG repeats of the TATA-binding protein (TBP) gene was initially reported in a Japanese patient with sporadic cerebellar ataxia and intellectual deterioration associated with de novo expansion The expanded allele consisted of impure CAG repeats encoding 63 glutamines and the de novo expansion involved partial duplication of the CAG repeat [89] In two German families four patients showed expanded CAG repeats in TBP gene coding for 50 to 55 polyglutamines while normal subjects had alleles ranging from 27 to 44 glutamines [90] Several additional Japanese families with phenotypes resembling Huntingtons disease or DRPLA also showed SCA17 CAG expansions [91]

Other SCAs

Anecdotally there are many ADCA families who are not linked to known genetic loci and who have no distinctive phenotype In one such French family SCAs 1 2 3 6 7 8 and 12 were excluded by mutation analysis and SCAs 4 5 10 11 13 14 by lod score less than 2 Affected members of this French family showed gait ataxia akinesia dysarthria hyporeflexia and anticipation [92] There are likely to be many similar families who have not yet been characterized or reported

DRPLA

DRPLA is a relatively frequent disease in Japan with an incidence of 02-07 per 100000 A few isolated families have been recognized worldwide [92] The DRPLA gene on the chromosome 12p was cloned in 1994 [9495] Early onset of the disease includes ataxia myoclonus epilepsy and progression to dementia later onset disease can present with cerebellar symptoms psychiatric symptoms seizures [9396] and choreoathetotic abnormal movements with a ldquoHuntington-likerdquo phenotype [97] Age of onset and severity correlate with the length of the CAG expansion The mutation in the DRPLA gene has also been found in the Haw River Syndrome which has some different clinical characteristics from DRPLA [98]

Episodic ataxia (EA)

In contrast to SCAs these rare diseases present with episodic ataxic attacks of variable frequency and duration with no symptoms between attacks Additional characteristic signs are associated with the different types of EA

EA type 1 (EA1)

EA1 is caused by mutations in a potassium channel gene KCNA1 on chromosome 12p [99] The onset is between childhood and adolescence Besides episodic ataxia clinical manifestations are myokymia around the eyes lips or fingers Brief attacks of ataxia and dysarthria lasting seconds are precipitated by exercise or startle

EA type 2 (EA2)

Clinical manifestations of EA2 consist of mild to severe intermittent cerebellar dysfunction associated with oculomotor abnormalities such as interictal nystagmus and diplopia and migraine Symptoms can be present for minutes to a few days Episodes are provoked by stress and exercise but not startle Like familial hemiplegic migraine (FHM) and spinocerebellar ataxia type 6 (SCA6) EA2 is associated with mutations in the gene encoding the -1A subunit of the calcium channel SCA6 is caused by a CAG repeat expansion [40] while point mutations in the CACNA1A gene cause EA2 and FHM [100] Missense mutations usually cause FHM and non-sense or splice site mutations cause EA2 [101] However this rule has many exceptions [102] and EA2 FHM and SCA6 may represent a clinical continuum of the distinct mutations in CACNA1A[103] Moreover an identical mutation can give various clinical expressions in a same family Paroxysmal symptoms could arise from reversible channel dysfunction while progressive neurodegeneration could reflect a toxic gain of function The latter appears to be a general phenomenon in polyglutamine diseases (see SCA 6) but it is not known how point mutations in CACNA1A are associated in some cases with neuronal degeneration [103] EA2 may respond to the treatment with acetazolamide [104105]

EA with paroxysmal choreoathetosis and spasticity

The onset of this disorder is at 2ndash15 years with ataxia dystonia and headaches [105] Episodes last for a few minutes with a daily to yearly frequency Spastic paraparesis can persist between the attacks Episodes are provoked by fatigue stress exercise and alcohol

AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET

Friedreichs ataxia

Friedreichs ataxia (FRDA) described in 1863 by Nicholaus Friedreich and characterized in detail by Harding [8] is the most frequent autosomal recessive ataxia It has an incidence in whites of 130000 [106] but has not been documented among Sub-Saharan Africans American Indians and peoples from China Japan and Southeast Asia [107108] FRDA is responsible for 30 to 40 percent of autosomal recessive ataxia among whites The disease is a progressive spinocerebellar degeneration with typical onset before the age of 25 years especially during childhood or puberty (7ndash14 y) [8] The degeneration of the posterior columns of the spinal cord afferent cerebellar pathways and selected nuclei of the cerebellum gives rise to an ataxic gait classically followed by dysarthria upper limb ataxia distal sensory loss decreased vibration and position sense and absence of reflexes Scoliosis and pes cavus also can develop The full picture of the disease often includes hypertrophic cardiomyopathy [109] impaired glucose tolerance or diabetes mellitus and occasionally hearing loss or optic atrophy [110] In early onset cases FRDA may need to be differentiated from adrenomyeloneuropathy by very long chain fatty acid (VLCFA) levels Refsums disease by serum phytanic acid levels and vitamin E deficiency by vitamin E levels In some cases dominant ataxias and Charcot-Marie-Tooth disease join in the differential diagnoses Neuropathological changes in FRDA include degeneration of the dorsal root ganglia Clarkes columns posterior columns corticospinalspinocerebellar tracts cerebellum pons and medulla [111] Nerve conduction studies show selective loss of sensory nerve action potentials

The FRDAX25 gene contains seven exons spanning 80 kb on chromosome 9q13 and encodes a 210 amino acid protein called frataxin [112129] Most FRDA patients have an expansion of the trinucleotide GAA in the first intron of the FRDAX25 gene [114] Normal alleles contain 6 to 28 GAA repeats while affected individuals have 60 to 1800 (Table 2) Point mutations in the FRDA gene (instead of the GAA expansion) are found in about two to four percent of the cases Compound heterozygous patients with one expanded GAA repeat allele and one point mutation are more likely to show variant clinical features such as optic atrophy or retained reflexes than patients carrying homozygous GAA expansions [115] Among patients with 2 alleles carrying expanded GAA repeats there is an inverse correlation between the size of the GAA expansion and the age of onset severity of the disease and the occurrence of cardiomyopathy and diabetes Patients with the ldquolate onsetrdquo (after 25 years old) variant (LOFA) and those with retained reflexes (FARR) are also caused by the FRDA gene mutation [5117] most commonly associated with modestly expanded alleles (ie lt400 repeats) [127] Genetic heterogeneity in FRDA has been proposed and a second locus (FRDA2) has recently been identified [118]

Table 2 Hereditary ataxia according to the age of onset

Age of onset Diagnostic clues pia Locusgene Diagnosis Early onset (connatal or childhood) Main Congenital Ataxia Syndromes

Jouberts syndrome abnormal eye movements AR Clinic Gillespies syndrome partial anyridia AR Clinic Behrs syndrome optic atrophy AR several Clinic Marinesco-Sjoumlgrens syndrome cataracts hypogonadism AR Clinic

Main Metabolic Ataxias Urea cycles disorders urinary organic acids AR several ClinicBiochemGenetAminoacidurias urinary amino acids AR several ClinicBiochemGenetDisorders of pyruvatelactate serum pyruvatelactate AR several ClinicBiochemGenet

Mitochondrial encephalomyopathies MELAS MERRF etc Mb several ClinicBiochemGenet

Peroxisomal disorders infantile Refsun syndrome AR several ClinicBiochemGenetDisorders of DNA repair

Ataxia telangiectasia skin sensitivity Icircplusmn-fetoprotein cancer AR 11q22-23ATM ClinicGenet

Xeroderma pigmentosum skin sensitivity cancer AR several ClinicGenet

Cockaynes syndrome skin sensitivity dysmorphology AR several ClinicGenet

Trichothiodystrophy skin sensitivity brittle hair AR several ClinicGenet

Intermediate onset (childhood or juvenile)

Friedreichs ataxia - FRDA sensorimotor loss cardiac skeletal AR 9q13frataxin ClinicGenet

Early onset ataxia with retained reflexes - EOARR

early onset retained reflexes AR several ClinicGenet

Isolated vitamin E deficiency - AVED

low serum levels of vitamin E AR 8q13TTP1 ClinicBiochemGenet

Spastic ataxia of Charlevoix-Saguenay - SACS

hypermyelation retinal-nerve fibers AR 13q11sacsin ClinicGenet

Recessive ataxia with ocular motor apraxia -AOA

ocular apraxia neuropathy AR 9q13HITZn-finger ClinicGenet

Progressive myoclonus ataxia - PMA

myoclonus ataxia seizures AR Clinic

Progressive myoclonus epilepsy - PMEc

Unverricht-Lundborg syndrome ARc 21q223cystatin B ClinicGenet

Abetalipoproteinemia abetalipoproteinemia AR 4q22-24MTP ClinicBiochemGenetHypobetalipoproteinemia hypobetalipoproteinemia AD 2p24 3p22 ClinicBiochem Niemman-Pick disease type C sphingomyelin lipidosis AR

18q11NPC1 (95)d ClinicBiochemGenet

Krabbes disease galactosylceramide lipidosis AR galactocerebrosidase ClinicBiochemGenet

Hexosaminidase deficiencies hexosaminidase deficit AR hexA and hexAB ClinicBiochemGenet

Late Onset (juvenile or adult) Autosomal dominant cerebellar ataxia - ADCA SCAs AD Several (see Table

1) ClinicGenet

Episodic ataxia EA-1 EA-2 and EPCA AD channelopaties ClinicGenet Von Hippel-Lindau syndrome

cerebellar hemangioblastomas AD 3p25VHL ClinicGenet

Cerebellar ataxia with hypogonadism hypogonadism ataxia AR Clinic

Mitochondrial multisystemic several ClinicBiochemGenet

[a] pattern of inheritance (ie AR autosomal recessive)

A fascinating concurrence of yeast and human genetics [119ndash124] led to the proposal that frataxin is involved in the homeostasis (probably the transport) of mitochondrial iron Accumulation of iron inside the mitochondria of FRDA cells could lead to increased oxidative stress by free radical production from hydrogen peroxide and hypersensitivity to the oxidative stress due to mitochondrial dysfunction Deficiencies found in mitochondrialcytoplasmic aconitase as well as in the respiratory chain complexes I II and III in FRDA patients [123125] are consistent with this hypothesis Moreover primary vitamin E deficiency (see later) a specific disease associated with a defect in a physiological free radical scavenger clinically resembles FRDA Interestingly all of the enzymes with defective activity in FRDA mitochondria have iron-sulfur (Fe-S) clusters at the active sites These moieties are highly sensitive to free radical damage An alternative or complementary hypothesis is that a primary activity of frataxin is related to the synthesis of the Fe-S cluster [112] In any case these findings led to the proposal that antioxidants could be useful for the treatment of FRDA Idebenone (a free-radical scavenger analogue of coenzyme Q10) may ameliorate andor to revert the cardiac hypertrophy in FRDA patients [126] This drug is currently being studied in clinical trials Although iron chelation by desferroxamine should decrease serum and cytoplasmic iron levels it may decrease aconitase activity which may be detrimental to the cellular function In addition whether chelation can alter mitochondrial iron levels without toxic side effects is unknown A recently developed mouse model of FRDA [113] raises a hope for providing a powerful means to explore many of these hypotheses and potential treatments

Other than the potential therapeutic effect of antioxidants on cardiomyopathy in FRDA the treatment remains supportive and symptomatic Physiotherapy and orthopedic management (prosthesis or surgery) are used either to preserve or to correct progressive deformations of the spine and feet It is important to provide appropriate management of cardiac functions glucose metabolism and secondary medical problems such as aspiration pneumonia

Early-onset cerebellar ataxia with retained reflexes

This disease was considered by Harding [128] to be a syndrome distinct from FRDA however genetic mapping of the early-onset cerebellar ataxia with retained reflexes (EOCARR) locus is necessary before it can be recognized as an independent genetic entity [127] Onset is before age 20 with a clinical picture similar to FRDA but with retained reflexes low incidence of sensory neuropathy less reduction of joint position sense and absence of skeletal abnormalities optic neuropathy cardiomyopathy or diabetes [127] Exclusion of FRDA by DNA testing is essential since some patients with the EOCARR phenotype have GAA expansions in the frataxin gene [127128] Moreover a branch of a recently described EOCARR family has the late onset form of FRDA while another branch has EOCARR phenotype [127] In EOCARR with very early onset differential diagnosis with ataxia telangiectasia mitochondrial disorders adrenoleukodystrophy and lysosomal storage diseases may be necessary

Ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency (AVED) is a rare treatable disorder with a phenotype that resembles FRDA In a patient with a clinical diagnosis of FRDA and a negative genetic result for FRDA serum vitamin E levels should be determined as patients with AVED have very low levels of vitamin E (lt5 gml) Age of onset is between childhood and young adulthood associated with slowly progressive gait and limb ataxia loss of deep tendon reflexes and vibratory and proprioceptive loss followed by progressive ophthalmoplegia dysarthria extensor plantar responses and muscle weakness The disorder is caused by a defect in the TTP1 gene [129] on chromosome 8q13 encoding the -tocopherol transfer protein [130] responsible for the transfer of -tocopherol to the circulating lipoproteins Early onset and severe forms of the disease are caused by truncating mutations or missense mutations in conserved amino acids [131] However DNA testing for the AVED mutations is not commercially available Early replacement therapy may prevent progression of the disease [132133]

Several diseases that lead to secondary vitamin E deficiency (ie by affecting the absorption andor transport of fat

[b] Mitochondrial diseases due to defective mitochondrial genes have maternal inheritance whereas mitochondrial diseases due to nuclear genes have ARAD

[c] Other clinical forms of PME (ie the neuronal ceroid lipofuscinoses Lafora disease type I sialidosis and MERRF) are associated with defects in various genes

[d] A causative second gene NPC2 has not been identified

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

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SUMMARY

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References

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[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

SCA8 presents with slowly progressive ataxia with marked cerebellar atrophy [71] The disease is variably associated with pyramidal and cognitive dysfunctions [72] SCA8 patients have an expansion of a CTG repeat on chromosome 13q21 to the pathogenic range of 100 to 152 repeats while normal individuals have 15 to 91 CTGs [73] Affected individuals usually inherit an expanded allele from their mothers SCA8 alleles show an instability bias toward expansion with maternal transmission whereas paternal transmissions mostly result in smaller alleles which appear to be due to contraction of the expanded alleles to the normal range (lt100 CTGs) in the sperm [717475] Variable penetrance has been identified in SCA8 pedigrees [7176] There has been no evidence of correlation between the repeat size and the age of onset Haplotype analyses showed multiple origins for the SCA8 expansions [72]

The SCA8 CTG repeat is preceded by a polymorphic but stable CTA tract with the configuration (CTA)1-21(CTG)n in the 3 untranslated region of the SCA8 gene Many SCA patients have expanded alleles with interruptions by cryptic repeats (CCG CTA CTC CCA or CTT) which may have newly arisen or changed from generation to generation [74] SCA8 contains no open reading frame but the most 5 exon is transcribed through the first exon of another gene KLHL1 which is transcribed in the opposite orientation This raises a possibility that the SCA8 transcript is an endogenous antisense RNA for KLHL1 KLHL1 encodes a cytoplasmic protein that may play a role in organizing the actin cytoskeleton of the brain cells Both SCA8 and KLHL1 are primarily expressed in specific brain tissues affected by SCA8 [77] Other gain-of-function mechanisms involving the mutant SCA8 transcript have not been investigated but by no means excluded

The major controversy in SCA8 stems from a lack of absolute specificity of the CTG repeat expansion for SCA8 which has raised a possibility that CTG expansions at the SCA8 locus represent a rare polymorphism rather than the disease-causing mutation [7879] Alleles greater than 100 CTG repeats at the SCA8 locus were also found in 12 (14 of 1120) of major psychosis patients and 07 (5 of 710) of normal control subjects who had no family history of ataxia [80]

SCA9 (vacant)

SCA10

The clinical phenotype of SCA10 is characterized by a combination of relatively pure cerebellar ataxia and epilepsy Ataxia is progressive and often leads to total disability Seizures are generalized motor seizures complex partial seizures or both Some patients show mild cognitive dysfunction sensory polyneuropathy andor soft corticospinal tract signs [81] Anticipation is conspicuous in some families but subtle or absent in others The disease has so far been confined to families of Mexican descent The SCA10 mutation is a very large expansion of the ATTCT pentanucleotide repeat located in intron 9 of the E46L (SCA10) gene on chromosome 22q13 [49] Normal alleles show 10 to 21 ATTCTs while affected individuals have 800ndash4500 repeats An inverse correlation exists between the size of the expanded allele and the age of onset The mechanism of the disease remains unknown

SCA11

SCA11 clinically defined as an ADCA-III has been mapped to chromosome 15q in a single British family [78]

SCA12

SCA12 is a rare ADCA characterized by adult onset ataxia upper body tremor hyperreflexia with bilateral extensor plantar responses paucity of movements and dementia [8283] The clinical picture includes oculomotor abnormalities (ie broken pursuit nystagmus slow saccades) The disease is slowly progressive and in the late stage psychiatric symptoms including depression anxiety or delusions may appear in some affected members Brain MRI shows cerebellar and cerebral cortical atrophy There is no evidence of anticipation The mutation of SCA12 is a CAG repeat expansion in the 5 untranslated region of the PPP2R2B gene on chromosome 5p31-p33 [84] Normal alleles have 17 to 28 CAG repeats while the pathologic alleles have 55 to 78 repeats The disease has been described in two kindreds one from US and the other from India [8587] It has been postulated that the expansion of the CAG repeat up-regulate PPP2R2B expression

SCA13

A French family presented with slowly progressive childhood-onset cerebellar gait ataxia dysarthria moderate mental retardation and mild motor developmental delays with in some cases nystagmus and pyramidal signs Brain MRI showed moderate cerebellar and pontine atrophy A genome wide search showed linkage to chromosome

19q133-q134 [86]

SCA14

A Japanese three-generation family with ADCA mapped to a locus on chromosome 19q134-qter [86] The family members with late onset (gt39 years old) exhibited pure cerebellar ataxia whereas those with an early onset (lt27 years old) showed intermittent axial myoclonus followed by ataxia Other neurological signs were sparse and neuroimaging studies revealed isolated cerebellar atrophy

SCA15 (vacant)

SCA16

This is a pure cerebellar ataxia with head tremor and thus a form of ADCA III [88] Although head tremor which is distinct from tittubation has been described in SCA2 SCA7 and SCA12 it is rare for all SCA types Age of onset ranges 20 to 66 years and anticipation was not apparent Brain MRI showed cerebellar atrophy without involving brainstem The SCA16 locus showed linkage to markers on chromosome 8q221-q241 [88]

SCA17

An expansion of CAG repeats of the TATA-binding protein (TBP) gene was initially reported in a Japanese patient with sporadic cerebellar ataxia and intellectual deterioration associated with de novo expansion The expanded allele consisted of impure CAG repeats encoding 63 glutamines and the de novo expansion involved partial duplication of the CAG repeat [89] In two German families four patients showed expanded CAG repeats in TBP gene coding for 50 to 55 polyglutamines while normal subjects had alleles ranging from 27 to 44 glutamines [90] Several additional Japanese families with phenotypes resembling Huntingtons disease or DRPLA also showed SCA17 CAG expansions [91]

Other SCAs

Anecdotally there are many ADCA families who are not linked to known genetic loci and who have no distinctive phenotype In one such French family SCAs 1 2 3 6 7 8 and 12 were excluded by mutation analysis and SCAs 4 5 10 11 13 14 by lod score less than 2 Affected members of this French family showed gait ataxia akinesia dysarthria hyporeflexia and anticipation [92] There are likely to be many similar families who have not yet been characterized or reported

DRPLA

DRPLA is a relatively frequent disease in Japan with an incidence of 02-07 per 100000 A few isolated families have been recognized worldwide [92] The DRPLA gene on the chromosome 12p was cloned in 1994 [9495] Early onset of the disease includes ataxia myoclonus epilepsy and progression to dementia later onset disease can present with cerebellar symptoms psychiatric symptoms seizures [9396] and choreoathetotic abnormal movements with a ldquoHuntington-likerdquo phenotype [97] Age of onset and severity correlate with the length of the CAG expansion The mutation in the DRPLA gene has also been found in the Haw River Syndrome which has some different clinical characteristics from DRPLA [98]

Episodic ataxia (EA)

In contrast to SCAs these rare diseases present with episodic ataxic attacks of variable frequency and duration with no symptoms between attacks Additional characteristic signs are associated with the different types of EA

EA type 1 (EA1)

EA1 is caused by mutations in a potassium channel gene KCNA1 on chromosome 12p [99] The onset is between childhood and adolescence Besides episodic ataxia clinical manifestations are myokymia around the eyes lips or fingers Brief attacks of ataxia and dysarthria lasting seconds are precipitated by exercise or startle

EA type 2 (EA2)

Clinical manifestations of EA2 consist of mild to severe intermittent cerebellar dysfunction associated with oculomotor abnormalities such as interictal nystagmus and diplopia and migraine Symptoms can be present for minutes to a few days Episodes are provoked by stress and exercise but not startle Like familial hemiplegic migraine (FHM) and spinocerebellar ataxia type 6 (SCA6) EA2 is associated with mutations in the gene encoding the -1A subunit of the calcium channel SCA6 is caused by a CAG repeat expansion [40] while point mutations in the CACNA1A gene cause EA2 and FHM [100] Missense mutations usually cause FHM and non-sense or splice site mutations cause EA2 [101] However this rule has many exceptions [102] and EA2 FHM and SCA6 may represent a clinical continuum of the distinct mutations in CACNA1A[103] Moreover an identical mutation can give various clinical expressions in a same family Paroxysmal symptoms could arise from reversible channel dysfunction while progressive neurodegeneration could reflect a toxic gain of function The latter appears to be a general phenomenon in polyglutamine diseases (see SCA 6) but it is not known how point mutations in CACNA1A are associated in some cases with neuronal degeneration [103] EA2 may respond to the treatment with acetazolamide [104105]

EA with paroxysmal choreoathetosis and spasticity

The onset of this disorder is at 2ndash15 years with ataxia dystonia and headaches [105] Episodes last for a few minutes with a daily to yearly frequency Spastic paraparesis can persist between the attacks Episodes are provoked by fatigue stress exercise and alcohol

AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET

Friedreichs ataxia

Friedreichs ataxia (FRDA) described in 1863 by Nicholaus Friedreich and characterized in detail by Harding [8] is the most frequent autosomal recessive ataxia It has an incidence in whites of 130000 [106] but has not been documented among Sub-Saharan Africans American Indians and peoples from China Japan and Southeast Asia [107108] FRDA is responsible for 30 to 40 percent of autosomal recessive ataxia among whites The disease is a progressive spinocerebellar degeneration with typical onset before the age of 25 years especially during childhood or puberty (7ndash14 y) [8] The degeneration of the posterior columns of the spinal cord afferent cerebellar pathways and selected nuclei of the cerebellum gives rise to an ataxic gait classically followed by dysarthria upper limb ataxia distal sensory loss decreased vibration and position sense and absence of reflexes Scoliosis and pes cavus also can develop The full picture of the disease often includes hypertrophic cardiomyopathy [109] impaired glucose tolerance or diabetes mellitus and occasionally hearing loss or optic atrophy [110] In early onset cases FRDA may need to be differentiated from adrenomyeloneuropathy by very long chain fatty acid (VLCFA) levels Refsums disease by serum phytanic acid levels and vitamin E deficiency by vitamin E levels In some cases dominant ataxias and Charcot-Marie-Tooth disease join in the differential diagnoses Neuropathological changes in FRDA include degeneration of the dorsal root ganglia Clarkes columns posterior columns corticospinalspinocerebellar tracts cerebellum pons and medulla [111] Nerve conduction studies show selective loss of sensory nerve action potentials

The FRDAX25 gene contains seven exons spanning 80 kb on chromosome 9q13 and encodes a 210 amino acid protein called frataxin [112129] Most FRDA patients have an expansion of the trinucleotide GAA in the first intron of the FRDAX25 gene [114] Normal alleles contain 6 to 28 GAA repeats while affected individuals have 60 to 1800 (Table 2) Point mutations in the FRDA gene (instead of the GAA expansion) are found in about two to four percent of the cases Compound heterozygous patients with one expanded GAA repeat allele and one point mutation are more likely to show variant clinical features such as optic atrophy or retained reflexes than patients carrying homozygous GAA expansions [115] Among patients with 2 alleles carrying expanded GAA repeats there is an inverse correlation between the size of the GAA expansion and the age of onset severity of the disease and the occurrence of cardiomyopathy and diabetes Patients with the ldquolate onsetrdquo (after 25 years old) variant (LOFA) and those with retained reflexes (FARR) are also caused by the FRDA gene mutation [5117] most commonly associated with modestly expanded alleles (ie lt400 repeats) [127] Genetic heterogeneity in FRDA has been proposed and a second locus (FRDA2) has recently been identified [118]

