Approach to the Differential Diagnosisof Cerebellar Ataxias

Francesc Palau and Carmen Espinós

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2The Natural History and Pathophysiological Approaches of Ataxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Autosomal Recessive Cerebellar Ataxias (ARCAs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Autosomal Dominant Cerebellar Ataxias (ADCAs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Episodic Ataxias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10X-Linked Cerebellar Ataxias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Mitochondrial Cerebellar Ataxias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Idiopathic Late-Onset Cerebellar Ataxias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Spastic Ataxias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Molecular Genetics of Ataxias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

AbstractAtaxias are a complex and heterogeneous group of disorders characterized bythe absence of order and coordination of voluntary movements and loss ofbalance. The global nosological spectrum includes early versus late onset,

F. Palau (*)Department of Genetic & Molecular Medicine and Pediatric Institute of Rare Diseases (IPER),Sant Joan de Déu Children’s Hospital, Barcelona, Spain

CIBER on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain

Division of Pediatrics, University of Barcelona School of Medicine and Health Sciences, and ClínicInstitute of Medicine and Dermatology, Hospital Clínic, Barcelona, Spaine-mail: fpalau@sjdhospitalbarcelona.org; fpalau@hsjdbcn.org

C. EspinósCentro de Investigación Príncipe Felipe, Valencia, Spaine-mail: fpalau@sjdhospitalbarcelona.org; fpalau@hsjdbcn.org

© Springer Nature Switzerland AG 2020M. Manto et al. (eds.), Handbook of the Cerebellum and Cerebellar Disorders,https://doi.org/10.1007/978-3-319-97911-3_81-2

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cerebellar versus sensory pathophysiology, and genetic versus nongenetic causes.In the diagnostic process, information on family history is a fundamental tool forclassifying the patient’s disorder as hereditary ataxia or sporadic ataxia. Thedifferential diagnosis should be addressed taking into account four clinical andbiological criteria: (1) clinical picture, age of onset, and natural history; (2) bio-chemical and neuroimaging markers; (3) Mendelian or mitochondrial inheritancepattern versus sporadic case without family history; and (4) genetic tests of ataxiagenes and specific mutations. Genome sequencing is becoming a crucial tool inthe differential diagnosis of ataxia.

KeywordsAnticipation (related to dynamic mutations) · Ataxia-telangiectasia (AT) ·Autosomal dominant cerebellar ataxia (ADCA) · Autosomal recessive cerebellarataxia (ARCA) · Carrier frequency · Carrier testing · Coenzyme Q10 · De novomutation · Dentatorubropallidoluysian atrophy (DRPLA) · Dynamic mutation ·Episodic ataxia (EA) · Ethnicity · Founder mutation · Fragile X-associatedtremor/ataxia syndrome (FXTAS) · Friedreich’s ataxia (FRDA) · Geneticcounseling · Genetic epidemiology · Genetic testing · Genome sequencing ·Geographic group · Hereditary ataxia · Heteroplasmy · Idiopathic late-onsetcerebellar ataxia (ILOCA) · Mitochondrial disorders with ataxia · Mitochondrialinheritance · Multiple system atrophy (MSA) · Polyglutamine tract · Prevalence ·Sensory ataxia · Spastic ataxia · Spinocerebellar ataxia · Sporadic adult-onsetataxia (SAOA) of unknown etiology · Trinucleotide repeat · Vestibular ataxia ·Whole exome sequencing (WES) · Whole genomic sequencing (WGS) · X-linked ataxia

Introduction

The term ataxia – literally meaning disorderliness, confusion, and irregularity –refers to the absence of order and coordination of voluntary movements and atendency on the part of the patient’s body to lose the balance. The uncoordinatedmovement or clumsiness occurs without loss of muscle power. In this way ataxiarepresents a clinical symptom that can be associated with a number of severalneurological disorders. Ataxia and vertigo are the main manifestations of the disor-ders associated with loss of equilibrium. Vertigo is the clinical expression ofmalfunction of central or peripheral vestibular pathways. On the other hand, ataxiais the consequence of pathological changes in the cerebellum or sensory pathways.The use, however, of the word ataxia has evolved in a wider concept, and currently itis used to define a large number of cerebellar and spinocerebellar degenerations forwhich ataxia are a prominent symptom. The involved structures of the nervoussystem in the pathology of ataxias are basal ganglia, midbrain, cerebellum and spinalcord, and the connecting tracts and pathways (Jafar-Nejad et al. 2017).

The history of the contemporaneous concept of ataxia started with the clinical andpathological description of degenerative disorders associated with ataxia, which

2 F. Palau and C. Espinós

included Friedreich’s ataxia (FRDA), olivopontocerebellar atrophy, cortical cerebel-lar atrophy, and other classical syndromes (see for review Berciano et al. 2000).Along with the clinicopathological recognition of ataxias as a group of differentiateddisorders, inheritance has become a relevant feature of ataxias. In fact, it wasNikolaus Friedreich who introduced the concept of hereditary ataxia in the fivepapers reported between 1863 and 1877 where he described Friedreich’s ataxia innine patients from five families. In 1983 Anita Harding (1983, 1993) proposed aclassification of ataxias based on clinical data and genetic information obtained fromthe family history and genealogical pedigree. This author distinguished congenitaldisorders associated with ataxia, ataxic disorders with known metabolic or defectiveDNA repair, and ataxic disorders of unknown etiology. The latter group includedearly-onset cerebellar ataxias that usually begin before the age of 20 years (most ofthem with autosomal recessive inheritance and currently referred to autosomalrecessive cerebellar ataxias or ARCA) and late-onset cerebellar ataxias (onsetusually after 20 years), which includes autosomal dominant cerebellar ataxias(ADCA), periodic autosomal dominant ataxias (episodic ataxias, EA), and idiopathiclate-onset cerebellar ataxias (ILOCA). Finally, a minor and less known groupincludes the X-linked forms.