Table 2 Hereditary ataxia according to the age of onset

Age of onset Diagnostic clues pia Locusgene Diagnosis Early onset (connatal or childhood) Main Congenital Ataxia Syndromes

Jouberts syndrome abnormal eye movements AR Clinic Gillespies syndrome partial anyridia AR Clinic Behrs syndrome optic atrophy AR several Clinic Marinesco-Sjoumlgrens syndrome cataracts hypogonadism AR Clinic

Main Metabolic Ataxias Urea cycles disorders urinary organic acids AR several ClinicBiochemGenetAminoacidurias urinary amino acids AR several ClinicBiochemGenetDisorders of pyruvatelactate serum pyruvatelactate AR several ClinicBiochemGenet

Mitochondrial encephalomyopathies MELAS MERRF etc Mb several ClinicBiochemGenet

Peroxisomal disorders infantile Refsun syndrome AR several ClinicBiochemGenetDisorders of DNA repair

Ataxia telangiectasia skin sensitivity Icircplusmn-fetoprotein cancer AR 11q22-23ATM ClinicGenet

Xeroderma pigmentosum skin sensitivity cancer AR several ClinicGenet

Cockaynes syndrome skin sensitivity dysmorphology AR several ClinicGenet

Trichothiodystrophy skin sensitivity brittle hair AR several ClinicGenet

Intermediate onset (childhood or juvenile)

Friedreichs ataxia - FRDA sensorimotor loss cardiac skeletal AR 9q13frataxin ClinicGenet

Early onset ataxia with retained reflexes - EOARR

early onset retained reflexes AR several ClinicGenet

Isolated vitamin E deficiency - AVED

low serum levels of vitamin E AR 8q13TTP1 ClinicBiochemGenet

Spastic ataxia of Charlevoix-Saguenay - SACS

hypermyelation retinal-nerve fibers AR 13q11sacsin ClinicGenet

Recessive ataxia with ocular motor apraxia -AOA

ocular apraxia neuropathy AR 9q13HITZn-finger ClinicGenet

Progressive myoclonus ataxia - PMA

myoclonus ataxia seizures AR Clinic

Progressive myoclonus epilepsy - PMEc

Unverricht-Lundborg syndrome ARc 21q223cystatin B ClinicGenet

Abetalipoproteinemia abetalipoproteinemia AR 4q22-24MTP ClinicBiochemGenetHypobetalipoproteinemia hypobetalipoproteinemia AD 2p24 3p22 ClinicBiochem Niemman-Pick disease type C sphingomyelin lipidosis AR

18q11NPC1 (95)d ClinicBiochemGenet

Krabbes disease galactosylceramide lipidosis AR galactocerebrosidase ClinicBiochemGenet

Hexosaminidase deficiencies hexosaminidase deficit AR hexA and hexAB ClinicBiochemGenet

Late Onset (juvenile or adult) Autosomal dominant cerebellar ataxia - ADCA SCAs AD Several (see Table

1) ClinicGenet

Episodic ataxia EA-1 EA-2 and EPCA AD channelopaties ClinicGenet Von Hippel-Lindau syndrome

cerebellar hemangioblastomas AD 3p25VHL ClinicGenet

Cerebellar ataxia with hypogonadism hypogonadism ataxia AR Clinic

Mitochondrial multisystemic several ClinicBiochemGenet

[a] pattern of inheritance (ie AR autosomal recessive)

A fascinating concurrence of yeast and human genetics [119ndash124] led to the proposal that frataxin is involved in the homeostasis (probably the transport) of mitochondrial iron Accumulation of iron inside the mitochondria of FRDA cells could lead to increased oxidative stress by free radical production from hydrogen peroxide and hypersensitivity to the oxidative stress due to mitochondrial dysfunction Deficiencies found in mitochondrialcytoplasmic aconitase as well as in the respiratory chain complexes I II and III in FRDA patients [123125] are consistent with this hypothesis Moreover primary vitamin E deficiency (see later) a specific disease associated with a defect in a physiological free radical scavenger clinically resembles FRDA Interestingly all of the enzymes with defective activity in FRDA mitochondria have iron-sulfur (Fe-S) clusters at the active sites These moieties are highly sensitive to free radical damage An alternative or complementary hypothesis is that a primary activity of frataxin is related to the synthesis of the Fe-S cluster [112] In any case these findings led to the proposal that antioxidants could be useful for the treatment of FRDA Idebenone (a free-radical scavenger analogue of coenzyme Q10) may ameliorate andor to revert the cardiac hypertrophy in FRDA patients [126] This drug is currently being studied in clinical trials Although iron chelation by desferroxamine should decrease serum and cytoplasmic iron levels it may decrease aconitase activity which may be detrimental to the cellular function In addition whether chelation can alter mitochondrial iron levels without toxic side effects is unknown A recently developed mouse model of FRDA [113] raises a hope for providing a powerful means to explore many of these hypotheses and potential treatments

Other than the potential therapeutic effect of antioxidants on cardiomyopathy in FRDA the treatment remains supportive and symptomatic Physiotherapy and orthopedic management (prosthesis or surgery) are used either to preserve or to correct progressive deformations of the spine and feet It is important to provide appropriate management of cardiac functions glucose metabolism and secondary medical problems such as aspiration pneumonia

Early-onset cerebellar ataxia with retained reflexes

This disease was considered by Harding [128] to be a syndrome distinct from FRDA however genetic mapping of the early-onset cerebellar ataxia with retained reflexes (EOCARR) locus is necessary before it can be recognized as an independent genetic entity [127] Onset is before age 20 with a clinical picture similar to FRDA but with retained reflexes low incidence of sensory neuropathy less reduction of joint position sense and absence of skeletal abnormalities optic neuropathy cardiomyopathy or diabetes [127] Exclusion of FRDA by DNA testing is essential since some patients with the EOCARR phenotype have GAA expansions in the frataxin gene [127128] Moreover a branch of a recently described EOCARR family has the late onset form of FRDA while another branch has EOCARR phenotype [127] In EOCARR with very early onset differential diagnosis with ataxia telangiectasia mitochondrial disorders adrenoleukodystrophy and lysosomal storage diseases may be necessary

Ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency (AVED) is a rare treatable disorder with a phenotype that resembles FRDA In a patient with a clinical diagnosis of FRDA and a negative genetic result for FRDA serum vitamin E levels should be determined as patients with AVED have very low levels of vitamin E (lt5 gml) Age of onset is between childhood and young adulthood associated with slowly progressive gait and limb ataxia loss of deep tendon reflexes and vibratory and proprioceptive loss followed by progressive ophthalmoplegia dysarthria extensor plantar responses and muscle weakness The disorder is caused by a defect in the TTP1 gene [129] on chromosome 8q13 encoding the -tocopherol transfer protein [130] responsible for the transfer of -tocopherol to the circulating lipoproteins Early onset and severe forms of the disease are caused by truncating mutations or missense mutations in conserved amino acids [131] However DNA testing for the AVED mutations is not commercially available Early replacement therapy may prevent progression of the disease [132133]

Several diseases that lead to secondary vitamin E deficiency (ie by affecting the absorption andor transport of fat

[b] Mitochondrial diseases due to defective mitochondrial genes have maternal inheritance whereas mitochondrial diseases due to nuclear genes have ARAD

[c] Other clinical forms of PME (ie the neuronal ceroid lipofuscinoses Lafora disease type I sialidosis and MERRF) are associated with defects in various genes

[d] A causative second gene NPC2 has not been identified

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

19q133-q134 [86]

SCA14

A Japanese three-generation family with ADCA mapped to a locus on chromosome 19q134-qter [86] The family members with late onset (gt39 years old) exhibited pure cerebellar ataxia whereas those with an early onset (lt27 years old) showed intermittent axial myoclonus followed by ataxia Other neurological signs were sparse and neuroimaging studies revealed isolated cerebellar atrophy

SCA15 (vacant)

SCA16

This is a pure cerebellar ataxia with head tremor and thus a form of ADCA III [88] Although head tremor which is distinct from tittubation has been described in SCA2 SCA7 and SCA12 it is rare for all SCA types Age of onset ranges 20 to 66 years and anticipation was not apparent Brain MRI showed cerebellar atrophy without involving brainstem The SCA16 locus showed linkage to markers on chromosome 8q221-q241 [88]

SCA17

An expansion of CAG repeats of the TATA-binding protein (TBP) gene was initially reported in a Japanese patient with sporadic cerebellar ataxia and intellectual deterioration associated with de novo expansion The expanded allele consisted of impure CAG repeats encoding 63 glutamines and the de novo expansion involved partial duplication of the CAG repeat [89] In two German families four patients showed expanded CAG repeats in TBP gene coding for 50 to 55 polyglutamines while normal subjects had alleles ranging from 27 to 44 glutamines [90] Several additional Japanese families with phenotypes resembling Huntingtons disease or DRPLA also showed SCA17 CAG expansions [91]

Other SCAs

Anecdotally there are many ADCA families who are not linked to known genetic loci and who have no distinctive phenotype In one such French family SCAs 1 2 3 6 7 8 and 12 were excluded by mutation analysis and SCAs 4 5 10 11 13 14 by lod score less than 2 Affected members of this French family showed gait ataxia akinesia dysarthria hyporeflexia and anticipation [92] There are likely to be many similar families who have not yet been characterized or reported

DRPLA

DRPLA is a relatively frequent disease in Japan with an incidence of 02-07 per 100000 A few isolated families have been recognized worldwide [92] The DRPLA gene on the chromosome 12p was cloned in 1994 [9495] Early onset of the disease includes ataxia myoclonus epilepsy and progression to dementia later onset disease can present with cerebellar symptoms psychiatric symptoms seizures [9396] and choreoathetotic abnormal movements with a ldquoHuntington-likerdquo phenotype [97] Age of onset and severity correlate with the length of the CAG expansion The mutation in the DRPLA gene has also been found in the Haw River Syndrome which has some different clinical characteristics from DRPLA [98]

Episodic ataxia (EA)

In contrast to SCAs these rare diseases present with episodic ataxic attacks of variable frequency and duration with no symptoms between attacks Additional characteristic signs are associated with the different types of EA

EA type 1 (EA1)

EA1 is caused by mutations in a potassium channel gene KCNA1 on chromosome 12p [99] The onset is between childhood and adolescence Besides episodic ataxia clinical manifestations are myokymia around the eyes lips or fingers Brief attacks of ataxia and dysarthria lasting seconds are precipitated by exercise or startle

EA type 2 (EA2)

Clinical manifestations of EA2 consist of mild to severe intermittent cerebellar dysfunction associated with oculomotor abnormalities such as interictal nystagmus and diplopia and migraine Symptoms can be present for minutes to a few days Episodes are provoked by stress and exercise but not startle Like familial hemiplegic migraine (FHM) and spinocerebellar ataxia type 6 (SCA6) EA2 is associated with mutations in the gene encoding the -1A subunit of the calcium channel SCA6 is caused by a CAG repeat expansion [40] while point mutations in the CACNA1A gene cause EA2 and FHM [100] Missense mutations usually cause FHM and non-sense or splice site mutations cause EA2 [101] However this rule has many exceptions [102] and EA2 FHM and SCA6 may represent a clinical continuum of the distinct mutations in CACNA1A[103] Moreover an identical mutation can give various clinical expressions in a same family Paroxysmal symptoms could arise from reversible channel dysfunction while progressive neurodegeneration could reflect a toxic gain of function The latter appears to be a general phenomenon in polyglutamine diseases (see SCA 6) but it is not known how point mutations in CACNA1A are associated in some cases with neuronal degeneration [103] EA2 may respond to the treatment with acetazolamide [104105]

EA with paroxysmal choreoathetosis and spasticity

The onset of this disorder is at 2ndash15 years with ataxia dystonia and headaches [105] Episodes last for a few minutes with a daily to yearly frequency Spastic paraparesis can persist between the attacks Episodes are provoked by fatigue stress exercise and alcohol

AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET

Friedreichs ataxia

Friedreichs ataxia (FRDA) described in 1863 by Nicholaus Friedreich and characterized in detail by Harding [8] is the most frequent autosomal recessive ataxia It has an incidence in whites of 130000 [106] but has not been documented among Sub-Saharan Africans American Indians and peoples from China Japan and Southeast Asia [107108] FRDA is responsible for 30 to 40 percent of autosomal recessive ataxia among whites The disease is a progressive spinocerebellar degeneration with typical onset before the age of 25 years especially during childhood or puberty (7ndash14 y) [8] The degeneration of the posterior columns of the spinal cord afferent cerebellar pathways and selected nuclei of the cerebellum gives rise to an ataxic gait classically followed by dysarthria upper limb ataxia distal sensory loss decreased vibration and position sense and absence of reflexes Scoliosis and pes cavus also can develop The full picture of the disease often includes hypertrophic cardiomyopathy [109] impaired glucose tolerance or diabetes mellitus and occasionally hearing loss or optic atrophy [110] In early onset cases FRDA may need to be differentiated from adrenomyeloneuropathy by very long chain fatty acid (VLCFA) levels Refsums disease by serum phytanic acid levels and vitamin E deficiency by vitamin E levels In some cases dominant ataxias and Charcot-Marie-Tooth disease join in the differential diagnoses Neuropathological changes in FRDA include degeneration of the dorsal root ganglia Clarkes columns posterior columns corticospinalspinocerebellar tracts cerebellum pons and medulla [111] Nerve conduction studies show selective loss of sensory nerve action potentials

The FRDAX25 gene contains seven exons spanning 80 kb on chromosome 9q13 and encodes a 210 amino acid protein called frataxin [112129] Most FRDA patients have an expansion of the trinucleotide GAA in the first intron of the FRDAX25 gene [114] Normal alleles contain 6 to 28 GAA repeats while affected individuals have 60 to 1800 (Table 2) Point mutations in the FRDA gene (instead of the GAA expansion) are found in about two to four percent of the cases Compound heterozygous patients with one expanded GAA repeat allele and one point mutation are more likely to show variant clinical features such as optic atrophy or retained reflexes than patients carrying homozygous GAA expansions [115] Among patients with 2 alleles carrying expanded GAA repeats there is an inverse correlation between the size of the GAA expansion and the age of onset severity of the disease and the occurrence of cardiomyopathy and diabetes Patients with the ldquolate onsetrdquo (after 25 years old) variant (LOFA) and those with retained reflexes (FARR) are also caused by the FRDA gene mutation [5117] most commonly associated with modestly expanded alleles (ie lt400 repeats) [127] Genetic heterogeneity in FRDA has been proposed and a second locus (FRDA2) has recently been identified [118]

Table 2 Hereditary ataxia according to the age of onset

Age of onset Diagnostic clues pia Locusgene Diagnosis Early onset (connatal or childhood) Main Congenital Ataxia Syndromes

Jouberts syndrome abnormal eye movements AR Clinic Gillespies syndrome partial anyridia AR Clinic Behrs syndrome optic atrophy AR several Clinic Marinesco-Sjoumlgrens syndrome cataracts hypogonadism AR Clinic

Main Metabolic Ataxias Urea cycles disorders urinary organic acids AR several ClinicBiochemGenetAminoacidurias urinary amino acids AR several ClinicBiochemGenetDisorders of pyruvatelactate serum pyruvatelactate AR several ClinicBiochemGenet

Mitochondrial encephalomyopathies MELAS MERRF etc Mb several ClinicBiochemGenet

Peroxisomal disorders infantile Refsun syndrome AR several ClinicBiochemGenetDisorders of DNA repair

Ataxia telangiectasia skin sensitivity Icircplusmn-fetoprotein cancer AR 11q22-23ATM ClinicGenet

Xeroderma pigmentosum skin sensitivity cancer AR several ClinicGenet

Cockaynes syndrome skin sensitivity dysmorphology AR several ClinicGenet

Trichothiodystrophy skin sensitivity brittle hair AR several ClinicGenet

Intermediate onset (childhood or juvenile)

Friedreichs ataxia - FRDA sensorimotor loss cardiac skeletal AR 9q13frataxin ClinicGenet

Early onset ataxia with retained reflexes - EOARR

early onset retained reflexes AR several ClinicGenet

Isolated vitamin E deficiency - AVED

low serum levels of vitamin E AR 8q13TTP1 ClinicBiochemGenet

Spastic ataxia of Charlevoix-Saguenay - SACS

hypermyelation retinal-nerve fibers AR 13q11sacsin ClinicGenet

Recessive ataxia with ocular motor apraxia -AOA

ocular apraxia neuropathy AR 9q13HITZn-finger ClinicGenet

Progressive myoclonus ataxia - PMA

myoclonus ataxia seizures AR Clinic

Progressive myoclonus epilepsy - PMEc

Unverricht-Lundborg syndrome ARc 21q223cystatin B ClinicGenet

Abetalipoproteinemia abetalipoproteinemia AR 4q22-24MTP ClinicBiochemGenetHypobetalipoproteinemia hypobetalipoproteinemia AD 2p24 3p22 ClinicBiochem Niemman-Pick disease type C sphingomyelin lipidosis AR

18q11NPC1 (95)d ClinicBiochemGenet

Krabbes disease galactosylceramide lipidosis AR galactocerebrosidase ClinicBiochemGenet

Hexosaminidase deficiencies hexosaminidase deficit AR hexA and hexAB ClinicBiochemGenet

Late Onset (juvenile or adult) Autosomal dominant cerebellar ataxia - ADCA SCAs AD Several (see Table

1) ClinicGenet

Episodic ataxia EA-1 EA-2 and EPCA AD channelopaties ClinicGenet Von Hippel-Lindau syndrome

cerebellar hemangioblastomas AD 3p25VHL ClinicGenet

Cerebellar ataxia with hypogonadism hypogonadism ataxia AR Clinic

Mitochondrial multisystemic several ClinicBiochemGenet

[a] pattern of inheritance (ie AR autosomal recessive)

A fascinating concurrence of yeast and human genetics [119ndash124] led to the proposal that frataxin is involved in the homeostasis (probably the transport) of mitochondrial iron Accumulation of iron inside the mitochondria of FRDA cells could lead to increased oxidative stress by free radical production from hydrogen peroxide and hypersensitivity to the oxidative stress due to mitochondrial dysfunction Deficiencies found in mitochondrialcytoplasmic aconitase as well as in the respiratory chain complexes I II and III in FRDA patients [123125] are consistent with this hypothesis Moreover primary vitamin E deficiency (see later) a specific disease associated with a defect in a physiological free radical scavenger clinically resembles FRDA Interestingly all of the enzymes with defective activity in FRDA mitochondria have iron-sulfur (Fe-S) clusters at the active sites These moieties are highly sensitive to free radical damage An alternative or complementary hypothesis is that a primary activity of frataxin is related to the synthesis of the Fe-S cluster [112] In any case these findings led to the proposal that antioxidants could be useful for the treatment of FRDA Idebenone (a free-radical scavenger analogue of coenzyme Q10) may ameliorate andor to revert the cardiac hypertrophy in FRDA patients [126] This drug is currently being studied in clinical trials Although iron chelation by desferroxamine should decrease serum and cytoplasmic iron levels it may decrease aconitase activity which may be detrimental to the cellular function In addition whether chelation can alter mitochondrial iron levels without toxic side effects is unknown A recently developed mouse model of FRDA [113] raises a hope for providing a powerful means to explore many of these hypotheses and potential treatments

Other than the potential therapeutic effect of antioxidants on cardiomyopathy in FRDA the treatment remains supportive and symptomatic Physiotherapy and orthopedic management (prosthesis or surgery) are used either to preserve or to correct progressive deformations of the spine and feet It is important to provide appropriate management of cardiac functions glucose metabolism and secondary medical problems such as aspiration pneumonia

Early-onset cerebellar ataxia with retained reflexes

This disease was considered by Harding [128] to be a syndrome distinct from FRDA however genetic mapping of the early-onset cerebellar ataxia with retained reflexes (EOCARR) locus is necessary before it can be recognized as an independent genetic entity [127] Onset is before age 20 with a clinical picture similar to FRDA but with retained reflexes low incidence of sensory neuropathy less reduction of joint position sense and absence of skeletal abnormalities optic neuropathy cardiomyopathy or diabetes [127] Exclusion of FRDA by DNA testing is essential since some patients with the EOCARR phenotype have GAA expansions in the frataxin gene [127128] Moreover a branch of a recently described EOCARR family has the late onset form of FRDA while another branch has EOCARR phenotype [127] In EOCARR with very early onset differential diagnosis with ataxia telangiectasia mitochondrial disorders adrenoleukodystrophy and lysosomal storage diseases may be necessary

Ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency (AVED) is a rare treatable disorder with a phenotype that resembles FRDA In a patient with a clinical diagnosis of FRDA and a negative genetic result for FRDA serum vitamin E levels should be determined as patients with AVED have very low levels of vitamin E (lt5 gml) Age of onset is between childhood and young adulthood associated with slowly progressive gait and limb ataxia loss of deep tendon reflexes and vibratory and proprioceptive loss followed by progressive ophthalmoplegia dysarthria extensor plantar responses and muscle weakness The disorder is caused by a defect in the TTP1 gene [129] on chromosome 8q13 encoding the -tocopherol transfer protein [130] responsible for the transfer of -tocopherol to the circulating lipoproteins Early onset and severe forms of the disease are caused by truncating mutations or missense mutations in conserved amino acids [131] However DNA testing for the AVED mutations is not commercially available Early replacement therapy may prevent progression of the disease [132133]

Several diseases that lead to secondary vitamin E deficiency (ie by affecting the absorption andor transport of fat

[b] Mitochondrial diseases due to defective mitochondrial genes have maternal inheritance whereas mitochondrial diseases due to nuclear genes have ARAD

[c] Other clinical forms of PME (ie the neuronal ceroid lipofuscinoses Lafora disease type I sialidosis and MERRF) are associated with defects in various genes

[d] A causative second gene NPC2 has not been identified

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

Clinical manifestations of EA2 consist of mild to severe intermittent cerebellar dysfunction associated with oculomotor abnormalities such as interictal nystagmus and diplopia and migraine Symptoms can be present for minutes to a few days Episodes are provoked by stress and exercise but not startle Like familial hemiplegic migraine (FHM) and spinocerebellar ataxia type 6 (SCA6) EA2 is associated with mutations in the gene encoding the -1A subunit of the calcium channel SCA6 is caused by a CAG repeat expansion [40] while point mutations in the CACNA1A gene cause EA2 and FHM [100] Missense mutations usually cause FHM and non-sense or splice site mutations cause EA2 [101] However this rule has many exceptions [102] and EA2 FHM and SCA6 may represent a clinical continuum of the distinct mutations in CACNA1A[103] Moreover an identical mutation can give various clinical expressions in a same family Paroxysmal symptoms could arise from reversible channel dysfunction while progressive neurodegeneration could reflect a toxic gain of function The latter appears to be a general phenomenon in polyglutamine diseases (see SCA 6) but it is not known how point mutations in CACNA1A are associated in some cases with neuronal degeneration [103] EA2 may respond to the treatment with acetazolamide [104105]

EA with paroxysmal choreoathetosis and spasticity

The onset of this disorder is at 2ndash15 years with ataxia dystonia and headaches [105] Episodes last for a few minutes with a daily to yearly frequency Spastic paraparesis can persist between the attacks Episodes are provoked by fatigue stress exercise and alcohol

AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET

Friedreichs ataxia

Friedreichs ataxia (FRDA) described in 1863 by Nicholaus Friedreich and characterized in detail by Harding [8] is the most frequent autosomal recessive ataxia It has an incidence in whites of 130000 [106] but has not been documented among Sub-Saharan Africans American Indians and peoples from China Japan and Southeast Asia [107108] FRDA is responsible for 30 to 40 percent of autosomal recessive ataxia among whites The disease is a progressive spinocerebellar degeneration with typical onset before the age of 25 years especially during childhood or puberty (7ndash14 y) [8] The degeneration of the posterior columns of the spinal cord afferent cerebellar pathways and selected nuclei of the cerebellum gives rise to an ataxic gait classically followed by dysarthria upper limb ataxia distal sensory loss decreased vibration and position sense and absence of reflexes Scoliosis and pes cavus also can develop The full picture of the disease often includes hypertrophic cardiomyopathy [109] impaired glucose tolerance or diabetes mellitus and occasionally hearing loss or optic atrophy [110] In early onset cases FRDA may need to be differentiated from adrenomyeloneuropathy by very long chain fatty acid (VLCFA) levels Refsums disease by serum phytanic acid levels and vitamin E deficiency by vitamin E levels In some cases dominant ataxias and Charcot-Marie-Tooth disease join in the differential diagnoses Neuropathological changes in FRDA include degeneration of the dorsal root ganglia Clarkes columns posterior columns corticospinalspinocerebellar tracts cerebellum pons and medulla [111] Nerve conduction studies show selective loss of sensory nerve action potentials

The FRDAX25 gene contains seven exons spanning 80 kb on chromosome 9q13 and encodes a 210 amino acid protein called frataxin [112129] Most FRDA patients have an expansion of the trinucleotide GAA in the first intron of the FRDAX25 gene [114] Normal alleles contain 6 to 28 GAA repeats while affected individuals have 60 to 1800 (Table 2) Point mutations in the FRDA gene (instead of the GAA expansion) are found in about two to four percent of the cases Compound heterozygous patients with one expanded GAA repeat allele and one point mutation are more likely to show variant clinical features such as optic atrophy or retained reflexes than patients carrying homozygous GAA expansions [115] Among patients with 2 alleles carrying expanded GAA repeats there is an inverse correlation between the size of the GAA expansion and the age of onset severity of the disease and the occurrence of cardiomyopathy and diabetes Patients with the ldquolate onsetrdquo (after 25 years old) variant (LOFA) and those with retained reflexes (FARR) are also caused by the FRDA gene mutation [5117] most commonly associated with modestly expanded alleles (ie lt400 repeats) [127] Genetic heterogeneity in FRDA has been proposed and a second locus (FRDA2) has recently been identified [118]

Table 2 Hereditary ataxia according to the age of onset

Age of onset Diagnostic clues pia Locusgene Diagnosis Early onset (connatal or childhood) Main Congenital Ataxia Syndromes

Jouberts syndrome abnormal eye movements AR Clinic Gillespies syndrome partial anyridia AR Clinic Behrs syndrome optic atrophy AR several Clinic Marinesco-Sjoumlgrens syndrome cataracts hypogonadism AR Clinic

Main Metabolic Ataxias Urea cycles disorders urinary organic acids AR several ClinicBiochemGenetAminoacidurias urinary amino acids AR several ClinicBiochemGenetDisorders of pyruvatelactate serum pyruvatelactate AR several ClinicBiochemGenet

Mitochondrial encephalomyopathies MELAS MERRF etc Mb several ClinicBiochemGenet

Peroxisomal disorders infantile Refsun syndrome AR several ClinicBiochemGenetDisorders of DNA repair

Ataxia telangiectasia skin sensitivity Icircplusmn-fetoprotein cancer AR 11q22-23ATM ClinicGenet

Xeroderma pigmentosum skin sensitivity cancer AR several ClinicGenet

Cockaynes syndrome skin sensitivity dysmorphology AR several ClinicGenet

Trichothiodystrophy skin sensitivity brittle hair AR several ClinicGenet

Intermediate onset (childhood or juvenile)

Friedreichs ataxia - FRDA sensorimotor loss cardiac skeletal AR 9q13frataxin ClinicGenet

Early onset ataxia with retained reflexes - EOARR

early onset retained reflexes AR several ClinicGenet

Isolated vitamin E deficiency - AVED

low serum levels of vitamin E AR 8q13TTP1 ClinicBiochemGenet

Spastic ataxia of Charlevoix-Saguenay - SACS

hypermyelation retinal-nerve fibers AR 13q11sacsin ClinicGenet

Recessive ataxia with ocular motor apraxia -AOA

ocular apraxia neuropathy AR 9q13HITZn-finger ClinicGenet

Progressive myoclonus ataxia - PMA

myoclonus ataxia seizures AR Clinic

Progressive myoclonus epilepsy - PMEc

Unverricht-Lundborg syndrome ARc 21q223cystatin B ClinicGenet

Abetalipoproteinemia abetalipoproteinemia AR 4q22-24MTP ClinicBiochemGenetHypobetalipoproteinemia hypobetalipoproteinemia AD 2p24 3p22 ClinicBiochem Niemman-Pick disease type C sphingomyelin lipidosis AR

18q11NPC1 (95)d ClinicBiochemGenet

Krabbes disease galactosylceramide lipidosis AR galactocerebrosidase ClinicBiochemGenet

Hexosaminidase deficiencies hexosaminidase deficit AR hexA and hexAB ClinicBiochemGenet

Late Onset (juvenile or adult) Autosomal dominant cerebellar ataxia - ADCA SCAs AD Several (see Table

1) ClinicGenet

Episodic ataxia EA-1 EA-2 and EPCA AD channelopaties ClinicGenet Von Hippel-Lindau syndrome

cerebellar hemangioblastomas AD 3p25VHL ClinicGenet

Cerebellar ataxia with hypogonadism hypogonadism ataxia AR Clinic

Mitochondrial multisystemic several ClinicBiochemGenet

[a] pattern of inheritance (ie AR autosomal recessive)

A fascinating concurrence of yeast and human genetics [119ndash124] led to the proposal that frataxin is involved in the homeostasis (probably the transport) of mitochondrial iron Accumulation of iron inside the mitochondria of FRDA cells could lead to increased oxidative stress by free radical production from hydrogen peroxide and hypersensitivity to the oxidative stress due to mitochondrial dysfunction Deficiencies found in mitochondrialcytoplasmic aconitase as well as in the respiratory chain complexes I II and III in FRDA patients [123125] are consistent with this hypothesis Moreover primary vitamin E deficiency (see later) a specific disease associated with a defect in a physiological free radical scavenger clinically resembles FRDA Interestingly all of the enzymes with defective activity in FRDA mitochondria have iron-sulfur (Fe-S) clusters at the active sites These moieties are highly sensitive to free radical damage An alternative or complementary hypothesis is that a primary activity of frataxin is related to the synthesis of the Fe-S cluster [112] In any case these findings led to the proposal that antioxidants could be useful for the treatment of FRDA Idebenone (a free-radical scavenger analogue of coenzyme Q10) may ameliorate andor to revert the cardiac hypertrophy in FRDA patients [126] This drug is currently being studied in clinical trials Although iron chelation by desferroxamine should decrease serum and cytoplasmic iron levels it may decrease aconitase activity which may be detrimental to the cellular function In addition whether chelation can alter mitochondrial iron levels without toxic side effects is unknown A recently developed mouse model of FRDA [113] raises a hope for providing a powerful means to explore many of these hypotheses and potential treatments

Other than the potential therapeutic effect of antioxidants on cardiomyopathy in FRDA the treatment remains supportive and symptomatic Physiotherapy and orthopedic management (prosthesis or surgery) are used either to preserve or to correct progressive deformations of the spine and feet It is important to provide appropriate management of cardiac functions glucose metabolism and secondary medical problems such as aspiration pneumonia

Early-onset cerebellar ataxia with retained reflexes

This disease was considered by Harding [128] to be a syndrome distinct from FRDA however genetic mapping of the early-onset cerebellar ataxia with retained reflexes (EOCARR) locus is necessary before it can be recognized as an independent genetic entity [127] Onset is before age 20 with a clinical picture similar to FRDA but with retained reflexes low incidence of sensory neuropathy less reduction of joint position sense and absence of skeletal abnormalities optic neuropathy cardiomyopathy or diabetes [127] Exclusion of FRDA by DNA testing is essential since some patients with the EOCARR phenotype have GAA expansions in the frataxin gene [127128] Moreover a branch of a recently described EOCARR family has the late onset form of FRDA while another branch has EOCARR phenotype [127] In EOCARR with very early onset differential diagnosis with ataxia telangiectasia mitochondrial disorders adrenoleukodystrophy and lysosomal storage diseases may be necessary

Ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency (AVED) is a rare treatable disorder with a phenotype that resembles FRDA In a patient with a clinical diagnosis of FRDA and a negative genetic result for FRDA serum vitamin E levels should be determined as patients with AVED have very low levels of vitamin E (lt5 gml) Age of onset is between childhood and young adulthood associated with slowly progressive gait and limb ataxia loss of deep tendon reflexes and vibratory and proprioceptive loss followed by progressive ophthalmoplegia dysarthria extensor plantar responses and muscle weakness The disorder is caused by a defect in the TTP1 gene [129] on chromosome 8q13 encoding the -tocopherol transfer protein [130] responsible for the transfer of -tocopherol to the circulating lipoproteins Early onset and severe forms of the disease are caused by truncating mutations or missense mutations in conserved amino acids [131] However DNA testing for the AVED mutations is not commercially available Early replacement therapy may prevent progression of the disease [132133]

Several diseases that lead to secondary vitamin E deficiency (ie by affecting the absorption andor transport of fat

[b] Mitochondrial diseases due to defective mitochondrial genes have maternal inheritance whereas mitochondrial diseases due to nuclear genes have ARAD

[c] Other clinical forms of PME (ie the neuronal ceroid lipofuscinoses Lafora disease type I sialidosis and MERRF) are associated with defects in various genes

[d] A causative second gene NPC2 has not been identified

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

Jouberts syndrome abnormal eye movements AR Clinic Gillespies syndrome partial anyridia AR Clinic Behrs syndrome optic atrophy AR several Clinic Marinesco-Sjoumlgrens syndrome cataracts hypogonadism AR Clinic

Main Metabolic Ataxias Urea cycles disorders urinary organic acids AR several ClinicBiochemGenetAminoacidurias urinary amino acids AR several ClinicBiochemGenetDisorders of pyruvatelactate serum pyruvatelactate AR several ClinicBiochemGenet

Mitochondrial encephalomyopathies MELAS MERRF etc Mb several ClinicBiochemGenet

Peroxisomal disorders infantile Refsun syndrome AR several ClinicBiochemGenetDisorders of DNA repair

Ataxia telangiectasia skin sensitivity Icircplusmn-fetoprotein cancer AR 11q22-23ATM ClinicGenet

Xeroderma pigmentosum skin sensitivity cancer AR several ClinicGenet

Cockaynes syndrome skin sensitivity dysmorphology AR several ClinicGenet

Trichothiodystrophy skin sensitivity brittle hair AR several ClinicGenet

Intermediate onset (childhood or juvenile)

Friedreichs ataxia - FRDA sensorimotor loss cardiac skeletal AR 9q13frataxin ClinicGenet

Early onset ataxia with retained reflexes - EOARR

early onset retained reflexes AR several ClinicGenet

Isolated vitamin E deficiency - AVED

low serum levels of vitamin E AR 8q13TTP1 ClinicBiochemGenet

Spastic ataxia of Charlevoix-Saguenay - SACS

hypermyelation retinal-nerve fibers AR 13q11sacsin ClinicGenet

Recessive ataxia with ocular motor apraxia -AOA

ocular apraxia neuropathy AR 9q13HITZn-finger ClinicGenet

Progressive myoclonus ataxia - PMA

myoclonus ataxia seizures AR Clinic

Progressive myoclonus epilepsy - PMEc

Unverricht-Lundborg syndrome ARc 21q223cystatin B ClinicGenet

Abetalipoproteinemia abetalipoproteinemia AR 4q22-24MTP ClinicBiochemGenetHypobetalipoproteinemia hypobetalipoproteinemia AD 2p24 3p22 ClinicBiochem Niemman-Pick disease type C sphingomyelin lipidosis AR

18q11NPC1 (95)d ClinicBiochemGenet

Krabbes disease galactosylceramide lipidosis AR galactocerebrosidase ClinicBiochemGenet

Hexosaminidase deficiencies hexosaminidase deficit AR hexA and hexAB ClinicBiochemGenet

Late Onset (juvenile or adult) Autosomal dominant cerebellar ataxia - ADCA SCAs AD Several (see Table

1) ClinicGenet

Episodic ataxia EA-1 EA-2 and EPCA AD channelopaties ClinicGenet Von Hippel-Lindau syndrome

cerebellar hemangioblastomas AD 3p25VHL ClinicGenet

Cerebellar ataxia with hypogonadism hypogonadism ataxia AR Clinic

Mitochondrial multisystemic several ClinicBiochemGenet

[a] pattern of inheritance (ie AR autosomal recessive)

A fascinating concurrence of yeast and human genetics [119ndash124] led to the proposal that frataxin is involved in the homeostasis (probably the transport) of mitochondrial iron Accumulation of iron inside the mitochondria of FRDA cells could lead to increased oxidative stress by free radical production from hydrogen peroxide and hypersensitivity to the oxidative stress due to mitochondrial dysfunction Deficiencies found in mitochondrialcytoplasmic aconitase as well as in the respiratory chain complexes I II and III in FRDA patients [123125] are consistent with this hypothesis Moreover primary vitamin E deficiency (see later) a specific disease associated with a defect in a physiological free radical scavenger clinically resembles FRDA Interestingly all of the enzymes with defective activity in FRDA mitochondria have iron-sulfur (Fe-S) clusters at the active sites These moieties are highly sensitive to free radical damage An alternative or complementary hypothesis is that a primary activity of frataxin is related to the synthesis of the Fe-S cluster [112] In any case these findings led to the proposal that antioxidants could be useful for the treatment of FRDA Idebenone (a free-radical scavenger analogue of coenzyme Q10) may ameliorate andor to revert the cardiac hypertrophy in FRDA patients [126] This drug is currently being studied in clinical trials Although iron chelation by desferroxamine should decrease serum and cytoplasmic iron levels it may decrease aconitase activity which may be detrimental to the cellular function In addition whether chelation can alter mitochondrial iron levels without toxic side effects is unknown A recently developed mouse model of FRDA [113] raises a hope for providing a powerful means to explore many of these hypotheses and potential treatments

Other than the potential therapeutic effect of antioxidants on cardiomyopathy in FRDA the treatment remains supportive and symptomatic Physiotherapy and orthopedic management (prosthesis or surgery) are used either to preserve or to correct progressive deformations of the spine and feet It is important to provide appropriate management of cardiac functions glucose metabolism and secondary medical problems such as aspiration pneumonia

Early-onset cerebellar ataxia with retained reflexes

This disease was considered by Harding [128] to be a syndrome distinct from FRDA however genetic mapping of the early-onset cerebellar ataxia with retained reflexes (EOCARR) locus is necessary before it can be recognized as an independent genetic entity [127] Onset is before age 20 with a clinical picture similar to FRDA but with retained reflexes low incidence of sensory neuropathy less reduction of joint position sense and absence of skeletal abnormalities optic neuropathy cardiomyopathy or diabetes [127] Exclusion of FRDA by DNA testing is essential since some patients with the EOCARR phenotype have GAA expansions in the frataxin gene [127128] Moreover a branch of a recently described EOCARR family has the late onset form of FRDA while another branch has EOCARR phenotype [127] In EOCARR with very early onset differential diagnosis with ataxia telangiectasia mitochondrial disorders adrenoleukodystrophy and lysosomal storage diseases may be necessary

Ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency (AVED) is a rare treatable disorder with a phenotype that resembles FRDA In a patient with a clinical diagnosis of FRDA and a negative genetic result for FRDA serum vitamin E levels should be determined as patients with AVED have very low levels of vitamin E (lt5 gml) Age of onset is between childhood and young adulthood associated with slowly progressive gait and limb ataxia loss of deep tendon reflexes and vibratory and proprioceptive loss followed by progressive ophthalmoplegia dysarthria extensor plantar responses and muscle weakness The disorder is caused by a defect in the TTP1 gene [129] on chromosome 8q13 encoding the -tocopherol transfer protein [130] responsible for the transfer of -tocopherol to the circulating lipoproteins Early onset and severe forms of the disease are caused by truncating mutations or missense mutations in conserved amino acids [131] However DNA testing for the AVED mutations is not commercially available Early replacement therapy may prevent progression of the disease [132133]

Several diseases that lead to secondary vitamin E deficiency (ie by affecting the absorption andor transport of fat

[b] Mitochondrial diseases due to defective mitochondrial genes have maternal inheritance whereas mitochondrial diseases due to nuclear genes have ARAD

[c] Other clinical forms of PME (ie the neuronal ceroid lipofuscinoses Lafora disease type I sialidosis and MERRF) are associated with defects in various genes

[d] A causative second gene NPC2 has not been identified

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

A fascinating concurrence of yeast and human genetics [119ndash124] led to the proposal that frataxin is involved in the homeostasis (probably the transport) of mitochondrial iron Accumulation of iron inside the mitochondria of FRDA cells could lead to increased oxidative stress by free radical production from hydrogen peroxide and hypersensitivity to the oxidative stress due to mitochondrial dysfunction Deficiencies found in mitochondrialcytoplasmic aconitase as well as in the respiratory chain complexes I II and III in FRDA patients [123125] are consistent with this hypothesis Moreover primary vitamin E deficiency (see later) a specific disease associated with a defect in a physiological free radical scavenger clinically resembles FRDA Interestingly all of the enzymes with defective activity in FRDA mitochondria have iron-sulfur (Fe-S) clusters at the active sites These moieties are highly sensitive to free radical damage An alternative or complementary hypothesis is that a primary activity of frataxin is related to the synthesis of the Fe-S cluster [112] In any case these findings led to the proposal that antioxidants could be useful for the treatment of FRDA Idebenone (a free-radical scavenger analogue of coenzyme Q10) may ameliorate andor to revert the cardiac hypertrophy in FRDA patients [126] This drug is currently being studied in clinical trials Although iron chelation by desferroxamine should decrease serum and cytoplasmic iron levels it may decrease aconitase activity which may be detrimental to the cellular function In addition whether chelation can alter mitochondrial iron levels without toxic side effects is unknown A recently developed mouse model of FRDA [113] raises a hope for providing a powerful means to explore many of these hypotheses and potential treatments

Other than the potential therapeutic effect of antioxidants on cardiomyopathy in FRDA the treatment remains supportive and symptomatic Physiotherapy and orthopedic management (prosthesis or surgery) are used either to preserve or to correct progressive deformations of the spine and feet It is important to provide appropriate management of cardiac functions glucose metabolism and secondary medical problems such as aspiration pneumonia

Early-onset cerebellar ataxia with retained reflexes

This disease was considered by Harding [128] to be a syndrome distinct from FRDA however genetic mapping of the early-onset cerebellar ataxia with retained reflexes (EOCARR) locus is necessary before it can be recognized as an independent genetic entity [127] Onset is before age 20 with a clinical picture similar to FRDA but with retained reflexes low incidence of sensory neuropathy less reduction of joint position sense and absence of skeletal abnormalities optic neuropathy cardiomyopathy or diabetes [127] Exclusion of FRDA by DNA testing is essential since some patients with the EOCARR phenotype have GAA expansions in the frataxin gene [127128] Moreover a branch of a recently described EOCARR family has the late onset form of FRDA while another branch has EOCARR phenotype [127] In EOCARR with very early onset differential diagnosis with ataxia telangiectasia mitochondrial disorders adrenoleukodystrophy and lysosomal storage diseases may be necessary

Ataxia with vitamin E deficiency

Ataxia with vitamin E deficiency (AVED) is a rare treatable disorder with a phenotype that resembles FRDA In a patient with a clinical diagnosis of FRDA and a negative genetic result for FRDA serum vitamin E levels should be determined as patients with AVED have very low levels of vitamin E (lt5 gml) Age of onset is between childhood and young adulthood associated with slowly progressive gait and limb ataxia loss of deep tendon reflexes and vibratory and proprioceptive loss followed by progressive ophthalmoplegia dysarthria extensor plantar responses and muscle weakness The disorder is caused by a defect in the TTP1 gene [129] on chromosome 8q13 encoding the -tocopherol transfer protein [130] responsible for the transfer of -tocopherol to the circulating lipoproteins Early onset and severe forms of the disease are caused by truncating mutations or missense mutations in conserved amino acids [131] However DNA testing for the AVED mutations is not commercially available Early replacement therapy may prevent progression of the disease [132133]

Several diseases that lead to secondary vitamin E deficiency (ie by affecting the absorption andor transport of fat

[b] Mitochondrial diseases due to defective mitochondrial genes have maternal inheritance whereas mitochondrial diseases due to nuclear genes have ARAD

[c] Other clinical forms of PME (ie the neuronal ceroid lipofuscinoses Lafora disease type I sialidosis and MERRF) are associated with defects in various genes

[d] A causative second gene NPC2 has not been identified

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

and vitamin E) also cause a slowly progressive spinocerebellar syndrome (ie ataxia hypoareflexia limitation in upward gaze proprioceptive loss etc) The main causes of secondary vitamin E deficiency are severe malnutrition cystic fibrosis cholestatic liver disease extensive intestinal resection hypolipoproteinemia abetalipoproteinemia (Bassen-Kornzweig disease see below) and Marinesco-Sjgren syndrome [134] Some of these patients have an associated retinopathy

Abetalipoproteinemia (Bassen-Kornzweig disease)

This rare autosomal recessive disorder results in secondary Vitamin E deficiency and a phenotype similar to that observed of acquired vitamin E deficiency consisting of spinocerebellar degeneration peripheral neuropathy and retinitis pigmentosa [135] Acanthocytosis (ldquothornyrdquo red blood cells) is observed in Bassen-Kornzweig disease (BKD) and other neurodegenerative diseases such as neuroacanthocytosis and the Mcleod syndrome [136] The onset of BKD is in childhood with steatorrhoea and fat malabsorption features resembling celiac disease Mutations in the microsomal triglyceride transfer protein (MTP) gene on 4q22-24 [137138] account the defects in some BKD patients This protein transports triglyceride cholesterol ester and phospholipids across various lipid membrane systems Vitamin E replacement therapy prevents further progression of the neurological symptoms Hypobetalipoproteinemia is a genetically distinct disorder with a similar clinical presentation to BKD

Recessive ataxia with ocular motor apraxia

This disease was originally described as mimicking ataxia-telangiectasia [139] A recent study of 22 patients from Portugal suggests that this entity is more frequent than initially postulated [140] A similar clinical entity Early-onset cerebellar ataxia with hypoalbuminemia (EOCA-HA) has been described in Japanese patients [141] The ataxia with ocular motor apraxia (AOA1) locus is located on 9q13 [142] AOA1 and EOCA-HA are allelic diseases as shown by the recent cloning of the gene encoding aprataxin a new HITZn-finger protein [141143] AOA is manifested by onset in childhood of gait imbalance followed by dysarthria cerebellar ataxia characteristic ocular apraxia [144] and peripheral neuropathy Severe motor neuropathy dominates the clinical picture in the advanced phases of the disease in which ocular apraxia evolves into external ophthalmoplegia [140] Proposed diagnostic criteria for AOA are autosomal recessive transmission childhood onset a clinical presentation of cerebellar ataxia ocular apraxia and areflexia followed by a later appearance of peripheral neuropathy Although dystonia scoliosis and pes cavus may be associated mental retardation telangiectasia and immunodeficiency do not occur in AOA AOA can resemble SCA2 clinically but the inheritance pattern should distinguish these disorders (see above)

Spastic ataxia of charlevoix-saguenay

Originally described in the region of Charlevoix-Saguenay at Quebec autosomol recessive spastic ataxia of charlevoix-saguenay (ARSACS) is an autosomal recessive disease with early onset manifesting initially with gait ataxia which is followed by progressive axonal neuropathy and spastic paraplegia Fundus examination of optic reveals hypermyelination of the nerve fiber layer [145] Intelligence is normal although lowered IQ has been recognized in some cases MRI studies show cerebellar atrophy The gene mapped to chromosome 13q11 [145] has a simple giant exon (12794 bp) encoding a protein named sacsin a putative chaperone highly expressed in the granular cell layer of the cerebellum [146] The same spastic ataxia of charlevoix-saguenay (SACS) locus has recently been linked to the hereditary ataxia in two Turkish families [147] raising a possibility that ARSACS could be more common than previously expected

Disorders associated with defective DNA repair

Ataxia telangiectasia

This is an autosomal recessive disorder with an incidence of 1100000 Gait ataxia is a prominent sign in these patients first observed during infancy or childhood [148] The disease has neurological (ocular apraxia slow horizontal saccades cerebellar syndrome dystonic postures chorea tics or jerks dysphagia and choking as well as peripheral neuropathy with the progression of the disease) dermatological (telangiectasia premature senile keratosis and graying of the hair) and immunological (atrophy of thymus and lymphoid tissues lymphopenia low levels of immunoglubulins) components DNA sensitivity is the basis of all of these manifestations as well as the occurrence of cancer (mostly lymphoma and leukemia) in about twenty percent of ataxia telangiectasia (AT) patients Elevated serum -fetoprotein levels are observed in about 90 to 95 percent of AT patients and non-random chromosomal aberrations (ie chromosomes 7 and 14) are found in lymphocytes Survival after the age of 30 is rare The disease is caused by mutations in the gene ataxia telangiectasia mutated (ATM) on 11q22-23 [149] ATM encodes a protein with serinethreonine kinase activity from the family of the phosphatidyl inositol-3-kinases [150]

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

Conversely a mutation in the gene hMRE11 involved in double strand break repair has been found in an ataxic patient with an AT-like phenotype [151]

Xeroderma pigmentosum Cockaynes syndrome and trichothiodystrophy

These autosomal recessive diseases combine extreme skin photosensitivity ataxia and occasionally other neurological manifestations such as seizures chorea dystonia peripheral neuropathy mental retardation deafness and dementia [152] No commercially available diagnostic tests are available at present

Xeroderma pigmentosum (XP) is associated with a strong predisposition to cutaneous cancers squamous cell carcinomas and melanomas and less frequently with nervous system neoplasms The age of onset is from childhood to adult The disease is heterogeneous with eight complementation groups XP-A through XP-G and XP-V (XP-Variant) [153] XP affects transcription-coupled repair and global genomic repair Not all the XP groups have neurological signs [152154]

Cockaynes syndrome (CS) is characterized by marked growth retardation moderate skin photosensitivity and premature aging The patients have short stature with disproportionally long arms and legs and large hands and feet Abnormal developmental features are associated with a characteristic facial appearance consisting of microcephaly thin nose deep set eyes progressive lack of subcutaneous fat and prognathism Neurological signs may include mental retardation retinal and cochlear degeneration demyelinating neuropathy and ataxia Severe atrophy of the white matter is observed in these patients No increased risk of cancer is recognized in CS patients The genes associated with CS are CS-A CS-B XP-B XP-D and XP-G Groups XP-B XP-D and XP-G correspond to genes whose mutations could produce either XP or CS phenotypes [155156] According to the severity and genetic basis two forms of CS have been described both representing mutations in the gene CS-B on chromosome 10q11 i) a classical severe infantile variant and ii) the cerebro-oculo-facial-skeletal syndrome [157] Mutations in the gene CS-A on chromosome 5 result in milder forms of the disease For a recent review about clinical and genetic aspects of CS see Rapin et al [152]

Trichothiodystrophy (TTD) is a disease with a clinical phenotype overlapping that of XP and CS with microcephaly mental retardation ataxia retinal and cochlear lesions with the additional characteristic of sulfur-deficient brittle hair TTD is associated with mutations in the genes XP-D XP-B and TTD-A (a TTD specific allele) [152156]

Other autosomal recessive ataxia

Other autosomal recessive ataxias include cerebellar ataxia associated with deficiency in muscle coenzyme Q10 [158] infantile-onset SCA with sensory neuropathy [159] periodic vestibulocerebellar ataxia [160] ataxia and familial Gerhardts syndrome [161] cerebellar ataxia and Whipples disease [162] cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) syndrome [163] posterior column ataxia and retinitis pigmentosa [164] Boucher-Neuhauser syndrome and ataxia with hypogonadism (Holmes) syndromes [165] and various ataxic syndromes associated with deafness [4] These syndromes are all defined purely on a clinical basis with no genetic markers or testing being presently available

X-LINKED ATAXIA

These are very rare syndromes and different entities have been described under this condition The syndromes are of childhood or juvenile onset with limb ataxia dysarthria plus in some cases dementia mental retardation and hearing impairment Like pyruvate dehydrogenase complex defects (deficits in the E1a subunit of the enzyme) most X-linked ataxias have metabolic causes For a list of the various syndromes described with X-linked ataxia see Evidente et al [4]

THE CONGENIAL AND METABOLIC ATAXIA

A congenital developmental defect or a metabolic cause should be suspected in very early onset progressive or intermittent ataxia Congenital ataxia patients have hypotonia abnormal motor development and early signs of cerebellar dysfunction Head CT scans or MRI studies in these patients may reveal the underlying morphological defect such as dysgenesis or agenesis of the cerebellar vermis cerebellar hemispheres andor part of the brainstem Specific congenital syndromes with ataxia are mentioned in Table 2 Metabolic intermittent ataxias are expected to be caused mainly by disorders in the urea cycle (ornithine transcarbamylase and arginino succinate synthase) some aminoacidurias (maple syrup urine disease isovaleric acidosis 2-glutaric aciduria and Hartnup disease) and disorders of pyruvate carboxylase pyruvate dehydrogenase and mitochondrial diseases (Table 2) Other early onset

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

metabolic diseases with ataxia include metachromatic leukodystrophy multiple sulfatase deficiency adrenoleukodystrophy sialidosis type I and ceroid lipofuscinosis Behrs syndrome represents a heterogeneous group of diseases characterized by optic atrophy beginning in early childhood associated with ataxia spasticity mental retardation and sensory loss [166167] Marinesco-Sjogren syndrome is a chylomicron retention disease [134]

Some childhood progressive ataxias present an even more complex picture as many of these metabolic disorders could be manifested after childhood in the adolescence or adult life and ataxia may not be a recognizable sign Syndromes with childhood or juvenile onset which could include ataxia are as follows (a) Kallman syndrome (hypogonadotrophic hypogonadism and anosmia with associated eye movement abnormalities and cerebellar ataxia) with an estimated incidence of 110000 in males and 150000 in females [168] (b) Pelizaeus-Merzbacher syndrome (PMS) (neonatal tremor and shaking movements of the head abnormal eye movements and progression to cerebellar ataxia dysarthria and intention tremor of the upper limbs) The disease progresses during the second decade of the life with increasing abnormal movements and mild dementia in PMS type I or classical form The connatal form or PMS type II shows a more severe presentation detectable at birth The gene responsible of PMS encodes for the myelin proteolipid protein and maps to Xq21 [169] PMS is allelic with a distinct clinical entity X-linked spastic paraplegia type 2 (SPG2) [170] Both diseases are part of the group of leukodystrophies (c) Deficit in hexosaminidase A and hexosaminidase AB clinically similar to FRDA is a slowly progressive ataxia with retained reflexes intention tremor early dysarthria and psychiatric components without sensory involvement [171172] (d) Niemann-Pick disease type C (hepatosplenomegaly supranuclear ophthalmoplegia ataxia seizures and progressive dementia with onset in early childhood) is an inherited autosomal recessive cholesterol storage disorder caused by impaired intracellular cholesterol trafficking [173] Patients of this group C Niemann-Pick disease like group D have normal levels of sphingomyelinase activity The general incidence of the disease has been estimated at about 1100000 live births although a higher prevalence is recognized in isolated populations [173] A major form of the disease (about 95 of the cases) is caused by mutations in the gene NPC1[174175] on 18q11 The causative second gene NPC2 has not been identified yet (e) Krabbes disease is an autosomal recessive disorder caused by galactocerebrosidase deficiency (EC 32146) leading to the accumulation of galactosylceramide Developmental delay extreme irritability and crying followed by limb stiffness are key signs About 10 of the patients have a childhood onset with ataxia dysarthria limb paresthesias and weakness visual loss and a very variable rate of mental and physical deterioration or a young-adult onset with optic nerve pallor weakness spasticity and sensory-motor demyelinating neuropathy [176] Patients with suspected metachromatic leukodystrophy or adrenoleukodystrophy could also have Krabbes disease (f) A deficit in galactose-1-phosphate-uridyl transferase may lead to late neurological manifestation with cerebellar syndrome and abnormal movements as a consequence of galactosemia [177]

Peroxisomal disorders

Peroxisomal disorders are autosomal recessive or X-linked metabolic diseases of neonatal or childhood onset characterized by facial dysmorphism hepatomegaly and complex neurological symptoms including retinopathy impaired hearing hypotonia psychomotor delay and seizures [178] Infantile Refsum disease (RD) is a severe and slowly progressive peroxisomal disorder where ataxia could be a predominant sign [179] The characteristics of the syndrome are dysmorphic facial features ataxia retinitis pigmentosa deafness peripheral neuropathy hepatomegaly elevated protein levels in the CSF and the accumulation of phytanic acid in blood and tissues RD is caused by phytanoyl-CoA hydroxylase deficiency [180ndash182]

Mitochondrial diseases

A detailed description of mitochondrial diseases which have variable multisystemic clinical features and complex genotype-phenotype correlations is beyond the scope of this review Another article in this issue describes these diseases in detail Concerning ataxia a mitochondrial basis for any ataxic patient should be suspected when ataxia is associated with or followed by a variable combination of progressive external ophthalmoplegia myoclonic seizures myopathy cardiomyopathy myoglobinuria neuropathy retinopathy optic atrophy hearing loss and other systemic manifestations such as diabetes renal tubular acidosis and gastrointestinal disorders

The patient with sporadic ataxia

The dramatic advances in our understanding of the molecular basis of genetic ataxia are diverting our attention from sporadic ataxias however many inherited ataxias can present without a family history and the diagnosis of a genetic ataxia in such cases could be challenging Conversely patients with ataxia who have a family history may not always have hereditary ataxia Ataxia may be due to a coincidental occurrence of a relatively common neurological

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

disease such as multiple sclerosis Furthermore the apparently positive family history may be based on ambiguous and inaccurate data In these circumstances differentiating hereditary ataxia from sporadic ataxia is an important diagnostic step Although reviewing sporadic ataxias is beyond the scope of this review a list of conditions to be considered for the differential diagnosis of sporadic ataxia are (a) cerebral tumors (b) paraneoplastic ataxia [183ndash186] (c) celiac disease [187188] and Ramsay Hunt syndrome with CSF anti-gliadin antibodies [189] (d) stroke (e) hypothyroidism [190] (f) toxins metals and drugs such as chronic exposures to alcohol thallium toluene lithium ion organic mercury barbiturates phenytoin etc (g) nutritional deficiencies (chronic alcoholism celiac diseases andor malabsorption syndromes) leading to deficit in vitamin B1 B12 and E (h) multiple sclerosis (i) infectious or post-infectious causes and (j) neurodegenerative processes like multiple system atrophy (MSA) [191] and progressive supranuclear palsy (PSP) [192ndash197] Even when ataxia is not a characteristic feature of some diseases motor impairments other than ataxia may be presented with postural instability oculomotor manifestations and dysarthria in the early stages of these diseases

DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES

Determining the inheritance pattern by obtaining detailed family history is a critical step in establishing an accurate diagnosis of inherited ataxia Unfortunately this is often a neglected part of neurological evaluation The family history must be detailed enough to differentiate autosomal X-linked vs mitochondrial inheritance and dominant vs recessive inheritance Further information such as the penetrance anticipation and other phenotypic variations among affected members should be documented Early parental death adoption non-paternity ethnic background and concomitant disorders within the family should be included in the history A detailed clinical documentation of the ataxic syndrome including the age of onset the course of the disease anatomical localization of the neurological deficits and associated extra-nervous system symptoms and signs in the patient and the affected family members also provides important clues for the correct diagnosis Most early onset (childhood or second decade of life) nonmetabolic disorders are autosomal recessive while later onset (after 20y) suggests autosomal dominant disorders (although there are exceptions) (Table 2) Nonmetabolic hereditary ataxias generally show an insidious onset followed by a slowly progressive course

For recessive ataxias differential diagnosis between treatable syndromes (Wilson disease AVED BKD and hypolipoproteinemia) and non-treatable ones (FRDA and most other recessive ataxias) at an early stage of the disease is critical because early treatment can prevent disease progression For autosomal dominant ataxias a first step is to recognize the ADCA clinical types (I II or III) Although this approach is not always useful because of the variable overlaps between different dominant SCAs ADCA subtypes may provide important diagnostic clues in many cases Some additional clinical characteristics could help with the differential diagnosis although there are again limitations in this approach (Table 1) Areflexia has been proposed as a main characteristic of SCA2 however a SCA2 family has recently been found with brisk reflexes as a very early sign of the disease which remains until advanced stages (A L Rosa unpublished) Other useful diagnostic pearls include (a) very early slow saccades in SCA2 (b) ataxia and blindness with marked anticipation under-represented paternal transmissions in the pedigree in SCA7 (c) epilepsy in some members of a family with relatively pure cerebellar ataxia in SCA10 (d) epilepsy complex movement disorders mental deteriorations in the absence of macular degeneration in DRPLA and SCA17 (e) ADCA-I with conspicuous upper motor neuron signs in SCA1 and SCA 3 (f) and episodic ataxia in EA1 EA2 and an early stage of some SCA6 cases (see Table 1)

The ethnic andor geographic background may also provide some clues SCA3Machado-Joseph disease (MJD) originally described in two MJD families of Azorean descent is now found in most ethnic populations around the world SCA3 appears to be the most common SCA in many countries such as United States China and Germany SCA1 and SCA2 appear to be more common in the United Kingdom and Italy and SCA2 in India and Cuba while SCAs 3 and 6 appear to predominate in Japan SCA10 has been exclusively seen in Mexicans DRPLA is rare outside Japan SCAs12 13 and 14 have been reported in German American French and Japanese families respectively SCA17 may be relatively more frequent in Japan FRDA has never been reported in sub-Saharan Africans East Asians and Native Americans A founder effect could create geographically different prevalence within the same ethnic population

If clinical evaluation suggests a specific genetic disorder for which genetic testing is available DNA testing should be considered as the first diagnostic test A positive DNA test provides the most cost-effective and definitive diagnosis however if the DNA test is negative it only excludes the disease tested In some diseases caused by repeat expansions there may be intermediate alleles whose diagnostic value is ambiguous Some intermediate alleles may represent mutable normal alleles that cause no disease in the individual may expand to the full mutation range in the offspring Other intermediate alleles may have reduced penetrance Algorithms for DNA testing strategies for ataxic disorders have been discussed [97] Presymptomatic and prenatal testing is available for many hereditary

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

ataxias through DNA analyses however ethical legal and social ramifications of DNA testing are complex and require appropriate counseling by qualified professionals such as geneticists or genetic counselors The importance of genetic counseling cannot be overemphasized in these cases If genetic testing is not available but there are other diagnostic tests specific for the suspected disorder they should be obtained MRI and CT of the central nervous system as well as electrophysiological biochemical and metabolic studies may be useful for establishing the diagnosis of other disorders and excluding secondary causes

SUMMARY

Clinical differentiation of various causes of progressive ataxia can be difficult [199] Pathologic examination of patients with progressive ataxia enables identification of three broad categories of diseases according to the site of the gross and histologic abnormalities [1 2] These three categories are the spinocerebellar forms of which Friedreichrsquos ataxia is the most common the corticocerebellar atrophies and the cerebellar-brainstem atrophies Histopathologic features of Friedreichrsquos ataxia include neuronal loss in the spinal ganglia and Clarkersquos column and loss of myelinated fibers with compensatory gliosis of the fasciculus gracilis and cuneatus in the posterior columns and of the spinocerebellar and pyramidal tracts in the lateral columns of the spinal cord [199 200] Spinal cord thinning is reported almost invariably in pathologic descriptions of the disease [1 200]

MR imaging can show selective loss of bulk in the cerebellum and brainstem in corticocerebellar and cerebellar-brainstem atrophies [199 203 203] hich are associated with brainstem and cerebellar white matter signal changes in olivopontocerebellar atrophy [204]

Atrophy of the upper portion of the cervical spinal cord has been emphasized in prior MR studies of patients with Friedreichrsquos ataxia [203 205 206] but intramedullary signal abnormalities were not mentioned

MR imaging could be used to depict the changes in the white matter tracts that are known to occur in the cervical spinal cord of patients with Friedreichrsquos ataxia Detection of such changes could increase information provided by MR imaging in patients with Friedreichrsquos ataxia and be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Loss of myelinated fibers and gliosis in the posterior and lateral columns of the spinal cord are histopathologic hallmarks of Friedreichrsquos ataxia These are accompanied by atrophy of the upper portion of the spinal cord MR imaging can be used to detect signal changes in the white matter tracts of the cervical spinal cord in patients with Friedreichrsquos ataxia

The anteroposterior diameter of the spinal cord is decreased in patients with Friedreichrsquos ataxia in the upper cervical spinal cord Abnormal signal in the posterior or lateral columns of the spinal cord is observed on sagittal andor axial images in patients with Friedreichrsquos ataxia and is not observed in other patients with corticocerebellar atrophies and the cerebellar-brainstem atrophies MR images of the cervical spinal cord in patients with Friedreichrsquos ataxia show thinning and intramedullary signal changes in the cervical portion of the spinal cord consistent with degeneration of posterior and lateral white matter tracts These MR findings might be helpful for differential diagnosis in patients with progressive ataxia of uncertain clinical type

Addendum

A new version of this PDF file (with a new case) is uploaded in my web site every week (every Saturday and remains available till Friday)

SUMMARY

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

To download the current version follow the link httppdfyassermetwallycomcasepdf You can also download the current version from my web site at httpyassermetwallycom To download the software version of the publication (crowexe) follow the link

httpneurologyyassermetwallycomcrowzip The case is also presented as a short case in PDF format to download the short case follow the link

httppdfyassermetwallycomshortpdf At the end of each year all the publications are compiled on a single CD-ROM please contact the author to

know more details Screen resolution is better set at 1024768 pixel screen area for optimum display Also to view a list of the previously published case records follow the following link

(httpwordpresscomtagcase-record) or click on it if it appears as a link in your PDF reader To inspect the patients full radiological study click on the attachment icon (The paper clip icon in the left

pane) of the acrobat reader then double click on the attached file Click here to download the short case version of this case record in PDF format

References

[1] Holmes GA A form of familiar degeneration of the cerebellum Brain 190730545-567

[2] Greenfield JG The spino-cerebellar degenerations Oxford Blackwell Scientific 1954

[3] Harding A Genetic aspects of autosomal dominant late onset cerebellar ataxia J Med Genet 198118(6)436-441

[4] Evidente V Gwinn-Hardy K Caviness J et al Hereditary ataxias Mayo Clin Proc 200075(5)475-490

[5] Klockgether T Wullner U Spauschus A et al The molecular biology of the autosomal-dominant cerebellar ataxias Mov Disord 200015604-612

[6] Stevanin G Durr A Brice A Clinical and molecular advances in autosomal dominant cerebellar ataxias from genotype to phenotype and physiopathology Eur J Hum Genet 200084-18

[7] Subramony S Vig P McDaniel D Dominantly inherited ataxias Semin Neurol 199919(4)419-425

[8] Harding A Friedreichs ataxia a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features Brain 1981104589-620

[9] Harding AE Clinical features and classification of inherited ataxias Adv Neurol 1993611-4

[10] Orr HT Beyond the Qs in the polyglutamine diseases Genes Dev 200115925-932

[11] Davies SW Beardsall K Turmaine M et al Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1997351131-133

[12] Perutz MF Glutamine repeats and neurodegenerative diseases molecular aspects Trends Biochem Sci 19992458-63

[13] Klement IA Skinner PJ Kaytor MD et al Ataxin-1 nuclear localization and aggregation role in polyglutamine-induced disease in SCA1 transgenic mice Cell 19989541-53

[14] Zoghbi HY Orr HT Glutamine repeats and neurodegeneration Ann Rev Neurosc 200023217-247

[15] Yakura H Wakisaka A Fujimoto S et al Hereditary ataxia and HL-A N Engl J Med 1974291(3)154-155

[16] Banfi S Servadio A Chung M et al Identification and characterization of the gene causing type 1

REFERENCES

spinocerebellar ataxia Nat Genet 19947513-520

[17] Sasaki H Fukazawa T Yanagihara T et al Clinical features and natural history of spinocerebellar ataxia type 1 Acta Neurol Scand 19969364-71

[18] Genis D Matilla T Volpini V et al Clinical neuropathologic and genetic studies of a large spinocerebellar ataxia type 1 (SCA1) kindred (CAG)n expansion and early premonitory signs and symptoms Neurology 19954524-30

[19] Ranum L Chung M Banfi S et al Molecular and clinical correlations in spinocerebellar ataxia type I evidence for familial effects on the age at onset Am J Hum Genet 199455244-252

[20] Gispert S Twells R Orozco G et al Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23ndash241 Nat Genet 19934295-299

[21] Imbert G Saudou F Yvert G et al Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAGglutamine repeats Nat Genet 199614285-291

[22] Pulst S Nechiporuk A Nechiporuk T et al Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2 Nat Genet 199614269-276

[23] Sanpei K Takano H Igarashi S et al Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique DIRECT Nat Genet 199614277-284

[24] Romanul F Fowler H Radvany J et al Azorean disease of the nervous system N Engl J Med 19772961505-1508

[25] Kawaguchi Y Okamoto T Taniwaki M et al CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q321 Nat Genet 19948221-228

[26] Cancel G Abbas N Stevanin G et al Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3Machado-Joseph disease locus Am J Hum Genet 199557809-816

[27] Matilla T McCall A Subramony S et al Molecular and clinical correlations in spinocerebellar ataxia type 3 and Machado-Joseph disease Ann Neurol 19953868-72

[28] Durr A Stevanin G Cancel G et al Spinocerebellar ataxia 3 and Machado-Joseph disease clinical molecular and neuropathological features Ann Neurol 199639490-499

[29] Flanigan K Gardner K Alderson K et al Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4) clinical description and genetic localization to chromosome 16q221 Am J Hum Genet 199659392-399

[30] Nagaoka U Takashima M Ishikawa K et al A gene on SCA4 locus causes dominantly inherited pure cerebellar ataxia Neurology 2000541971-1975

[31] Takashima M Ishikawa K Nagaoka U et al A linkage disequilibrium at the candidate gene locus for 16q-linked autosomal dominant cerebellar ataxia type III in Japan J Hum Genet 200146167-171

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[215] Temae 5 Taneichi H Abumi K MRI of wallerian degeneration

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20004317-22

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[194] Wenning GK Tison F Ben Shlomo Y et al Multiple system atrophy a review of 203 pathologically proven cases Mov Disord 199712133-147

[195] Albers D Augood S New insights into progressive supranuclear palsy Trends Neurosci 200124347-353

[196] Santacruz P Uttl B Litvan I et al Progressive supranuclear palsy a survey of the disease course Neurology 1998501637-1647

[197] Tan E-K Ashizawa T Genetic testing in spinocerebellar ataxias Defining a clinical role Arch Neurol 200158191-195

[198] Metwally MYM Textbook of neuroimaging A CD-ROM publication (Metwally MYM editor) WEB-CD agency for electronic publication version 112a April 2010

[199] Adams RD Victor M Degenerative diseases of the nervous system In Adams RD Victor M eds Principles of neurology 3rd ed New York McGraw-Hill 1985859-901

[200] Rewcastle NB Degenerative diseases of the central nervous system In Davis RL Robertson DM eds Textbook ofneuropathology 2nd ed Baltimore Williams amp Wilkins 1991904-961

[201] Klockgether T Petersen 0 Grodd W Dichgans J Early onset cerebellar ataxia with retained tendon reflexes clinical electrophys1ological and MRI observations in comparison with Friedreichrsquos ataxia Brain 199i114 1559-1573

[202] Savoiamdo M Strada L Girotti F et al Olivopontocerebollar atrophy MR diagnosis and relationship to multisystem atrophy Radiology 1990174 693-696

[203] Wessel K Schmoth G Dienem HC Murell-Forell W Dichgans J Significance of MRI-confimmed atrophy of the cranial spinal cord in Friedreichrsquos ataxia EurArch Psychiatry Clin Neurosci 1989238225-230

[204] Nicolau A Diard F Fontan 0 et al Magnetic resonance imaging in spinocerebellam degenerative diseases Pediatrie 198742359-365

[205] Bydder GM Young IR MR imaging clinical use ofthe inversion recovery sequence J Comput Assist Tomogr 19859659-675

[206] Mascalchi M Bartolozzi C Dal Pozzo G Effectiveness of the short TI inversion recovery (STIR) sequence in MR imaging of intramedullary apinal lesions Magn Reson Imaging 1993l117-25

[207] Sherman JL Nassaux PY Citrin CM Measurements of the normal cervical spinal cord on MR imaging AJNR 199011 369-372

[208] Kuhn MJ Johnson KA Davis KR Wallerian degeneration evaluation with MR imaging Radiology 1988168i99-202 11 Goodin OS Rowley HA Olney RK Magnetic resonance imaging in amyotrophic lateral sclerosis Ann Neurol 198823418-420

[209] Mascalchi M Salvi F Bartolozzi C MRI ofwallerian degeneration in the carvical spinal cord (case report) J ComputAssist Tomogr l99317824-825

[210] Friedman OP Tartaglino LM Amyotrophic lateral sclerosis hyperintensity of the corticospinal tracts on MR images of the spinal cord AJR 1993 160604-606

[211] Mascalchi M Salvi F Valzania F et al Cortico-spinal tracts degeneration in motor neuron disease report of two cases AJNR (in press)

[212] Weller RO Color atlas of neuropathology New York Oxford University Press 1984

[213] Enzmann OR DeLaPaz RL Rubin J Magnetic resonance of the spine St Louis Mosby 1990

[214] Timms SR Curersquo JK Kument JE Subacute combined degeneration of the spinal cord MR findings AJNR 1993141224-i 227

[215] Temae 5 Taneichi H Abumi K MRI of wallerian degeneration

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[55] Gomez C Polyglutamine aggregates in SCA6 Purkinje cells a tail of two toxicities Neurology 2001561618-1619

[56] David G Durr A Stevanin G et al Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7) Hum Mol Genet 19987165-167

[57] Oh A Jacobson K Jen J et al Slowing of voluntary and involuntary saccades an early sign in spinocerebellar ataxia type 7 Ann Neurol 200149801-804

[58] Benton C de Silva R Rutledge S et al Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype Neurology 1998511081-1086

[59] David G Abbas N Stevanin G et al Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion Nat Genet 19971765-70

[60] Koob M Benzow K Bird T et al Rapid cloning of expanded trinucleotide repeat sequences from genomic DNA Nat Genet 19981872-75

[61] Del-Favero J Krols L Michalik A et al Molecular genetic analysis of autosomal dominant cerebellar ataxia with retinal degeneration (ADCA type II) caused by CAG triplet repeat expansion Hum Mol Genet 19987177-186

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[63] Giunti P Stevanin G Worth P et al Molecular and clinical study of 18 families with ADCA type II evidence for genetic heterogeneity and de novo mutation Am J Hum Genet 1999641594-1603

[64] Stevanin G Giunti P Belal G et al De novo expansion of intermediate alleles in spinocerebellar ataxia 7 Hum Mol Genet 199871809-1813

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[69] Kaytor M Duvick L Skinner P et al Nuclear localization of the spinocerebellar ataxia type 7 protein ataxin-7 Hum Mol Genet 199981657-1664

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[95] Nagafuchi S Yanagisawa H Sato K et al Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p Nat Genet 1994614-18

[96] Nielsen J Sorensen S Hasholt L et al Dentatorubral-pallidoluysian atrophy Clinical features of a five-generation Danish family Mov Disord 199611533-541

[97] Warner T Williams L Walker R et al A clinical and molecular genetic study of dentatorubropallidoluysian atrophy in four European families Ann Neurol 199537452-459

[98] Borke J Wingfield M Lewis K et al The Haw River Syndrome dentatorubropallido-luysian atrophy (DRPLA) in an African-American family Nat Genet 19947521-524

[99] Browne D Gancher S Nutt J et al Episodic ataxiamyokymia syndrome is associated with point mutations in the human potassium channel gene KCNA1 Nat Genet 19948136-140

[100] Ophoff R Terwindt G Vergouwe M et al Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4 Cell 199687543-552

[101] Tournier-Lasserve E CACNA1A mutations hemiplegic migraine episodic ataxia type 2 and the others Neurology 1999533-4

[102] Denier C Ducros A Durr A et al Missense CACNA1A mutation causing episodic ataxia type 2 Arch Neurol 200158292-295

[103] Jen J Geschwind D Ataxia and calcium channels what a headache Arch Neurol 200158179-180

[104] Griggs R Moxley 3rd R Lafrance R et al Hereditary paroxysmal ataxia response to acetazolamide Neurology 1978281259-1264

[105] Battistini S Stenirri S Piatti M et al A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia Neurology 19995338-43

[106] Auburger G Ratzlaff T Lunkes A et al A gene for autosomal dominant paroxysmal choreoathetosisspasticity (CSE) maps to the vicinity of a potassium channel gene cluster on chromosome 1p probably within 2 cM between D1S443 and D1S197 Genomics 19963190-94

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[120] Foury F Cazzalini O Deletion of the yeast homologue of the human gene associated with Friedreichs ataxia elicits iron accumulation in mitochondria FEBS Lett 1997411373-377

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[124] Wilson RB Roof DM Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue Nat Genet 199716352-357

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[193] Selim M Drachman D Ataxia associated with Hashimotos disease progressive non-familial adult onset cerebellardegeneration with autoimmune thyroiditis J Neurol Neurosurg Psychiatry 20017181-87

[194] Wenning GK Tison F Ben Shlomo Y et al Multiple system atrophy a review of 203 pathologically proven cases Mov Disord 199712133-147

[195] Albers D Augood S New insights into progressive supranuclear palsy Trends Neurosci 200124347-353

[196] Santacruz P Uttl B Litvan I et al Progressive supranuclear palsy a survey of the disease course Neurology 1998501637-1647

[197] Tan E-K Ashizawa T Genetic testing in spinocerebellar ataxias Defining a clinical role Arch Neurol 200158191-195

[198] Metwally MYM Textbook of neuroimaging A CD-ROM publication (Metwally MYM editor) WEB-CD agency for electronic publication version 112a April 2010

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[200] Rewcastle NB Degenerative diseases of the central nervous system In Davis RL Robertson DM eds Textbook ofneuropathology 2nd ed Baltimore Williams amp Wilkins 1991904-961

[201] Klockgether T Petersen 0 Grodd W Dichgans J Early onset cerebellar ataxia with retained tendon reflexes clinical electrophys1ological and MRI observations in comparison with Friedreichrsquos ataxia Brain 199i114 1559-1573

[202] Savoiamdo M Strada L Girotti F et al Olivopontocerebollar atrophy MR diagnosis and relationship to multisystem atrophy Radiology 1990174 693-696

[203] Wessel K Schmoth G Dienem HC Murell-Forell W Dichgans J Significance of MRI-confimmed atrophy of the cranial spinal cord in Friedreichrsquos ataxia EurArch Psychiatry Clin Neurosci 1989238225-230

[204] Nicolau A Diard F Fontan 0 et al Magnetic resonance imaging in spinocerebellam degenerative diseases Pediatrie 198742359-365

[205] Bydder GM Young IR MR imaging clinical use ofthe inversion recovery sequence J Comput Assist Tomogr 19859659-675

[206] Mascalchi M Bartolozzi C Dal Pozzo G Effectiveness of the short TI inversion recovery (STIR) sequence in MR imaging of intramedullary apinal lesions Magn Reson Imaging 1993l117-25

[207] Sherman JL Nassaux PY Citrin CM Measurements of the normal cervical spinal cord on MR imaging AJNR 199011 369-372

[208] Kuhn MJ Johnson KA Davis KR Wallerian degeneration evaluation with MR imaging Radiology 1988168i99-202 11 Goodin OS Rowley HA Olney RK Magnetic resonance imaging in amyotrophic lateral sclerosis Ann Neurol 198823418-420

[209] Mascalchi M Salvi F Bartolozzi C MRI ofwallerian degeneration in the carvical spinal cord (case report) J ComputAssist Tomogr l99317824-825

[210] Friedman OP Tartaglino LM Amyotrophic lateral sclerosis hyperintensity of the corticospinal tracts on MR images of the spinal cord AJR 1993 160604-606

[211] Mascalchi M Salvi F Valzania F et al Cortico-spinal tracts degeneration in motor neuron disease report of two cases AJNR (in press)

[212] Weller RO Color atlas of neuropathology New York Oxford University Press 1984

[213] Enzmann OR DeLaPaz RL Rubin J Magnetic resonance of the spine St Louis Mosby 1990

[214] Timms SR Curersquo JK Kument JE Subacute combined degeneration of the spinal cord MR findings AJNR 1993141224-i 227

[215] Temae 5 Taneichi H Abumi K MRI of wallerian degeneration

• HOME
• CLINICAL PICTURE
• RADIOLOGICAL FINDINGS
• • Figure1
  • Figur 2
  • Figur 3
  • Figure4
  • Pathophysiology of Friedreich ataxia
  • Histologic Findings in Friedreich ataxia
  • Comment on the radiology of the previously reported case
  • • DIAGNOSIS
    • DISCUSSION
    • • AUTOSOMAL DOMINANT ATAXIA
      • AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET
      • X-LINKED ATAXIA
      • THE CONGENIAL AND METABOLIC ATAXIA
      • DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES
      • • SUMMARY
        • REFERENCES
        • MY WEB SITE
        • SHORT CASE VERSION
        • DOWNLOAD ATTACHED FILE
        • • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MY WEB SITE
          • Long case version
          • Short case version

ataxia (SCA8) Nat Genet 199921379-384

[74] Moseley M Schut L Bird T et al SCA8 CTG repeat en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance Hum Mol Genet 200092125-2130

[75] Silveira I Alonso I Guimaraes L et al High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles Am J Hum Genet 200066830-840

[76] Ikeda Y Shizuka-Ikeda M Watanabe M et al Asymptomatic CTG expansion at the SCA8 locus is associated with cerebellar atrophy on MRI J Neurol Sci 200018276-79

[77] Nemes J Benzow K Moseley M et al The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1) Hum Mol Genet 200091543-1551

[78] Worth PF Houlden H Giunti P et al Large expanded repeats in SCA8 are not confined to patients with cerebellar ataxia Nat Genet 200024214

[79] Stevanin G Herman A Durr A et al Are (CTG)n expansions at the SCA8 locus rare polymorphisms Nat Genet 200024213-215

[80] Vincent J Neves-Pereira M Paterson A et al An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia a common expansion locus Am J Hum Genet 200066819-829

[81] Rasmussen A Matsuura T Ruano L et al Clinical and genetic analysis of four Mexican families with spinocerebellar ataxia type 10 Ann Neurol 200150234-239

[82] Worth PF Giunti P Gardner-Thorpe C et al Autosomal dominant cerebellar ataxia type III linkage in a large British family to a 76-cM region on chromosome 15q14ndash213 Am J Hum Genet 199965420-426

[83] OHearn E Holmes S Calvert P et al SCA-12 Tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion Neurology 200156299-303

[84] Holmes S OHearn E McInnis M et al Expansion of a novel CAG trinucleotide repeat in the 5 region of PPP2R2B is associated with SCA12 Nat Genet 199923391-392

[85] Fujigasaki H Verma I Camuzat A et al SCA12 is a rare locus for autosomal dominant cerebellar ataxia a study of an Indian family Ann Neurol 200149117-121

[86] Herman-Bert A Stevanin G Netter J et al Mapping of spinocerebellar ataxia 13 to chromosome 19q133-q134 in a family with autosomal dominant cerebellar ataxia and mental retardation Am J Hum Genet 200067229-235

[87] Yamashita I Sasaki H Yabe I et al A novel locus for dominant cerebellar ataxia (SCA14) maps to a 102-cM interval flanked by D19S206 and D19S605 on chromosome 19q134-qter Ann Neurol 200048156-163

[88] Miyoshi Y Yamada T Tanimura M et al A novel autosomal dominant spinocerebellar ataxia (SCA16) linked to chromosome 8q221ndash241 Neurology 20015796-100

[89] Koide R Kobayashi S Shimohata T et al A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene a new polyglutamine disease Hum Mol Genet 199982047-2053

[90] Zuhlke C Hellenbroich Y Dalski A et al Different types of repeat expansion in the TATA-binding protein gene are associated with a new form of inherited ataxia Eur J Hum Genet 20019160-164

[91] Nakamura K Jeong S Uchihara T et al SCA17 a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein Hum Mol Genet 2001101441-1448

[92] Devos D Schraen-Maschke S Vuillaume I et al Clinical features and genetic analysis of a new form of spinocerebellar ataxia Neurology 200156234-238

[93] Potter N Meyer M Zimmerman A et al Molecular and clinical findings in a family with dentatorubral-pallidoluysian atrophy Ann Neurol 199537273-277

[94] Koide R Ikeuchi T Onodera O et al Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) Nat Genet 199469-13

[95] Nagafuchi S Yanagisawa H Sato K et al Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p Nat Genet 1994614-18

[96] Nielsen J Sorensen S Hasholt L et al Dentatorubral-pallidoluysian atrophy Clinical features of a five-generation Danish family Mov Disord 199611533-541

[97] Warner T Williams L Walker R et al A clinical and molecular genetic study of dentatorubropallidoluysian atrophy in four European families Ann Neurol 199537452-459

[98] Borke J Wingfield M Lewis K et al The Haw River Syndrome dentatorubropallido-luysian atrophy (DRPLA) in an African-American family Nat Genet 19947521-524

[99] Browne D Gancher S Nutt J et al Episodic ataxiamyokymia syndrome is associated with point mutations in the human potassium channel gene KCNA1 Nat Genet 19948136-140

[100] Ophoff R Terwindt G Vergouwe M et al Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4 Cell 199687543-552

[101] Tournier-Lasserve E CACNA1A mutations hemiplegic migraine episodic ataxia type 2 and the others Neurology 1999533-4

[102] Denier C Ducros A Durr A et al Missense CACNA1A mutation causing episodic ataxia type 2 Arch Neurol 200158292-295

[103] Jen J Geschwind D Ataxia and calcium channels what a headache Arch Neurol 200158179-180

[104] Griggs R Moxley 3rd R Lafrance R et al Hereditary paroxysmal ataxia response to acetazolamide Neurology 1978281259-1264

[105] Battistini S Stenirri S Piatti M et al A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia Neurology 19995338-43

[106] Auburger G Ratzlaff T Lunkes A et al A gene for autosomal dominant paroxysmal choreoathetosisspasticity (CSE) maps to the vicinity of a potassium channel gene cluster on chromosome 1p probably within 2 cM between D1S443 and D1S197 Genomics 19963190-94

[107] Cossee M Schmitt M Campuzano V et al Evolution of the Friedreichs ataxia trinucleotide repeat expansion founder effect and premutations Proc Natl Acad Sci USA 1997947452-7457

[108] Labuda M Labuda D Miranda C et al Unique origin and specific ethnic distribution of the Friedreich ataxia GAA expansion Neurology 2000542322-2334

[109] Harding A Hewer R The heart disease of Friedreichs ataxia a clinical and electrocardiographic study of 115 patients with an analysis of serial electrocardiographic changes in 30 cases Q J Med 198352489-502

[110] Finocchiaro G Baio G Micossi P et al Glucose metabolism alterations in Friedreichs ataxia Neurology 1988381292-1296

[111] Oppenheimer D Brain lesions in Friedreichs ataxia Can J Neurol Sci 19796173-176

[112] Pandolfo M Molecular basis of Friedreich ataxia Mov Disord 200116815-821

[113] Puccio H Koenig M Recent advances in the molecular pathogenesis of Friedreich ataxia Hum Mol Genet

20009887-892

[114] Campuzano V Montermini L Molto M et al Friedreichs ataxia autosomal recessive disease caused by an intronic GAA triplet repeat expansion Science 19962711423-1427

[115] Forrest S Knight M Delatycki M et al The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene Neurogenetics 19981253-257

[116] Klockgether T Chamberlain S Wullner U et al Late-onset Friedreichs ataxia Molecular genetics clinical neurophysiology and magnetic resonance imaging Arch Neurol 199350803-806

[117] Ragno M De Michele G Cavalcanti F et al Broadened Friedreichs ataxia phenotype after gene cloning Minimal GAA expansion causes late-onset spastic ataxia Neurology 1997491617-1620

[118] Christodoulou K Deymeer F Serdaroglu P et al Mapping of the second Friedreichs ataxia (FRDA2) locus to chromosome 9p23-p11 evidence for further locus heterogeneity Neurogenetics 20013127-132

[119] Babcock M de Silva D Oaks R et al Regulation of mitochondrial iron accumulation by Yfh1p a putative homolog of frataxin Science 19972761709-1712

[120] Foury F Cazzalini O Deletion of the yeast homologue of the human gene associated with Friedreichs ataxia elicits iron accumulation in mitochondria FEBS Lett 1997411373-377

[121] Gibson T Koonin E Musco G et al Friedreichs ataxia protein phylogenetic evidence for mitochondrial dysfunction Trends Neurosci 199619465-468

[122] Koutnikova H Campuzano V Foury F et al Studies of human mouse and yeast homologues indicate a mitochondrial function for frataxin Nat Genet 199716345-351

[123] Rotig A de Lonlay P Chretien D et al Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia Nat Genet 199717215-217

[124] Wilson RB Roof DM Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue Nat Genet 199716352-357

[125] Bradley J Blake J Chamberlain S et al Clinical biochemical and molecular genetic correlations in Friedreichs ataxia Hum Mol Genet 20009275-282

[126] Rustin P von Kleist-Retzow J Chantrel-Groussard K et al Effect of idebenone on cardiomyopathy in Friedreichs ataxia a preliminary study Lancet 1999354477-479

[127] Puccio H Simon D Cossee M et al Mouse models for Friedreich ataxia exhibit cardiomyopathy sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits Nat Genet 200127181-186

[128] Harding A Early onset cerebellar ataxia with retained tendon reflexes a clinical and genetic study of a disorder distinct from Friedreichs ataxia J Neurol Neurosurg Psychiatry 198144503-508

[129] Marzouki N Belal S Benhamida C et al Genetic analysis of early onset cerebellar ataxia with retained tendon reflexes in four Tunisian families Clin Genet 200159257-262

[130] Palau F De Michele G Vilchez J et al Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreichs ataxia locus on chromosome 9q Ann Neurol 199537359-362

[131] Ouahchi K Arita M Kayden H et al Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein Nat Genet 19959141-145

[132] Catignani G Bieri J Rat liver alpha-tocopherol binding protein Biochim Biophys Acta 1977497349-357

[133] Cavalier L Ouahchi K Kayden H et al Ataxia with isolated vitamin E deficiency heterogeneity of mutations

and phenotypic variability in a large number of families Am J Hum Genet 199862301-310

[134] Jackson C Amato A Barohn R Isolated vitamin E deficiency Muscle Nerve 1996191161-1165

[135] Schuelke M Mayatepek E Inter M et al Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency J Pediatr 1999134240-244

[136] Aguglia U Annesi G Pasquinelli G et al Vitamin E deficiency due to chylomicron retention disease in Marinesco-Sjogren syndrome Ann Neurol 200047260-264

[137] Triantafillidis J Kottaras G Sgourous S et al A-beta-lipoproteinemia clinical and laboratory features therapeutic manipulations and follow-upstudy of three members of a Greek family J Clin Gastroenterol 199826207-211

[138] Stevenson V Hardie R Acanthocytosis and neurological disorders J Neurol 200124887-94

[139] Narcisi T Shoulders C Chester S et al Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia Am J Hum Genet 1995571298-1310

[140] Sharp D Blinderman L Combs K et al Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia Nature 1993365(6441)65-69

[141] Aicardi J Barbosa C Andermann E et al Ataxiandashocular motor apraxia a syndrome mimicking ataxia-telangiectasia Ann Neurol 198824497-502

[142] Barbot C Coutinho P Choro R et al Recessive ataxia with ocular apraxia review of 22 Portuguese patients Arch Neurol 200158201-205

[143] Date H Onodera O Tanaka H et al Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene Nat Genet 200129184-188

[144] Moreira MC Barbot C Tachi N et al Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13 and evidence for genetic heterogeneity Am J Hum Genet 200168501-508

[145] Moreira MC Barbot C Tachi N et al The gene mutated in ataxia-ocular apraxia 1 encodes the new HITZn-finger protein aprataxin Nat Genet 200129189-193

[146] Dawson D Recessive Ataxia With Ocular Motor Apraxia Arch Neurol 200158173-174

[147] Bouchard J Richter A Mathieu J et al Autosomal recessive spastic ataxia of Charlevoix-Saguenay Neuromuscul Disord 19988474-479

[148] Engert J Berube P Mercier J et al ARSACS a spastic ataxia common in northeastern Quebec is caused by mutations in a new gene encoding an 115-kb ORF Nat Genet 200024120-125

[149] Gucuyener K Ozgul K Paternotte C et al Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay in Two Unrelated Turkish Families Neuropediatrics 200132142-146

[150] Crawford T Ataxia telangiectasia Semin Pediatr Neurol 19985287-294

[151] Savitsky K Bar-Shira A Gilad S et al A single ataxia telangiectasia gene with a product similar to PI-3 kinase Science 19952681749-1753

[152] Lavin M Shiloh Y The genetic defect in ataxia-telangiectasia Annu Rev Immunol 199715177-202

[153] Stewart G Maser R Stankovic T et al The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder Cell 199999577-587

[154] Rapin I Lindenbaum Y Dickson D et al Cockayne syndrome and xeroderma pigmentosum Neurology

2000551442-1449

[155] Johnson R Kondratick C Prakash S et al hRAD30 mutations in the variant form of xeroderma pigmentosum Science 1999285263-265

[156] Cleaver J Thompson L Richardson A et al A summary of mutations in the UV-sensitive disorders xeroderma pigmentosum Cockayne syndrome and trichothiodystrophy Hum Mutat 1999149-22

[157] Nouspikel T Lalle P Leadon S et al A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G implications for a second XPG function Proc Natl Acad Sci USA 1997943116-3121

[158] Rolig R McKinnon P Linking DNA damage and neurodegeneration Trends Neurosci 200023417-424

[159] Meira L Graham Jr J Greenberg C et al Manitoba aboriginal kindred with original cerebro-oculo-facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene Am J Hum Genet 2000661221-1228

[160] Musumeci O Naini A Slonim A et al Familial cerebellar ataxia with muscle coenzyme Q10 deficiency Neurology 200156849-855

[161] Koskinen T Santavuori P Sainio K et al Infantile onset spinocerebellar ataxia with sensory neuropathy a new inherited disease J Neurol Sci 199412150-56

[162] Damji K Allingham R Pollock S et al Periodic vestibulocerebellar ataxia an autosomal dominant ataxia with defective smooth pursuit is genetically distinct from other autosomal dominant ataxias Arch Neurol 199653338-344

[163] Barbieri F Pellecchia M Esposito E et al Adult-onset familial laryngeal abductor paralysis cerebellar ataxia and pure motor neuropathy Neurology 2001561412-1414

[164] Quinn N Rhythmic tremor of the palate and other cranial limb muscles with cerebellar ataxia consider Whipples disease Mov Disord 200116787

[165] Nicolaides P Appleton R Fryer A Cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) a new syndrome J Med Genet 199633419-421

[166] Higgins JJ Morton DH Patronas N et al An autosonal recessive disorder with posterior column ataxia and retinitis pigmentosa Neurology 1997491717-1720

[167] Tojo K Ichinose M Nakayama M et al A new family of Boucher-Heuhauser syndrome coexistance o Holmes type cerebellar atrophy hypogonadotropic hyogonadism and retino-choroidal degeneration case reports and review of literature Endocr J 199542367-376

[168] Lerman-Sagie T Behr syndrome Pediatr Neurol 19951290

[169] Pizzatto M Pascual-Castroviejo I Behrs syndrome a report of seven cases Rev Neurol 200132721-724

[170] Jones J Kemmann E Olfacto-genital dysplasia in the female Obstet Gynecol Annu 19765443-466

[171] Hudson LD Puckett C Berndt J et al Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder Proc Natl Acad Sci USA 1989868128-8131

[172] Saugier-Veber P Munnich A Bonneau D et al X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus Nat Genet 19946257-262

[173] Johnson W The clinical spectrum of hexosaminidase deficiency diseases Neurology 1981311453-1456

[174] Hund E Grau A Fogel W et al Progressive cerebellar ataxia proximal neurogenic weakness and ocular

motor disturbances hexosaminidase A deficiency with late clinical onset in four siblings J Neurol Sci 199714525-33

[175] Ory D Niemann-Pick type C a disorder of cellular cholesterol trafficking Biochim Biophys Acta 20001529331-339

[176] Carstea E Morris J Coleman K et al Niemann-Pick C1 disease gene homology to mediators of cholesterol homeostasis Science 1997277228-231

[177] Millat G Marcais C Rafi M et al Niemann-Pick C1 disease the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype Am J Hum Genet 1999651321-1329

[178] Loonen M Van Diggelen O Janse H et al Late-onset globoid cell leucodystrophy (Krabbes disease) Clinical and genetic delineation of two forms and their relation to the early-infantile form Neuropediatrics 198516137-142

[179] Koch T Schmidt K Wagstaff J et al Neurologic complications in galactosemia Pediatr Neurol 19928217-220

[180] Moser H Molecular genetics of peroxisomal disorders Front Biosci 20015D298-D306

[181] Scotto J Hadchouel M Odievre M et al Infantile phytanic acid storage disease a possible variant of Refsums disease three cases including ultrastructural studies of the liver J Inherit Metab Dis 1982583-90

[182] Jansen G Mihalik S Watkins P et al Phytanoyl-CoA hydroxylase is present in human liver located in peroxisomes and deficient in Zellweger syndrome direct unequivocal evidence for the new revised pathway of phytanic acid alpha-oxidation in humans Biochem Biophys Res Commun 1996229205-210

[183] Jansen G Ofman R Ferdinandusse S et al Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene Nat Genet 199717190-193

[184] Mihalik S Morrell J Kim D et al Identification of PAHX a Refsum disease gene Nat Genet 199717185-189

[185] Bolla L Palmer R Paraneoplastic cerebellar degeneration Case report and literature review Arch Intern Med 19971571258-1262

[186] Dalmau J Gultekin H Posner J Paraneoplastic neurologic syndromes pathogenesis and physiopathology Brain Pathol 19999275-284

[187] Dalmau J Posner J Paraneoplastic syndromes Arch Neurol 199956405-408

[188] Trivedi R Mundanthanam G Amyes E et al Autoantibody screening in subacute cerebellar ataxia Lancet 2000356565-566

[189] Cooke W Smith W Neurological disorders associated with adult coeliac disease Brain 196689683-722

[190] Bushara K Goebel S Shill H et al Gluten sensitivity in sporadic and hereditary cerebellar ataxia Ann Neurol 200149540-543

[191] Honnorat J Saiz A Giometto B et al Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies study of 14 patients Arch Neurol 200158225-230

[192] Chinnery PF Reading PJ Milne D et al CSF antigliadin antibodies and the Ramsay Hunt syndrome Neurology 1997491131-1133

[193] Selim M Drachman D Ataxia associated with Hashimotos disease progressive non-familial adult onset cerebellardegeneration with autoimmune thyroiditis J Neurol Neurosurg Psychiatry 20017181-87

[194] Wenning GK Tison F Ben Shlomo Y et al Multiple system atrophy a review of 203 pathologically proven cases Mov Disord 199712133-147

[195] Albers D Augood S New insights into progressive supranuclear palsy Trends Neurosci 200124347-353

[196] Santacruz P Uttl B Litvan I et al Progressive supranuclear palsy a survey of the disease course Neurology 1998501637-1647

[197] Tan E-K Ashizawa T Genetic testing in spinocerebellar ataxias Defining a clinical role Arch Neurol 200158191-195

[198] Metwally MYM Textbook of neuroimaging A CD-ROM publication (Metwally MYM editor) WEB-CD agency for electronic publication version 112a April 2010

[199] Adams RD Victor M Degenerative diseases of the nervous system In Adams RD Victor M eds Principles of neurology 3rd ed New York McGraw-Hill 1985859-901

[200] Rewcastle NB Degenerative diseases of the central nervous system In Davis RL Robertson DM eds Textbook ofneuropathology 2nd ed Baltimore Williams amp Wilkins 1991904-961

[201] Klockgether T Petersen 0 Grodd W Dichgans J Early onset cerebellar ataxia with retained tendon reflexes clinical electrophys1ological and MRI observations in comparison with Friedreichrsquos ataxia Brain 199i114 1559-1573

[202] Savoiamdo M Strada L Girotti F et al Olivopontocerebollar atrophy MR diagnosis and relationship to multisystem atrophy Radiology 1990174 693-696

[203] Wessel K Schmoth G Dienem HC Murell-Forell W Dichgans J Significance of MRI-confimmed atrophy of the cranial spinal cord in Friedreichrsquos ataxia EurArch Psychiatry Clin Neurosci 1989238225-230

[204] Nicolau A Diard F Fontan 0 et al Magnetic resonance imaging in spinocerebellam degenerative diseases Pediatrie 198742359-365

[205] Bydder GM Young IR MR imaging clinical use ofthe inversion recovery sequence J Comput Assist Tomogr 19859659-675

[206] Mascalchi M Bartolozzi C Dal Pozzo G Effectiveness of the short TI inversion recovery (STIR) sequence in MR imaging of intramedullary apinal lesions Magn Reson Imaging 1993l117-25

[207] Sherman JL Nassaux PY Citrin CM Measurements of the normal cervical spinal cord on MR imaging AJNR 199011 369-372

[208] Kuhn MJ Johnson KA Davis KR Wallerian degeneration evaluation with MR imaging Radiology 1988168i99-202 11 Goodin OS Rowley HA Olney RK Magnetic resonance imaging in amyotrophic lateral sclerosis Ann Neurol 198823418-420

[209] Mascalchi M Salvi F Bartolozzi C MRI ofwallerian degeneration in the carvical spinal cord (case report) J ComputAssist Tomogr l99317824-825

[210] Friedman OP Tartaglino LM Amyotrophic lateral sclerosis hyperintensity of the corticospinal tracts on MR images of the spinal cord AJR 1993 160604-606

[211] Mascalchi M Salvi F Valzania F et al Cortico-spinal tracts degeneration in motor neuron disease report of two cases AJNR (in press)

[212] Weller RO Color atlas of neuropathology New York Oxford University Press 1984

[213] Enzmann OR DeLaPaz RL Rubin J Magnetic resonance of the spine St Louis Mosby 1990

[214] Timms SR Curersquo JK Kument JE Subacute combined degeneration of the spinal cord MR findings AJNR 1993141224-i 227

[215] Temae 5 Taneichi H Abumi K MRI of wallerian degeneration

• HOME
• CLINICAL PICTURE
• RADIOLOGICAL FINDINGS
• • Figure1
  • Figur 2
  • Figur 3
  • Figure4
  • Pathophysiology of Friedreich ataxia
  • Histologic Findings in Friedreich ataxia
  • Comment on the radiology of the previously reported case
  • • DIAGNOSIS
    • DISCUSSION
    • • AUTOSOMAL DOMINANT ATAXIA
      • AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET
      • X-LINKED ATAXIA
      • THE CONGENIAL AND METABOLIC ATAXIA
      • DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES
      • • SUMMARY
        • REFERENCES
        • MY WEB SITE
        • SHORT CASE VERSION
        • DOWNLOAD ATTACHED FILE
        • • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MY WEB SITE
          • Long case version
          • Short case version

[93] Potter N Meyer M Zimmerman A et al Molecular and clinical findings in a family with dentatorubral-pallidoluysian atrophy Ann Neurol 199537273-277

[94] Koide R Ikeuchi T Onodera O et al Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) Nat Genet 199469-13

[95] Nagafuchi S Yanagisawa H Sato K et al Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p Nat Genet 1994614-18

[96] Nielsen J Sorensen S Hasholt L et al Dentatorubral-pallidoluysian atrophy Clinical features of a five-generation Danish family Mov Disord 199611533-541

[97] Warner T Williams L Walker R et al A clinical and molecular genetic study of dentatorubropallidoluysian atrophy in four European families Ann Neurol 199537452-459

[98] Borke J Wingfield M Lewis K et al The Haw River Syndrome dentatorubropallido-luysian atrophy (DRPLA) in an African-American family Nat Genet 19947521-524

[99] Browne D Gancher S Nutt J et al Episodic ataxiamyokymia syndrome is associated with point mutations in the human potassium channel gene KCNA1 Nat Genet 19948136-140

[100] Ophoff R Terwindt G Vergouwe M et al Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4 Cell 199687543-552

[101] Tournier-Lasserve E CACNA1A mutations hemiplegic migraine episodic ataxia type 2 and the others Neurology 1999533-4

[102] Denier C Ducros A Durr A et al Missense CACNA1A mutation causing episodic ataxia type 2 Arch Neurol 200158292-295

[103] Jen J Geschwind D Ataxia and calcium channels what a headache Arch Neurol 200158179-180

[104] Griggs R Moxley 3rd R Lafrance R et al Hereditary paroxysmal ataxia response to acetazolamide Neurology 1978281259-1264

[105] Battistini S Stenirri S Piatti M et al A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia Neurology 19995338-43

[106] Auburger G Ratzlaff T Lunkes A et al A gene for autosomal dominant paroxysmal choreoathetosisspasticity (CSE) maps to the vicinity of a potassium channel gene cluster on chromosome 1p probably within 2 cM between D1S443 and D1S197 Genomics 19963190-94

[107] Cossee M Schmitt M Campuzano V et al Evolution of the Friedreichs ataxia trinucleotide repeat expansion founder effect and premutations Proc Natl Acad Sci USA 1997947452-7457

[108] Labuda M Labuda D Miranda C et al Unique origin and specific ethnic distribution of the Friedreich ataxia GAA expansion Neurology 2000542322-2334

[109] Harding A Hewer R The heart disease of Friedreichs ataxia a clinical and electrocardiographic study of 115 patients with an analysis of serial electrocardiographic changes in 30 cases Q J Med 198352489-502

[110] Finocchiaro G Baio G Micossi P et al Glucose metabolism alterations in Friedreichs ataxia Neurology 1988381292-1296

[111] Oppenheimer D Brain lesions in Friedreichs ataxia Can J Neurol Sci 19796173-176

[112] Pandolfo M Molecular basis of Friedreich ataxia Mov Disord 200116815-821

[113] Puccio H Koenig M Recent advances in the molecular pathogenesis of Friedreich ataxia Hum Mol Genet

20009887-892

[114] Campuzano V Montermini L Molto M et al Friedreichs ataxia autosomal recessive disease caused by an intronic GAA triplet repeat expansion Science 19962711423-1427

[115] Forrest S Knight M Delatycki M et al The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene Neurogenetics 19981253-257

[116] Klockgether T Chamberlain S Wullner U et al Late-onset Friedreichs ataxia Molecular genetics clinical neurophysiology and magnetic resonance imaging Arch Neurol 199350803-806

[117] Ragno M De Michele G Cavalcanti F et al Broadened Friedreichs ataxia phenotype after gene cloning Minimal GAA expansion causes late-onset spastic ataxia Neurology 1997491617-1620

[118] Christodoulou K Deymeer F Serdaroglu P et al Mapping of the second Friedreichs ataxia (FRDA2) locus to chromosome 9p23-p11 evidence for further locus heterogeneity Neurogenetics 20013127-132

[119] Babcock M de Silva D Oaks R et al Regulation of mitochondrial iron accumulation by Yfh1p a putative homolog of frataxin Science 19972761709-1712

[120] Foury F Cazzalini O Deletion of the yeast homologue of the human gene associated with Friedreichs ataxia elicits iron accumulation in mitochondria FEBS Lett 1997411373-377

[121] Gibson T Koonin E Musco G et al Friedreichs ataxia protein phylogenetic evidence for mitochondrial dysfunction Trends Neurosci 199619465-468

[122] Koutnikova H Campuzano V Foury F et al Studies of human mouse and yeast homologues indicate a mitochondrial function for frataxin Nat Genet 199716345-351

[123] Rotig A de Lonlay P Chretien D et al Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia Nat Genet 199717215-217

[124] Wilson RB Roof DM Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue Nat Genet 199716352-357

[125] Bradley J Blake J Chamberlain S et al Clinical biochemical and molecular genetic correlations in Friedreichs ataxia Hum Mol Genet 20009275-282

[126] Rustin P von Kleist-Retzow J Chantrel-Groussard K et al Effect of idebenone on cardiomyopathy in Friedreichs ataxia a preliminary study Lancet 1999354477-479

[127] Puccio H Simon D Cossee M et al Mouse models for Friedreich ataxia exhibit cardiomyopathy sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits Nat Genet 200127181-186

[128] Harding A Early onset cerebellar ataxia with retained tendon reflexes a clinical and genetic study of a disorder distinct from Friedreichs ataxia J Neurol Neurosurg Psychiatry 198144503-508

[129] Marzouki N Belal S Benhamida C et al Genetic analysis of early onset cerebellar ataxia with retained tendon reflexes in four Tunisian families Clin Genet 200159257-262

[130] Palau F De Michele G Vilchez J et al Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreichs ataxia locus on chromosome 9q Ann Neurol 199537359-362

[131] Ouahchi K Arita M Kayden H et al Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein Nat Genet 19959141-145

[132] Catignani G Bieri J Rat liver alpha-tocopherol binding protein Biochim Biophys Acta 1977497349-357

[133] Cavalier L Ouahchi K Kayden H et al Ataxia with isolated vitamin E deficiency heterogeneity of mutations

and phenotypic variability in a large number of families Am J Hum Genet 199862301-310

[134] Jackson C Amato A Barohn R Isolated vitamin E deficiency Muscle Nerve 1996191161-1165

[135] Schuelke M Mayatepek E Inter M et al Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency J Pediatr 1999134240-244

[136] Aguglia U Annesi G Pasquinelli G et al Vitamin E deficiency due to chylomicron retention disease in Marinesco-Sjogren syndrome Ann Neurol 200047260-264

[137] Triantafillidis J Kottaras G Sgourous S et al A-beta-lipoproteinemia clinical and laboratory features therapeutic manipulations and follow-upstudy of three members of a Greek family J Clin Gastroenterol 199826207-211

[138] Stevenson V Hardie R Acanthocytosis and neurological disorders J Neurol 200124887-94

[139] Narcisi T Shoulders C Chester S et al Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia Am J Hum Genet 1995571298-1310

[140] Sharp D Blinderman L Combs K et al Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia Nature 1993365(6441)65-69

[141] Aicardi J Barbosa C Andermann E et al Ataxiandashocular motor apraxia a syndrome mimicking ataxia-telangiectasia Ann Neurol 198824497-502

[142] Barbot C Coutinho P Choro R et al Recessive ataxia with ocular apraxia review of 22 Portuguese patients Arch Neurol 200158201-205

[143] Date H Onodera O Tanaka H et al Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene Nat Genet 200129184-188

[144] Moreira MC Barbot C Tachi N et al Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13 and evidence for genetic heterogeneity Am J Hum Genet 200168501-508

[145] Moreira MC Barbot C Tachi N et al The gene mutated in ataxia-ocular apraxia 1 encodes the new HITZn-finger protein aprataxin Nat Genet 200129189-193

[146] Dawson D Recessive Ataxia With Ocular Motor Apraxia Arch Neurol 200158173-174

[147] Bouchard J Richter A Mathieu J et al Autosomal recessive spastic ataxia of Charlevoix-Saguenay Neuromuscul Disord 19988474-479

[148] Engert J Berube P Mercier J et al ARSACS a spastic ataxia common in northeastern Quebec is caused by mutations in a new gene encoding an 115-kb ORF Nat Genet 200024120-125

[149] Gucuyener K Ozgul K Paternotte C et al Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay in Two Unrelated Turkish Families Neuropediatrics 200132142-146

[150] Crawford T Ataxia telangiectasia Semin Pediatr Neurol 19985287-294

[151] Savitsky K Bar-Shira A Gilad S et al A single ataxia telangiectasia gene with a product similar to PI-3 kinase Science 19952681749-1753

[152] Lavin M Shiloh Y The genetic defect in ataxia-telangiectasia Annu Rev Immunol 199715177-202

[153] Stewart G Maser R Stankovic T et al The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder Cell 199999577-587

[154] Rapin I Lindenbaum Y Dickson D et al Cockayne syndrome and xeroderma pigmentosum Neurology

2000551442-1449

[155] Johnson R Kondratick C Prakash S et al hRAD30 mutations in the variant form of xeroderma pigmentosum Science 1999285263-265

[156] Cleaver J Thompson L Richardson A et al A summary of mutations in the UV-sensitive disorders xeroderma pigmentosum Cockayne syndrome and trichothiodystrophy Hum Mutat 1999149-22

[157] Nouspikel T Lalle P Leadon S et al A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G implications for a second XPG function Proc Natl Acad Sci USA 1997943116-3121

[158] Rolig R McKinnon P Linking DNA damage and neurodegeneration Trends Neurosci 200023417-424

[159] Meira L Graham Jr J Greenberg C et al Manitoba aboriginal kindred with original cerebro-oculo-facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene Am J Hum Genet 2000661221-1228

[160] Musumeci O Naini A Slonim A et al Familial cerebellar ataxia with muscle coenzyme Q10 deficiency Neurology 200156849-855

[161] Koskinen T Santavuori P Sainio K et al Infantile onset spinocerebellar ataxia with sensory neuropathy a new inherited disease J Neurol Sci 199412150-56

[162] Damji K Allingham R Pollock S et al Periodic vestibulocerebellar ataxia an autosomal dominant ataxia with defective smooth pursuit is genetically distinct from other autosomal dominant ataxias Arch Neurol 199653338-344

[163] Barbieri F Pellecchia M Esposito E et al Adult-onset familial laryngeal abductor paralysis cerebellar ataxia and pure motor neuropathy Neurology 2001561412-1414

[164] Quinn N Rhythmic tremor of the palate and other cranial limb muscles with cerebellar ataxia consider Whipples disease Mov Disord 200116787

[165] Nicolaides P Appleton R Fryer A Cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) a new syndrome J Med Genet 199633419-421

[166] Higgins JJ Morton DH Patronas N et al An autosonal recessive disorder with posterior column ataxia and retinitis pigmentosa Neurology 1997491717-1720

[167] Tojo K Ichinose M Nakayama M et al A new family of Boucher-Heuhauser syndrome coexistance o Holmes type cerebellar atrophy hypogonadotropic hyogonadism and retino-choroidal degeneration case reports and review of literature Endocr J 199542367-376

[168] Lerman-Sagie T Behr syndrome Pediatr Neurol 19951290

[169] Pizzatto M Pascual-Castroviejo I Behrs syndrome a report of seven cases Rev Neurol 200132721-724

[170] Jones J Kemmann E Olfacto-genital dysplasia in the female Obstet Gynecol Annu 19765443-466

[171] Hudson LD Puckett C Berndt J et al Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder Proc Natl Acad Sci USA 1989868128-8131

[172] Saugier-Veber P Munnich A Bonneau D et al X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus Nat Genet 19946257-262

[173] Johnson W The clinical spectrum of hexosaminidase deficiency diseases Neurology 1981311453-1456

[174] Hund E Grau A Fogel W et al Progressive cerebellar ataxia proximal neurogenic weakness and ocular

motor disturbances hexosaminidase A deficiency with late clinical onset in four siblings J Neurol Sci 199714525-33

[175] Ory D Niemann-Pick type C a disorder of cellular cholesterol trafficking Biochim Biophys Acta 20001529331-339

[176] Carstea E Morris J Coleman K et al Niemann-Pick C1 disease gene homology to mediators of cholesterol homeostasis Science 1997277228-231

[177] Millat G Marcais C Rafi M et al Niemann-Pick C1 disease the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype Am J Hum Genet 1999651321-1329

[178] Loonen M Van Diggelen O Janse H et al Late-onset globoid cell leucodystrophy (Krabbes disease) Clinical and genetic delineation of two forms and their relation to the early-infantile form Neuropediatrics 198516137-142

[179] Koch T Schmidt K Wagstaff J et al Neurologic complications in galactosemia Pediatr Neurol 19928217-220

[180] Moser H Molecular genetics of peroxisomal disorders Front Biosci 20015D298-D306

[181] Scotto J Hadchouel M Odievre M et al Infantile phytanic acid storage disease a possible variant of Refsums disease three cases including ultrastructural studies of the liver J Inherit Metab Dis 1982583-90

[182] Jansen G Mihalik S Watkins P et al Phytanoyl-CoA hydroxylase is present in human liver located in peroxisomes and deficient in Zellweger syndrome direct unequivocal evidence for the new revised pathway of phytanic acid alpha-oxidation in humans Biochem Biophys Res Commun 1996229205-210

[183] Jansen G Ofman R Ferdinandusse S et al Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene Nat Genet 199717190-193

[184] Mihalik S Morrell J Kim D et al Identification of PAHX a Refsum disease gene Nat Genet 199717185-189

[185] Bolla L Palmer R Paraneoplastic cerebellar degeneration Case report and literature review Arch Intern Med 19971571258-1262

[186] Dalmau J Gultekin H Posner J Paraneoplastic neurologic syndromes pathogenesis and physiopathology Brain Pathol 19999275-284

[187] Dalmau J Posner J Paraneoplastic syndromes Arch Neurol 199956405-408

[188] Trivedi R Mundanthanam G Amyes E et al Autoantibody screening in subacute cerebellar ataxia Lancet 2000356565-566

[189] Cooke W Smith W Neurological disorders associated with adult coeliac disease Brain 196689683-722

[190] Bushara K Goebel S Shill H et al Gluten sensitivity in sporadic and hereditary cerebellar ataxia Ann Neurol 200149540-543

[191] Honnorat J Saiz A Giometto B et al Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies study of 14 patients Arch Neurol 200158225-230

[192] Chinnery PF Reading PJ Milne D et al CSF antigliadin antibodies and the Ramsay Hunt syndrome Neurology 1997491131-1133

[193] Selim M Drachman D Ataxia associated with Hashimotos disease progressive non-familial adult onset cerebellardegeneration with autoimmune thyroiditis J Neurol Neurosurg Psychiatry 20017181-87

[194] Wenning GK Tison F Ben Shlomo Y et al Multiple system atrophy a review of 203 pathologically proven cases Mov Disord 199712133-147

[195] Albers D Augood S New insights into progressive supranuclear palsy Trends Neurosci 200124347-353

[196] Santacruz P Uttl B Litvan I et al Progressive supranuclear palsy a survey of the disease course Neurology 1998501637-1647

[197] Tan E-K Ashizawa T Genetic testing in spinocerebellar ataxias Defining a clinical role Arch Neurol 200158191-195

[198] Metwally MYM Textbook of neuroimaging A CD-ROM publication (Metwally MYM editor) WEB-CD agency for electronic publication version 112a April 2010

[199] Adams RD Victor M Degenerative diseases of the nervous system In Adams RD Victor M eds Principles of neurology 3rd ed New York McGraw-Hill 1985859-901

[200] Rewcastle NB Degenerative diseases of the central nervous system In Davis RL Robertson DM eds Textbook ofneuropathology 2nd ed Baltimore Williams amp Wilkins 1991904-961

[201] Klockgether T Petersen 0 Grodd W Dichgans J Early onset cerebellar ataxia with retained tendon reflexes clinical electrophys1ological and MRI observations in comparison with Friedreichrsquos ataxia Brain 199i114 1559-1573

[202] Savoiamdo M Strada L Girotti F et al Olivopontocerebollar atrophy MR diagnosis and relationship to multisystem atrophy Radiology 1990174 693-696

[203] Wessel K Schmoth G Dienem HC Murell-Forell W Dichgans J Significance of MRI-confimmed atrophy of the cranial spinal cord in Friedreichrsquos ataxia EurArch Psychiatry Clin Neurosci 1989238225-230

[204] Nicolau A Diard F Fontan 0 et al Magnetic resonance imaging in spinocerebellam degenerative diseases Pediatrie 198742359-365

[205] Bydder GM Young IR MR imaging clinical use ofthe inversion recovery sequence J Comput Assist Tomogr 19859659-675

[206] Mascalchi M Bartolozzi C Dal Pozzo G Effectiveness of the short TI inversion recovery (STIR) sequence in MR imaging of intramedullary apinal lesions Magn Reson Imaging 1993l117-25

[207] Sherman JL Nassaux PY Citrin CM Measurements of the normal cervical spinal cord on MR imaging AJNR 199011 369-372

[208] Kuhn MJ Johnson KA Davis KR Wallerian degeneration evaluation with MR imaging Radiology 1988168i99-202 11 Goodin OS Rowley HA Olney RK Magnetic resonance imaging in amyotrophic lateral sclerosis Ann Neurol 198823418-420

[209] Mascalchi M Salvi F Bartolozzi C MRI ofwallerian degeneration in the carvical spinal cord (case report) J ComputAssist Tomogr l99317824-825

[210] Friedman OP Tartaglino LM Amyotrophic lateral sclerosis hyperintensity of the corticospinal tracts on MR images of the spinal cord AJR 1993 160604-606

[211] Mascalchi M Salvi F Valzania F et al Cortico-spinal tracts degeneration in motor neuron disease report of two cases AJNR (in press)

[212] Weller RO Color atlas of neuropathology New York Oxford University Press 1984

[213] Enzmann OR DeLaPaz RL Rubin J Magnetic resonance of the spine St Louis Mosby 1990

[214] Timms SR Curersquo JK Kument JE Subacute combined degeneration of the spinal cord MR findings AJNR 1993141224-i 227

[215] Temae 5 Taneichi H Abumi K MRI of wallerian degeneration

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20009887-892

[114] Campuzano V Montermini L Molto M et al Friedreichs ataxia autosomal recessive disease caused by an intronic GAA triplet repeat expansion Science 19962711423-1427

[115] Forrest S Knight M Delatycki M et al The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene Neurogenetics 19981253-257

[116] Klockgether T Chamberlain S Wullner U et al Late-onset Friedreichs ataxia Molecular genetics clinical neurophysiology and magnetic resonance imaging Arch Neurol 199350803-806

[117] Ragno M De Michele G Cavalcanti F et al Broadened Friedreichs ataxia phenotype after gene cloning Minimal GAA expansion causes late-onset spastic ataxia Neurology 1997491617-1620

[118] Christodoulou K Deymeer F Serdaroglu P et al Mapping of the second Friedreichs ataxia (FRDA2) locus to chromosome 9p23-p11 evidence for further locus heterogeneity Neurogenetics 20013127-132

[119] Babcock M de Silva D Oaks R et al Regulation of mitochondrial iron accumulation by Yfh1p a putative homolog of frataxin Science 19972761709-1712

[120] Foury F Cazzalini O Deletion of the yeast homologue of the human gene associated with Friedreichs ataxia elicits iron accumulation in mitochondria FEBS Lett 1997411373-377

[121] Gibson T Koonin E Musco G et al Friedreichs ataxia protein phylogenetic evidence for mitochondrial dysfunction Trends Neurosci 199619465-468

[122] Koutnikova H Campuzano V Foury F et al Studies of human mouse and yeast homologues indicate a mitochondrial function for frataxin Nat Genet 199716345-351

[123] Rotig A de Lonlay P Chretien D et al Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia Nat Genet 199717215-217

[124] Wilson RB Roof DM Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue Nat Genet 199716352-357

[125] Bradley J Blake J Chamberlain S et al Clinical biochemical and molecular genetic correlations in Friedreichs ataxia Hum Mol Genet 20009275-282

[126] Rustin P von Kleist-Retzow J Chantrel-Groussard K et al Effect of idebenone on cardiomyopathy in Friedreichs ataxia a preliminary study Lancet 1999354477-479

[127] Puccio H Simon D Cossee M et al Mouse models for Friedreich ataxia exhibit cardiomyopathy sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits Nat Genet 200127181-186

[128] Harding A Early onset cerebellar ataxia with retained tendon reflexes a clinical and genetic study of a disorder distinct from Friedreichs ataxia J Neurol Neurosurg Psychiatry 198144503-508

[129] Marzouki N Belal S Benhamida C et al Genetic analysis of early onset cerebellar ataxia with retained tendon reflexes in four Tunisian families Clin Genet 200159257-262

[130] Palau F De Michele G Vilchez J et al Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreichs ataxia locus on chromosome 9q Ann Neurol 199537359-362

[131] Ouahchi K Arita M Kayden H et al Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein Nat Genet 19959141-145

[132] Catignani G Bieri J Rat liver alpha-tocopherol binding protein Biochim Biophys Acta 1977497349-357

[133] Cavalier L Ouahchi K Kayden H et al Ataxia with isolated vitamin E deficiency heterogeneity of mutations

and phenotypic variability in a large number of families Am J Hum Genet 199862301-310

[134] Jackson C Amato A Barohn R Isolated vitamin E deficiency Muscle Nerve 1996191161-1165

[135] Schuelke M Mayatepek E Inter M et al Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency J Pediatr 1999134240-244

[136] Aguglia U Annesi G Pasquinelli G et al Vitamin E deficiency due to chylomicron retention disease in Marinesco-Sjogren syndrome Ann Neurol 200047260-264

[137] Triantafillidis J Kottaras G Sgourous S et al A-beta-lipoproteinemia clinical and laboratory features therapeutic manipulations and follow-upstudy of three members of a Greek family J Clin Gastroenterol 199826207-211

[138] Stevenson V Hardie R Acanthocytosis and neurological disorders J Neurol 200124887-94

[139] Narcisi T Shoulders C Chester S et al Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia Am J Hum Genet 1995571298-1310

[140] Sharp D Blinderman L Combs K et al Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia Nature 1993365(6441)65-69

[141] Aicardi J Barbosa C Andermann E et al Ataxiandashocular motor apraxia a syndrome mimicking ataxia-telangiectasia Ann Neurol 198824497-502

[142] Barbot C Coutinho P Choro R et al Recessive ataxia with ocular apraxia review of 22 Portuguese patients Arch Neurol 200158201-205

[143] Date H Onodera O Tanaka H et al Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene Nat Genet 200129184-188

[144] Moreira MC Barbot C Tachi N et al Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13 and evidence for genetic heterogeneity Am J Hum Genet 200168501-508

[145] Moreira MC Barbot C Tachi N et al The gene mutated in ataxia-ocular apraxia 1 encodes the new HITZn-finger protein aprataxin Nat Genet 200129189-193

[146] Dawson D Recessive Ataxia With Ocular Motor Apraxia Arch Neurol 200158173-174

[147] Bouchard J Richter A Mathieu J et al Autosomal recessive spastic ataxia of Charlevoix-Saguenay Neuromuscul Disord 19988474-479

[148] Engert J Berube P Mercier J et al ARSACS a spastic ataxia common in northeastern Quebec is caused by mutations in a new gene encoding an 115-kb ORF Nat Genet 200024120-125

[149] Gucuyener K Ozgul K Paternotte C et al Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay in Two Unrelated Turkish Families Neuropediatrics 200132142-146

[150] Crawford T Ataxia telangiectasia Semin Pediatr Neurol 19985287-294

[151] Savitsky K Bar-Shira A Gilad S et al A single ataxia telangiectasia gene with a product similar to PI-3 kinase Science 19952681749-1753

[152] Lavin M Shiloh Y The genetic defect in ataxia-telangiectasia Annu Rev Immunol 199715177-202

[153] Stewart G Maser R Stankovic T et al The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder Cell 199999577-587

[154] Rapin I Lindenbaum Y Dickson D et al Cockayne syndrome and xeroderma pigmentosum Neurology

2000551442-1449

[155] Johnson R Kondratick C Prakash S et al hRAD30 mutations in the variant form of xeroderma pigmentosum Science 1999285263-265

[156] Cleaver J Thompson L Richardson A et al A summary of mutations in the UV-sensitive disorders xeroderma pigmentosum Cockayne syndrome and trichothiodystrophy Hum Mutat 1999149-22

[157] Nouspikel T Lalle P Leadon S et al A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G implications for a second XPG function Proc Natl Acad Sci USA 1997943116-3121

[158] Rolig R McKinnon P Linking DNA damage and neurodegeneration Trends Neurosci 200023417-424

[159] Meira L Graham Jr J Greenberg C et al Manitoba aboriginal kindred with original cerebro-oculo-facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene Am J Hum Genet 2000661221-1228

[160] Musumeci O Naini A Slonim A et al Familial cerebellar ataxia with muscle coenzyme Q10 deficiency Neurology 200156849-855

[161] Koskinen T Santavuori P Sainio K et al Infantile onset spinocerebellar ataxia with sensory neuropathy a new inherited disease J Neurol Sci 199412150-56

[162] Damji K Allingham R Pollock S et al Periodic vestibulocerebellar ataxia an autosomal dominant ataxia with defective smooth pursuit is genetically distinct from other autosomal dominant ataxias Arch Neurol 199653338-344

[163] Barbieri F Pellecchia M Esposito E et al Adult-onset familial laryngeal abductor paralysis cerebellar ataxia and pure motor neuropathy Neurology 2001561412-1414

[164] Quinn N Rhythmic tremor of the palate and other cranial limb muscles with cerebellar ataxia consider Whipples disease Mov Disord 200116787

[165] Nicolaides P Appleton R Fryer A Cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) a new syndrome J Med Genet 199633419-421

[166] Higgins JJ Morton DH Patronas N et al An autosonal recessive disorder with posterior column ataxia and retinitis pigmentosa Neurology 1997491717-1720

[167] Tojo K Ichinose M Nakayama M et al A new family of Boucher-Heuhauser syndrome coexistance o Holmes type cerebellar atrophy hypogonadotropic hyogonadism and retino-choroidal degeneration case reports and review of literature Endocr J 199542367-376

[168] Lerman-Sagie T Behr syndrome Pediatr Neurol 19951290

[169] Pizzatto M Pascual-Castroviejo I Behrs syndrome a report of seven cases Rev Neurol 200132721-724

[170] Jones J Kemmann E Olfacto-genital dysplasia in the female Obstet Gynecol Annu 19765443-466

[171] Hudson LD Puckett C Berndt J et al Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder Proc Natl Acad Sci USA 1989868128-8131

[172] Saugier-Veber P Munnich A Bonneau D et al X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus Nat Genet 19946257-262

[173] Johnson W The clinical spectrum of hexosaminidase deficiency diseases Neurology 1981311453-1456

[174] Hund E Grau A Fogel W et al Progressive cerebellar ataxia proximal neurogenic weakness and ocular

motor disturbances hexosaminidase A deficiency with late clinical onset in four siblings J Neurol Sci 199714525-33

[175] Ory D Niemann-Pick type C a disorder of cellular cholesterol trafficking Biochim Biophys Acta 20001529331-339

[176] Carstea E Morris J Coleman K et al Niemann-Pick C1 disease gene homology to mediators of cholesterol homeostasis Science 1997277228-231

[177] Millat G Marcais C Rafi M et al Niemann-Pick C1 disease the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype Am J Hum Genet 1999651321-1329

[178] Loonen M Van Diggelen O Janse H et al Late-onset globoid cell leucodystrophy (Krabbes disease) Clinical and genetic delineation of two forms and their relation to the early-infantile form Neuropediatrics 198516137-142

[179] Koch T Schmidt K Wagstaff J et al Neurologic complications in galactosemia Pediatr Neurol 19928217-220

[180] Moser H Molecular genetics of peroxisomal disorders Front Biosci 20015D298-D306

[181] Scotto J Hadchouel M Odievre M et al Infantile phytanic acid storage disease a possible variant of Refsums disease three cases including ultrastructural studies of the liver J Inherit Metab Dis 1982583-90

[182] Jansen G Mihalik S Watkins P et al Phytanoyl-CoA hydroxylase is present in human liver located in peroxisomes and deficient in Zellweger syndrome direct unequivocal evidence for the new revised pathway of phytanic acid alpha-oxidation in humans Biochem Biophys Res Commun 1996229205-210

[183] Jansen G Ofman R Ferdinandusse S et al Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene Nat Genet 199717190-193

[184] Mihalik S Morrell J Kim D et al Identification of PAHX a Refsum disease gene Nat Genet 199717185-189

[185] Bolla L Palmer R Paraneoplastic cerebellar degeneration Case report and literature review Arch Intern Med 19971571258-1262

[186] Dalmau J Gultekin H Posner J Paraneoplastic neurologic syndromes pathogenesis and physiopathology Brain Pathol 19999275-284

[187] Dalmau J Posner J Paraneoplastic syndromes Arch Neurol 199956405-408

[188] Trivedi R Mundanthanam G Amyes E et al Autoantibody screening in subacute cerebellar ataxia Lancet 2000356565-566

[189] Cooke W Smith W Neurological disorders associated with adult coeliac disease Brain 196689683-722

[190] Bushara K Goebel S Shill H et al Gluten sensitivity in sporadic and hereditary cerebellar ataxia Ann Neurol 200149540-543

[191] Honnorat J Saiz A Giometto B et al Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies study of 14 patients Arch Neurol 200158225-230

[192] Chinnery PF Reading PJ Milne D et al CSF antigliadin antibodies and the Ramsay Hunt syndrome Neurology 1997491131-1133

[193] Selim M Drachman D Ataxia associated with Hashimotos disease progressive non-familial adult onset cerebellardegeneration with autoimmune thyroiditis J Neurol Neurosurg Psychiatry 20017181-87

[194] Wenning GK Tison F Ben Shlomo Y et al Multiple system atrophy a review of 203 pathologically proven cases Mov Disord 199712133-147

[195] Albers D Augood S New insights into progressive supranuclear palsy Trends Neurosci 200124347-353

[196] Santacruz P Uttl B Litvan I et al Progressive supranuclear palsy a survey of the disease course Neurology 1998501637-1647

[197] Tan E-K Ashizawa T Genetic testing in spinocerebellar ataxias Defining a clinical role Arch Neurol 200158191-195

[198] Metwally MYM Textbook of neuroimaging A CD-ROM publication (Metwally MYM editor) WEB-CD agency for electronic publication version 112a April 2010

[199] Adams RD Victor M Degenerative diseases of the nervous system In Adams RD Victor M eds Principles of neurology 3rd ed New York McGraw-Hill 1985859-901

[200] Rewcastle NB Degenerative diseases of the central nervous system In Davis RL Robertson DM eds Textbook ofneuropathology 2nd ed Baltimore Williams amp Wilkins 1991904-961

[201] Klockgether T Petersen 0 Grodd W Dichgans J Early onset cerebellar ataxia with retained tendon reflexes clinical electrophys1ological and MRI observations in comparison with Friedreichrsquos ataxia Brain 199i114 1559-1573

[202] Savoiamdo M Strada L Girotti F et al Olivopontocerebollar atrophy MR diagnosis and relationship to multisystem atrophy Radiology 1990174 693-696

[203] Wessel K Schmoth G Dienem HC Murell-Forell W Dichgans J Significance of MRI-confimmed atrophy of the cranial spinal cord in Friedreichrsquos ataxia EurArch Psychiatry Clin Neurosci 1989238225-230

[204] Nicolau A Diard F Fontan 0 et al Magnetic resonance imaging in spinocerebellam degenerative diseases Pediatrie 198742359-365

[205] Bydder GM Young IR MR imaging clinical use ofthe inversion recovery sequence J Comput Assist Tomogr 19859659-675

[206] Mascalchi M Bartolozzi C Dal Pozzo G Effectiveness of the short TI inversion recovery (STIR) sequence in MR imaging of intramedullary apinal lesions Magn Reson Imaging 1993l117-25

[207] Sherman JL Nassaux PY Citrin CM Measurements of the normal cervical spinal cord on MR imaging AJNR 199011 369-372

[208] Kuhn MJ Johnson KA Davis KR Wallerian degeneration evaluation with MR imaging Radiology 1988168i99-202 11 Goodin OS Rowley HA Olney RK Magnetic resonance imaging in amyotrophic lateral sclerosis Ann Neurol 198823418-420

[209] Mascalchi M Salvi F Bartolozzi C MRI ofwallerian degeneration in the carvical spinal cord (case report) J ComputAssist Tomogr l99317824-825

[210] Friedman OP Tartaglino LM Amyotrophic lateral sclerosis hyperintensity of the corticospinal tracts on MR images of the spinal cord AJR 1993 160604-606

[211] Mascalchi M Salvi F Valzania F et al Cortico-spinal tracts degeneration in motor neuron disease report of two cases AJNR (in press)

[212] Weller RO Color atlas of neuropathology New York Oxford University Press 1984

[213] Enzmann OR DeLaPaz RL Rubin J Magnetic resonance of the spine St Louis Mosby 1990

[214] Timms SR Curersquo JK Kument JE Subacute combined degeneration of the spinal cord MR findings AJNR 1993141224-i 227

[215] Temae 5 Taneichi H Abumi K MRI of wallerian degeneration

• HOME
• CLINICAL PICTURE
• RADIOLOGICAL FINDINGS
• • Figure1
  • Figur 2
  • Figur 3
  • Figure4
  • Pathophysiology of Friedreich ataxia
  • Histologic Findings in Friedreich ataxia
  • Comment on the radiology of the previously reported case
  • • DIAGNOSIS
    • DISCUSSION
    • • AUTOSOMAL DOMINANT ATAXIA
      • AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET
      • X-LINKED ATAXIA
      • THE CONGENIAL AND METABOLIC ATAXIA
      • DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES
      • • SUMMARY
        • REFERENCES
        • MY WEB SITE
        • SHORT CASE VERSION
        • DOWNLOAD ATTACHED FILE
        • • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MY WEB SITE
          • Long case version
          • Short case version

and phenotypic variability in a large number of families Am J Hum Genet 199862301-310

[134] Jackson C Amato A Barohn R Isolated vitamin E deficiency Muscle Nerve 1996191161-1165

[135] Schuelke M Mayatepek E Inter M et al Treatment of ataxia in isolated vitamin E deficiency caused by alpha-tocopherol transfer protein deficiency J Pediatr 1999134240-244

[136] Aguglia U Annesi G Pasquinelli G et al Vitamin E deficiency due to chylomicron retention disease in Marinesco-Sjogren syndrome Ann Neurol 200047260-264

[137] Triantafillidis J Kottaras G Sgourous S et al A-beta-lipoproteinemia clinical and laboratory features therapeutic manipulations and follow-upstudy of three members of a Greek family J Clin Gastroenterol 199826207-211

[138] Stevenson V Hardie R Acanthocytosis and neurological disorders J Neurol 200124887-94

[139] Narcisi T Shoulders C Chester S et al Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia Am J Hum Genet 1995571298-1310

[140] Sharp D Blinderman L Combs K et al Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia Nature 1993365(6441)65-69

[141] Aicardi J Barbosa C Andermann E et al Ataxiandashocular motor apraxia a syndrome mimicking ataxia-telangiectasia Ann Neurol 198824497-502

[142] Barbot C Coutinho P Choro R et al Recessive ataxia with ocular apraxia review of 22 Portuguese patients Arch Neurol 200158201-205

[143] Date H Onodera O Tanaka H et al Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene Nat Genet 200129184-188

[144] Moreira MC Barbot C Tachi N et al Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13 and evidence for genetic heterogeneity Am J Hum Genet 200168501-508

[145] Moreira MC Barbot C Tachi N et al The gene mutated in ataxia-ocular apraxia 1 encodes the new HITZn-finger protein aprataxin Nat Genet 200129189-193

[146] Dawson D Recessive Ataxia With Ocular Motor Apraxia Arch Neurol 200158173-174

[147] Bouchard J Richter A Mathieu J et al Autosomal recessive spastic ataxia of Charlevoix-Saguenay Neuromuscul Disord 19988474-479

[148] Engert J Berube P Mercier J et al ARSACS a spastic ataxia common in northeastern Quebec is caused by mutations in a new gene encoding an 115-kb ORF Nat Genet 200024120-125

[149] Gucuyener K Ozgul K Paternotte C et al Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay in Two Unrelated Turkish Families Neuropediatrics 200132142-146

[150] Crawford T Ataxia telangiectasia Semin Pediatr Neurol 19985287-294

[151] Savitsky K Bar-Shira A Gilad S et al A single ataxia telangiectasia gene with a product similar to PI-3 kinase Science 19952681749-1753

[152] Lavin M Shiloh Y The genetic defect in ataxia-telangiectasia Annu Rev Immunol 199715177-202

[153] Stewart G Maser R Stankovic T et al The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder Cell 199999577-587

[154] Rapin I Lindenbaum Y Dickson D et al Cockayne syndrome and xeroderma pigmentosum Neurology

2000551442-1449

[155] Johnson R Kondratick C Prakash S et al hRAD30 mutations in the variant form of xeroderma pigmentosum Science 1999285263-265

[156] Cleaver J Thompson L Richardson A et al A summary of mutations in the UV-sensitive disorders xeroderma pigmentosum Cockayne syndrome and trichothiodystrophy Hum Mutat 1999149-22

[157] Nouspikel T Lalle P Leadon S et al A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G implications for a second XPG function Proc Natl Acad Sci USA 1997943116-3121

[158] Rolig R McKinnon P Linking DNA damage and neurodegeneration Trends Neurosci 200023417-424

[159] Meira L Graham Jr J Greenberg C et al Manitoba aboriginal kindred with original cerebro-oculo-facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene Am J Hum Genet 2000661221-1228

[160] Musumeci O Naini A Slonim A et al Familial cerebellar ataxia with muscle coenzyme Q10 deficiency Neurology 200156849-855

[161] Koskinen T Santavuori P Sainio K et al Infantile onset spinocerebellar ataxia with sensory neuropathy a new inherited disease J Neurol Sci 199412150-56

[162] Damji K Allingham R Pollock S et al Periodic vestibulocerebellar ataxia an autosomal dominant ataxia with defective smooth pursuit is genetically distinct from other autosomal dominant ataxias Arch Neurol 199653338-344

[163] Barbieri F Pellecchia M Esposito E et al Adult-onset familial laryngeal abductor paralysis cerebellar ataxia and pure motor neuropathy Neurology 2001561412-1414

[164] Quinn N Rhythmic tremor of the palate and other cranial limb muscles with cerebellar ataxia consider Whipples disease Mov Disord 200116787

[165] Nicolaides P Appleton R Fryer A Cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) a new syndrome J Med Genet 199633419-421

[166] Higgins JJ Morton DH Patronas N et al An autosonal recessive disorder with posterior column ataxia and retinitis pigmentosa Neurology 1997491717-1720

[167] Tojo K Ichinose M Nakayama M et al A new family of Boucher-Heuhauser syndrome coexistance o Holmes type cerebellar atrophy hypogonadotropic hyogonadism and retino-choroidal degeneration case reports and review of literature Endocr J 199542367-376

[168] Lerman-Sagie T Behr syndrome Pediatr Neurol 19951290

[169] Pizzatto M Pascual-Castroviejo I Behrs syndrome a report of seven cases Rev Neurol 200132721-724

[170] Jones J Kemmann E Olfacto-genital dysplasia in the female Obstet Gynecol Annu 19765443-466

[171] Hudson LD Puckett C Berndt J et al Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder Proc Natl Acad Sci USA 1989868128-8131

[172] Saugier-Veber P Munnich A Bonneau D et al X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus Nat Genet 19946257-262

[173] Johnson W The clinical spectrum of hexosaminidase deficiency diseases Neurology 1981311453-1456

[174] Hund E Grau A Fogel W et al Progressive cerebellar ataxia proximal neurogenic weakness and ocular

motor disturbances hexosaminidase A deficiency with late clinical onset in four siblings J Neurol Sci 199714525-33

[175] Ory D Niemann-Pick type C a disorder of cellular cholesterol trafficking Biochim Biophys Acta 20001529331-339

[176] Carstea E Morris J Coleman K et al Niemann-Pick C1 disease gene homology to mediators of cholesterol homeostasis Science 1997277228-231

[177] Millat G Marcais C Rafi M et al Niemann-Pick C1 disease the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype Am J Hum Genet 1999651321-1329

[178] Loonen M Van Diggelen O Janse H et al Late-onset globoid cell leucodystrophy (Krabbes disease) Clinical and genetic delineation of two forms and their relation to the early-infantile form Neuropediatrics 198516137-142

[179] Koch T Schmidt K Wagstaff J et al Neurologic complications in galactosemia Pediatr Neurol 19928217-220

[180] Moser H Molecular genetics of peroxisomal disorders Front Biosci 20015D298-D306

[181] Scotto J Hadchouel M Odievre M et al Infantile phytanic acid storage disease a possible variant of Refsums disease three cases including ultrastructural studies of the liver J Inherit Metab Dis 1982583-90

[182] Jansen G Mihalik S Watkins P et al Phytanoyl-CoA hydroxylase is present in human liver located in peroxisomes and deficient in Zellweger syndrome direct unequivocal evidence for the new revised pathway of phytanic acid alpha-oxidation in humans Biochem Biophys Res Commun 1996229205-210

[183] Jansen G Ofman R Ferdinandusse S et al Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene Nat Genet 199717190-193

[184] Mihalik S Morrell J Kim D et al Identification of PAHX a Refsum disease gene Nat Genet 199717185-189

[185] Bolla L Palmer R Paraneoplastic cerebellar degeneration Case report and literature review Arch Intern Med 19971571258-1262

[186] Dalmau J Gultekin H Posner J Paraneoplastic neurologic syndromes pathogenesis and physiopathology Brain Pathol 19999275-284

[187] Dalmau J Posner J Paraneoplastic syndromes Arch Neurol 199956405-408

[188] Trivedi R Mundanthanam G Amyes E et al Autoantibody screening in subacute cerebellar ataxia Lancet 2000356565-566

[189] Cooke W Smith W Neurological disorders associated with adult coeliac disease Brain 196689683-722

[190] Bushara K Goebel S Shill H et al Gluten sensitivity in sporadic and hereditary cerebellar ataxia Ann Neurol 200149540-543

[191] Honnorat J Saiz A Giometto B et al Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies study of 14 patients Arch Neurol 200158225-230

[192] Chinnery PF Reading PJ Milne D et al CSF antigliadin antibodies and the Ramsay Hunt syndrome Neurology 1997491131-1133

[193] Selim M Drachman D Ataxia associated with Hashimotos disease progressive non-familial adult onset cerebellardegeneration with autoimmune thyroiditis J Neurol Neurosurg Psychiatry 20017181-87

[194] Wenning GK Tison F Ben Shlomo Y et al Multiple system atrophy a review of 203 pathologically proven cases Mov Disord 199712133-147

[195] Albers D Augood S New insights into progressive supranuclear palsy Trends Neurosci 200124347-353

[196] Santacruz P Uttl B Litvan I et al Progressive supranuclear palsy a survey of the disease course Neurology 1998501637-1647

[197] Tan E-K Ashizawa T Genetic testing in spinocerebellar ataxias Defining a clinical role Arch Neurol 200158191-195

[198] Metwally MYM Textbook of neuroimaging A CD-ROM publication (Metwally MYM editor) WEB-CD agency for electronic publication version 112a April 2010

[199] Adams RD Victor M Degenerative diseases of the nervous system In Adams RD Victor M eds Principles of neurology 3rd ed New York McGraw-Hill 1985859-901

[200] Rewcastle NB Degenerative diseases of the central nervous system In Davis RL Robertson DM eds Textbook ofneuropathology 2nd ed Baltimore Williams amp Wilkins 1991904-961

[201] Klockgether T Petersen 0 Grodd W Dichgans J Early onset cerebellar ataxia with retained tendon reflexes clinical electrophys1ological and MRI observations in comparison with Friedreichrsquos ataxia Brain 199i114 1559-1573

[202] Savoiamdo M Strada L Girotti F et al Olivopontocerebollar atrophy MR diagnosis and relationship to multisystem atrophy Radiology 1990174 693-696

[203] Wessel K Schmoth G Dienem HC Murell-Forell W Dichgans J Significance of MRI-confimmed atrophy of the cranial spinal cord in Friedreichrsquos ataxia EurArch Psychiatry Clin Neurosci 1989238225-230

[204] Nicolau A Diard F Fontan 0 et al Magnetic resonance imaging in spinocerebellam degenerative diseases Pediatrie 198742359-365

[205] Bydder GM Young IR MR imaging clinical use ofthe inversion recovery sequence J Comput Assist Tomogr 19859659-675

[206] Mascalchi M Bartolozzi C Dal Pozzo G Effectiveness of the short TI inversion recovery (STIR) sequence in MR imaging of intramedullary apinal lesions Magn Reson Imaging 1993l117-25

[207] Sherman JL Nassaux PY Citrin CM Measurements of the normal cervical spinal cord on MR imaging AJNR 199011 369-372

[208] Kuhn MJ Johnson KA Davis KR Wallerian degeneration evaluation with MR imaging Radiology 1988168i99-202 11 Goodin OS Rowley HA Olney RK Magnetic resonance imaging in amyotrophic lateral sclerosis Ann Neurol 198823418-420

[209] Mascalchi M Salvi F Bartolozzi C MRI ofwallerian degeneration in the carvical spinal cord (case report) J ComputAssist Tomogr l99317824-825

[210] Friedman OP Tartaglino LM Amyotrophic lateral sclerosis hyperintensity of the corticospinal tracts on MR images of the spinal cord AJR 1993 160604-606

[211] Mascalchi M Salvi F Valzania F et al Cortico-spinal tracts degeneration in motor neuron disease report of two cases AJNR (in press)

[212] Weller RO Color atlas of neuropathology New York Oxford University Press 1984

[213] Enzmann OR DeLaPaz RL Rubin J Magnetic resonance of the spine St Louis Mosby 1990

[214] Timms SR Curersquo JK Kument JE Subacute combined degeneration of the spinal cord MR findings AJNR 1993141224-i 227

[215] Temae 5 Taneichi H Abumi K MRI of wallerian degeneration

• HOME
• CLINICAL PICTURE
• RADIOLOGICAL FINDINGS
• • Figure1
  • Figur 2
  • Figur 3
  • Figure4
  • Pathophysiology of Friedreich ataxia
  • Histologic Findings in Friedreich ataxia
  • Comment on the radiology of the previously reported case
  • • DIAGNOSIS
    • DISCUSSION
    • • AUTOSOMAL DOMINANT ATAXIA
      • AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET
      • X-LINKED ATAXIA
      • THE CONGENIAL AND METABOLIC ATAXIA
      • DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES
      • • SUMMARY
        • REFERENCES
        • MY WEB SITE
        • SHORT CASE VERSION
        • DOWNLOAD ATTACHED FILE
        • • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MY WEB SITE
          • Long case version
          • Short case version

2000551442-1449

[155] Johnson R Kondratick C Prakash S et al hRAD30 mutations in the variant form of xeroderma pigmentosum Science 1999285263-265

[156] Cleaver J Thompson L Richardson A et al A summary of mutations in the UV-sensitive disorders xeroderma pigmentosum Cockayne syndrome and trichothiodystrophy Hum Mutat 1999149-22

[157] Nouspikel T Lalle P Leadon S et al A common mutational pattern in Cockayne syndrome patients from xeroderma pigmentosum group G implications for a second XPG function Proc Natl Acad Sci USA 1997943116-3121

[158] Rolig R McKinnon P Linking DNA damage and neurodegeneration Trends Neurosci 200023417-424

[159] Meira L Graham Jr J Greenberg C et al Manitoba aboriginal kindred with original cerebro-oculo-facio-skeletal syndrome has a mutation in the Cockayne syndrome group B (CSB) gene Am J Hum Genet 2000661221-1228

[160] Musumeci O Naini A Slonim A et al Familial cerebellar ataxia with muscle coenzyme Q10 deficiency Neurology 200156849-855

[161] Koskinen T Santavuori P Sainio K et al Infantile onset spinocerebellar ataxia with sensory neuropathy a new inherited disease J Neurol Sci 199412150-56

[162] Damji K Allingham R Pollock S et al Periodic vestibulocerebellar ataxia an autosomal dominant ataxia with defective smooth pursuit is genetically distinct from other autosomal dominant ataxias Arch Neurol 199653338-344

[163] Barbieri F Pellecchia M Esposito E et al Adult-onset familial laryngeal abductor paralysis cerebellar ataxia and pure motor neuropathy Neurology 2001561412-1414

[164] Quinn N Rhythmic tremor of the palate and other cranial limb muscles with cerebellar ataxia consider Whipples disease Mov Disord 200116787

[165] Nicolaides P Appleton R Fryer A Cerebellar ataxia areflexia pes cavus optic atrophy and sensorineural hearing loss (CAPOS) a new syndrome J Med Genet 199633419-421

[166] Higgins JJ Morton DH Patronas N et al An autosonal recessive disorder with posterior column ataxia and retinitis pigmentosa Neurology 1997491717-1720

[167] Tojo K Ichinose M Nakayama M et al A new family of Boucher-Heuhauser syndrome coexistance o Holmes type cerebellar atrophy hypogonadotropic hyogonadism and retino-choroidal degeneration case reports and review of literature Endocr J 199542367-376

[168] Lerman-Sagie T Behr syndrome Pediatr Neurol 19951290

[169] Pizzatto M Pascual-Castroviejo I Behrs syndrome a report of seven cases Rev Neurol 200132721-724

[170] Jones J Kemmann E Olfacto-genital dysplasia in the female Obstet Gynecol Annu 19765443-466

[171] Hudson LD Puckett C Berndt J et al Mutation of the proteolipid protein gene PLP in a human X chromosome-linked myelin disorder Proc Natl Acad Sci USA 1989868128-8131

[172] Saugier-Veber P Munnich A Bonneau D et al X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus Nat Genet 19946257-262

[173] Johnson W The clinical spectrum of hexosaminidase deficiency diseases Neurology 1981311453-1456

[174] Hund E Grau A Fogel W et al Progressive cerebellar ataxia proximal neurogenic weakness and ocular

motor disturbances hexosaminidase A deficiency with late clinical onset in four siblings J Neurol Sci 199714525-33

[175] Ory D Niemann-Pick type C a disorder of cellular cholesterol trafficking Biochim Biophys Acta 20001529331-339

[176] Carstea E Morris J Coleman K et al Niemann-Pick C1 disease gene homology to mediators of cholesterol homeostasis Science 1997277228-231

[177] Millat G Marcais C Rafi M et al Niemann-Pick C1 disease the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype Am J Hum Genet 1999651321-1329

[178] Loonen M Van Diggelen O Janse H et al Late-onset globoid cell leucodystrophy (Krabbes disease) Clinical and genetic delineation of two forms and their relation to the early-infantile form Neuropediatrics 198516137-142

[179] Koch T Schmidt K Wagstaff J et al Neurologic complications in galactosemia Pediatr Neurol 19928217-220

[180] Moser H Molecular genetics of peroxisomal disorders Front Biosci 20015D298-D306

[181] Scotto J Hadchouel M Odievre M et al Infantile phytanic acid storage disease a possible variant of Refsums disease three cases including ultrastructural studies of the liver J Inherit Metab Dis 1982583-90

[182] Jansen G Mihalik S Watkins P et al Phytanoyl-CoA hydroxylase is present in human liver located in peroxisomes and deficient in Zellweger syndrome direct unequivocal evidence for the new revised pathway of phytanic acid alpha-oxidation in humans Biochem Biophys Res Commun 1996229205-210

[183] Jansen G Ofman R Ferdinandusse S et al Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene Nat Genet 199717190-193

[184] Mihalik S Morrell J Kim D et al Identification of PAHX a Refsum disease gene Nat Genet 199717185-189

[185] Bolla L Palmer R Paraneoplastic cerebellar degeneration Case report and literature review Arch Intern Med 19971571258-1262

[186] Dalmau J Gultekin H Posner J Paraneoplastic neurologic syndromes pathogenesis and physiopathology Brain Pathol 19999275-284

[187] Dalmau J Posner J Paraneoplastic syndromes Arch Neurol 199956405-408

[188] Trivedi R Mundanthanam G Amyes E et al Autoantibody screening in subacute cerebellar ataxia Lancet 2000356565-566

[189] Cooke W Smith W Neurological disorders associated with adult coeliac disease Brain 196689683-722

[190] Bushara K Goebel S Shill H et al Gluten sensitivity in sporadic and hereditary cerebellar ataxia Ann Neurol 200149540-543

[191] Honnorat J Saiz A Giometto B et al Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies study of 14 patients Arch Neurol 200158225-230

[192] Chinnery PF Reading PJ Milne D et al CSF antigliadin antibodies and the Ramsay Hunt syndrome Neurology 1997491131-1133

[193] Selim M Drachman D Ataxia associated with Hashimotos disease progressive non-familial adult onset cerebellardegeneration with autoimmune thyroiditis J Neurol Neurosurg Psychiatry 20017181-87

[194] Wenning GK Tison F Ben Shlomo Y et al Multiple system atrophy a review of 203 pathologically proven cases Mov Disord 199712133-147

[195] Albers D Augood S New insights into progressive supranuclear palsy Trends Neurosci 200124347-353

[196] Santacruz P Uttl B Litvan I et al Progressive supranuclear palsy a survey of the disease course Neurology 1998501637-1647

[197] Tan E-K Ashizawa T Genetic testing in spinocerebellar ataxias Defining a clinical role Arch Neurol 200158191-195

[198] Metwally MYM Textbook of neuroimaging A CD-ROM publication (Metwally MYM editor) WEB-CD agency for electronic publication version 112a April 2010

[199] Adams RD Victor M Degenerative diseases of the nervous system In Adams RD Victor M eds Principles of neurology 3rd ed New York McGraw-Hill 1985859-901

[200] Rewcastle NB Degenerative diseases of the central nervous system In Davis RL Robertson DM eds Textbook ofneuropathology 2nd ed Baltimore Williams amp Wilkins 1991904-961

[201] Klockgether T Petersen 0 Grodd W Dichgans J Early onset cerebellar ataxia with retained tendon reflexes clinical electrophys1ological and MRI observations in comparison with Friedreichrsquos ataxia Brain 199i114 1559-1573

[202] Savoiamdo M Strada L Girotti F et al Olivopontocerebollar atrophy MR diagnosis and relationship to multisystem atrophy Radiology 1990174 693-696

[203] Wessel K Schmoth G Dienem HC Murell-Forell W Dichgans J Significance of MRI-confimmed atrophy of the cranial spinal cord in Friedreichrsquos ataxia EurArch Psychiatry Clin Neurosci 1989238225-230

[204] Nicolau A Diard F Fontan 0 et al Magnetic resonance imaging in spinocerebellam degenerative diseases Pediatrie 198742359-365

[205] Bydder GM Young IR MR imaging clinical use ofthe inversion recovery sequence J Comput Assist Tomogr 19859659-675

[206] Mascalchi M Bartolozzi C Dal Pozzo G Effectiveness of the short TI inversion recovery (STIR) sequence in MR imaging of intramedullary apinal lesions Magn Reson Imaging 1993l117-25

[207] Sherman JL Nassaux PY Citrin CM Measurements of the normal cervical spinal cord on MR imaging AJNR 199011 369-372

[208] Kuhn MJ Johnson KA Davis KR Wallerian degeneration evaluation with MR imaging Radiology 1988168i99-202 11 Goodin OS Rowley HA Olney RK Magnetic resonance imaging in amyotrophic lateral sclerosis Ann Neurol 198823418-420

[209] Mascalchi M Salvi F Bartolozzi C MRI ofwallerian degeneration in the carvical spinal cord (case report) J ComputAssist Tomogr l99317824-825

[210] Friedman OP Tartaglino LM Amyotrophic lateral sclerosis hyperintensity of the corticospinal tracts on MR images of the spinal cord AJR 1993 160604-606

[211] Mascalchi M Salvi F Valzania F et al Cortico-spinal tracts degeneration in motor neuron disease report of two cases AJNR (in press)

[212] Weller RO Color atlas of neuropathology New York Oxford University Press 1984

[213] Enzmann OR DeLaPaz RL Rubin J Magnetic resonance of the spine St Louis Mosby 1990

[214] Timms SR Curersquo JK Kument JE Subacute combined degeneration of the spinal cord MR findings AJNR 1993141224-i 227

[215] Temae 5 Taneichi H Abumi K MRI of wallerian degeneration

• HOME
• CLINICAL PICTURE
• RADIOLOGICAL FINDINGS
• • Figure1
  • Figur 2
  • Figur 3
  • Figure4
  • Pathophysiology of Friedreich ataxia
  • Histologic Findings in Friedreich ataxia
  • Comment on the radiology of the previously reported case
  • • DIAGNOSIS
    • DISCUSSION
    • • AUTOSOMAL DOMINANT ATAXIA
      • AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET
      • X-LINKED ATAXIA
      • THE CONGENIAL AND METABOLIC ATAXIA
      • DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES
      • • SUMMARY
        • REFERENCES
        • MY WEB SITE
        • SHORT CASE VERSION
        • DOWNLOAD ATTACHED FILE
        • • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MY WEB SITE
          • Long case version
          • Short case version

motor disturbances hexosaminidase A deficiency with late clinical onset in four siblings J Neurol Sci 199714525-33

[175] Ory D Niemann-Pick type C a disorder of cellular cholesterol trafficking Biochim Biophys Acta 20001529331-339

[176] Carstea E Morris J Coleman K et al Niemann-Pick C1 disease gene homology to mediators of cholesterol homeostasis Science 1997277228-231

[177] Millat G Marcais C Rafi M et al Niemann-Pick C1 disease the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype Am J Hum Genet 1999651321-1329

[178] Loonen M Van Diggelen O Janse H et al Late-onset globoid cell leucodystrophy (Krabbes disease) Clinical and genetic delineation of two forms and their relation to the early-infantile form Neuropediatrics 198516137-142

[179] Koch T Schmidt K Wagstaff J et al Neurologic complications in galactosemia Pediatr Neurol 19928217-220

[180] Moser H Molecular genetics of peroxisomal disorders Front Biosci 20015D298-D306

[181] Scotto J Hadchouel M Odievre M et al Infantile phytanic acid storage disease a possible variant of Refsums disease three cases including ultrastructural studies of the liver J Inherit Metab Dis 1982583-90

[182] Jansen G Mihalik S Watkins P et al Phytanoyl-CoA hydroxylase is present in human liver located in peroxisomes and deficient in Zellweger syndrome direct unequivocal evidence for the new revised pathway of phytanic acid alpha-oxidation in humans Biochem Biophys Res Commun 1996229205-210

[183] Jansen G Ofman R Ferdinandusse S et al Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene Nat Genet 199717190-193

[184] Mihalik S Morrell J Kim D et al Identification of PAHX a Refsum disease gene Nat Genet 199717185-189

[185] Bolla L Palmer R Paraneoplastic cerebellar degeneration Case report and literature review Arch Intern Med 19971571258-1262

[186] Dalmau J Gultekin H Posner J Paraneoplastic neurologic syndromes pathogenesis and physiopathology Brain Pathol 19999275-284

[187] Dalmau J Posner J Paraneoplastic syndromes Arch Neurol 199956405-408

[188] Trivedi R Mundanthanam G Amyes E et al Autoantibody screening in subacute cerebellar ataxia Lancet 2000356565-566

[189] Cooke W Smith W Neurological disorders associated with adult coeliac disease Brain 196689683-722

[190] Bushara K Goebel S Shill H et al Gluten sensitivity in sporadic and hereditary cerebellar ataxia Ann Neurol 200149540-543

[191] Honnorat J Saiz A Giometto B et al Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies study of 14 patients Arch Neurol 200158225-230

[192] Chinnery PF Reading PJ Milne D et al CSF antigliadin antibodies and the Ramsay Hunt syndrome Neurology 1997491131-1133

[193] Selim M Drachman D Ataxia associated with Hashimotos disease progressive non-familial adult onset cerebellardegeneration with autoimmune thyroiditis J Neurol Neurosurg Psychiatry 20017181-87

[194] Wenning GK Tison F Ben Shlomo Y et al Multiple system atrophy a review of 203 pathologically proven cases Mov Disord 199712133-147

[195] Albers D Augood S New insights into progressive supranuclear palsy Trends Neurosci 200124347-353

[196] Santacruz P Uttl B Litvan I et al Progressive supranuclear palsy a survey of the disease course Neurology 1998501637-1647

[197] Tan E-K Ashizawa T Genetic testing in spinocerebellar ataxias Defining a clinical role Arch Neurol 200158191-195

[198] Metwally MYM Textbook of neuroimaging A CD-ROM publication (Metwally MYM editor) WEB-CD agency for electronic publication version 112a April 2010

[199] Adams RD Victor M Degenerative diseases of the nervous system In Adams RD Victor M eds Principles of neurology 3rd ed New York McGraw-Hill 1985859-901

[200] Rewcastle NB Degenerative diseases of the central nervous system In Davis RL Robertson DM eds Textbook ofneuropathology 2nd ed Baltimore Williams amp Wilkins 1991904-961

[201] Klockgether T Petersen 0 Grodd W Dichgans J Early onset cerebellar ataxia with retained tendon reflexes clinical electrophys1ological and MRI observations in comparison with Friedreichrsquos ataxia Brain 199i114 1559-1573

[202] Savoiamdo M Strada L Girotti F et al Olivopontocerebollar atrophy MR diagnosis and relationship to multisystem atrophy Radiology 1990174 693-696

[203] Wessel K Schmoth G Dienem HC Murell-Forell W Dichgans J Significance of MRI-confimmed atrophy of the cranial spinal cord in Friedreichrsquos ataxia EurArch Psychiatry Clin Neurosci 1989238225-230

[204] Nicolau A Diard F Fontan 0 et al Magnetic resonance imaging in spinocerebellam degenerative diseases Pediatrie 198742359-365

[205] Bydder GM Young IR MR imaging clinical use ofthe inversion recovery sequence J Comput Assist Tomogr 19859659-675

[206] Mascalchi M Bartolozzi C Dal Pozzo G Effectiveness of the short TI inversion recovery (STIR) sequence in MR imaging of intramedullary apinal lesions Magn Reson Imaging 1993l117-25

[207] Sherman JL Nassaux PY Citrin CM Measurements of the normal cervical spinal cord on MR imaging AJNR 199011 369-372

[208] Kuhn MJ Johnson KA Davis KR Wallerian degeneration evaluation with MR imaging Radiology 1988168i99-202 11 Goodin OS Rowley HA Olney RK Magnetic resonance imaging in amyotrophic lateral sclerosis Ann Neurol 198823418-420

[209] Mascalchi M Salvi F Bartolozzi C MRI ofwallerian degeneration in the carvical spinal cord (case report) J ComputAssist Tomogr l99317824-825

[210] Friedman OP Tartaglino LM Amyotrophic lateral sclerosis hyperintensity of the corticospinal tracts on MR images of the spinal cord AJR 1993 160604-606

[211] Mascalchi M Salvi F Valzania F et al Cortico-spinal tracts degeneration in motor neuron disease report of two cases AJNR (in press)

[212] Weller RO Color atlas of neuropathology New York Oxford University Press 1984

[213] Enzmann OR DeLaPaz RL Rubin J Magnetic resonance of the spine St Louis Mosby 1990

[214] Timms SR Curersquo JK Kument JE Subacute combined degeneration of the spinal cord MR findings AJNR 1993141224-i 227

[215] Temae 5 Taneichi H Abumi K MRI of wallerian degeneration

• HOME
• CLINICAL PICTURE
• RADIOLOGICAL FINDINGS
• • Figure1
  • Figur 2
  • Figur 3
  • Figure4
  • Pathophysiology of Friedreich ataxia
  • Histologic Findings in Friedreich ataxia
  • Comment on the radiology of the previously reported case
  • • DIAGNOSIS
    • DISCUSSION
    • • AUTOSOMAL DOMINANT ATAXIA
      • AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET
      • X-LINKED ATAXIA
      • THE CONGENIAL AND METABOLIC ATAXIA
      • DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES
      • • SUMMARY
        • REFERENCES
        • MY WEB SITE
        • SHORT CASE VERSION
        • DOWNLOAD ATTACHED FILE
        • • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MY WEB SITE
          • Long case version
          • Short case version

[194] Wenning GK Tison F Ben Shlomo Y et al Multiple system atrophy a review of 203 pathologically proven cases Mov Disord 199712133-147

[195] Albers D Augood S New insights into progressive supranuclear palsy Trends Neurosci 200124347-353

[196] Santacruz P Uttl B Litvan I et al Progressive supranuclear palsy a survey of the disease course Neurology 1998501637-1647

[197] Tan E-K Ashizawa T Genetic testing in spinocerebellar ataxias Defining a clinical role Arch Neurol 200158191-195

[198] Metwally MYM Textbook of neuroimaging A CD-ROM publication (Metwally MYM editor) WEB-CD agency for electronic publication version 112a April 2010

[199] Adams RD Victor M Degenerative diseases of the nervous system In Adams RD Victor M eds Principles of neurology 3rd ed New York McGraw-Hill 1985859-901

[200] Rewcastle NB Degenerative diseases of the central nervous system In Davis RL Robertson DM eds Textbook ofneuropathology 2nd ed Baltimore Williams amp Wilkins 1991904-961

[201] Klockgether T Petersen 0 Grodd W Dichgans J Early onset cerebellar ataxia with retained tendon reflexes clinical electrophys1ological and MRI observations in comparison with Friedreichrsquos ataxia Brain 199i114 1559-1573

[202] Savoiamdo M Strada L Girotti F et al Olivopontocerebollar atrophy MR diagnosis and relationship to multisystem atrophy Radiology 1990174 693-696

[203] Wessel K Schmoth G Dienem HC Murell-Forell W Dichgans J Significance of MRI-confimmed atrophy of the cranial spinal cord in Friedreichrsquos ataxia EurArch Psychiatry Clin Neurosci 1989238225-230

[204] Nicolau A Diard F Fontan 0 et al Magnetic resonance imaging in spinocerebellam degenerative diseases Pediatrie 198742359-365

[205] Bydder GM Young IR MR imaging clinical use ofthe inversion recovery sequence J Comput Assist Tomogr 19859659-675

[206] Mascalchi M Bartolozzi C Dal Pozzo G Effectiveness of the short TI inversion recovery (STIR) sequence in MR imaging of intramedullary apinal lesions Magn Reson Imaging 1993l117-25

[207] Sherman JL Nassaux PY Citrin CM Measurements of the normal cervical spinal cord on MR imaging AJNR 199011 369-372

[208] Kuhn MJ Johnson KA Davis KR Wallerian degeneration evaluation with MR imaging Radiology 1988168i99-202 11 Goodin OS Rowley HA Olney RK Magnetic resonance imaging in amyotrophic lateral sclerosis Ann Neurol 198823418-420

[209] Mascalchi M Salvi F Bartolozzi C MRI ofwallerian degeneration in the carvical spinal cord (case report) J ComputAssist Tomogr l99317824-825

[210] Friedman OP Tartaglino LM Amyotrophic lateral sclerosis hyperintensity of the corticospinal tracts on MR images of the spinal cord AJR 1993 160604-606

[211] Mascalchi M Salvi F Valzania F et al Cortico-spinal tracts degeneration in motor neuron disease report of two cases AJNR (in press)

[212] Weller RO Color atlas of neuropathology New York Oxford University Press 1984

[213] Enzmann OR DeLaPaz RL Rubin J Magnetic resonance of the spine St Louis Mosby 1990

[214] Timms SR Curersquo JK Kument JE Subacute combined degeneration of the spinal cord MR findings AJNR 1993141224-i 227

[215] Temae 5 Taneichi H Abumi K MRI of wallerian degeneration

• HOME
• CLINICAL PICTURE
• RADIOLOGICAL FINDINGS
• • Figure1
  • Figur 2
  • Figur 3
  • Figure4
  • Pathophysiology of Friedreich ataxia
  • Histologic Findings in Friedreich ataxia
  • Comment on the radiology of the previously reported case
  • • DIAGNOSIS
    • DISCUSSION
    • • AUTOSOMAL DOMINANT ATAXIA
      • AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET
      • X-LINKED ATAXIA
      • THE CONGENIAL AND METABOLIC ATAXIA
      • DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES
      • • SUMMARY
        • REFERENCES
        • MY WEB SITE
        • SHORT CASE VERSION
        • DOWNLOAD ATTACHED FILE
        • • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MY WEB SITE
          • Long case version
          • Short case version

[214] Timms SR Curersquo JK Kument JE Subacute combined degeneration of the spinal cord MR findings AJNR 1993141224-i 227

[215] Temae 5 Taneichi H Abumi K MRI of wallerian degeneration

• HOME
• CLINICAL PICTURE
• RADIOLOGICAL FINDINGS
• • Figure1
  • Figur 2
  • Figur 3
  • Figure4
  • Pathophysiology of Friedreich ataxia
  • Histologic Findings in Friedreich ataxia
  • Comment on the radiology of the previously reported case
  • • DIAGNOSIS
    • DISCUSSION
    • • AUTOSOMAL DOMINANT ATAXIA
      • AUTOSOMAL RECESSIVE ATAXIA WITH CHILDHOOD OR JUVENILE ONSET
      • X-LINKED ATAXIA
      • THE CONGENIAL AND METABOLIC ATAXIA
      • DIAGNOSTIC STRATEGY FOR ATAXIC SYNDROMES
      • • SUMMARY
        • REFERENCES
        • MY WEB SITE
        • SHORT CASE VERSION
        • DOWNLOAD ATTACHED FILE
        • • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • Precontrast MRI T1
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MRI T2
          • MY WEB SITE
          • Long case version
          • Short case version