The seminal Harding’s classification of hereditary ataxias – and also spasticparaplegias – coincided with the beginning of modern human molecular geneticsand the application of linkage analysis and positional cloning to map disease genesand mutant gene identification. The first gene associated with ADCA was thatcausing spinocerebellar ataxia type 1 (SCA1) in 1993 associated with the exonicexpansion of a CAG trinucleotide repeat that encodes for a polyglutamine tract(Orr et al. 1993). This finding allowed to include autosomal dominant cerebellarataxias (referred to as spinocerebellar ataxias or SCA in the genetic terminology) inthe new field of dynamic mutations previously described for X-fragile syndrome,myotonic dystrophy, and Huntington disease. In 1996, the Friedreich’s ataxia geneFXN, mapped on chromosome 9q13 in 1988, was described along with the expan-sion on the intronic GAA repeat as the main mutation causing the disease. Sincethen, a large number of genes associated with inherited ataxias have been reported.Currently, more than 120 genes that may be inherited following any type ofMendelian or mitochondrial inheritance pattern have been reported (Bird 2019;Javadev and Bird 2013). A genetic classification of ataxias based on both Mendelianinheritance and molecular genetics is being used in clinical medicine. In addition,modern genomics is now a powerful diagnostic tool that allows differential diagnosisof familial and sporadic ataxias more efficiently and is also applied in geneticcounseling of patients and families. This chapter will focus on differential diagnosisof ataxias based on clinical features, topology (somatotopic) organization of ataxicsyndromes, chronobiology and progression pattern, inheritance, and moleculargenetics.

Approach to the Differential Diagnosis of Cerebellar Ataxias 3

The Natural History and Pathophysiological Approaches of Ataxia

Four aspects of the disease presentation are relevant when orienting a clinical andsyndromic diagnosis of ataxias, that is, the topological level at the nervous systeminvolvement, the focal versus nonfocal extension of the disorder, the progressionrate, and the age at onset.

Equilibrium depends upon continuous provision of proprioceptive, visual, andlabyrinthine information and its integration in the brainstem and the cerebellum.Hence, ataxia is caused by cerebellar, sensory, or vestibular disorders. The patho-logical pattern underlying the type of ataxia affects stance and posture, gait, trunkand limbs, eye movement, and speech, in a different fashion. Cerebellar ataxia isproduced by lesions of the cerebellum itself or its afferent or efferent connectionswith spinal cord (ventral spinocerebellar tract), reticular nucleus, red nucleus, andthalamus. Patients may present hypotonia, which results in defective maintenance ofposture. Voluntary movements are uncoordinated and delayed in onset; the rate,rhythm, amplitude, and force of movement fluctuate, showing a jerky appearance.The stance and gait are wide-based and unsteady. Patients with cerebellar ataxiacannot stand up with either open or closed eyes. Common symptoms are dysarthria,intention tremor, dysmetria, and asynergia. Movements that involve rapid changes indirection are severely affected. Because of the role of cerebellum in the control ofeye movements, abnormal ocular movements are frequently observed in cerebellardiseases. These include nystagmus, gaze paresis due to concomitant brainsteminvolvement, and defective saccadic and pursuit movements. Sensory ataxia resultsfrom disorders that affect one or several parts of the proprioceptive pathway thatincludes peripheral sensory nerves, dorsal root ganglia, posterior columns of thespinal cord (fasciculus gracilis and fasciculus cuneatus), or medial lemnisci. Sensoryataxia from peripheral neuropathy or posterior cord lesion or degeneration typicallyaffects gait and legs in a symmetrical way. Patients show impaired sensation of jointposition and vibration sense of affected limbs. Lower limb reflexes are depressed orabsent, and further in the evolution, upper limb reflexes may be also affected in thesame way. Patients show the Romberg’s sign. They are able to stand with feettogether and eyes open but not with eyes closed. Nystagmus, dysarthria, and vertigoare absent. Vestibular ataxia represents abnormal movement coordination usuallyassociated with vertigo. It results from identical peripheral and central lesions atvestibular semicircular canals and vestibular nucleus that cause vertigo. Nystagmusis frequent and often unilateral and dysarthria does not occur. Limb ataxia is absent.Reflexes and position and vibration senses are normal as well.

Causes of focal cerebellar disease are tumor, abscess, hemorrhage, or focaldemyelination. The clinical expression is related to the localization of the lesion inthe middle zone of the cerebellum – the vermis and flocculonodular lobe and thesubcortical fastigial nuclei – or in the cerebellar hemispheres. Distinction betweenfocal and diffuse disease – degenerative, metabolic, toxic, paraneoplastic syndrome– is easily made by the information provides by the history and examination of thepatient. Acute onset, vomiting, headache, and unilateral symptoms strongly argue infavor of a focal disorder. Neuroimaging of the cerebellum, brainstem, and brain,

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especially magnetic resonance imaging (MRI), is very useful to distinguish betweenfocal and diffuse lesions and to define the specific zone where focal lesion is located.

Information about the time course is frequently useful to establish a workingdiagnosis. Sudden onset and rapid progression of ataxia or associated symptomsoccurs in ischemic or hemorrhagic disorders, acute presentation of a tumor, or drugintoxication by ethanol, sedative-hypnotics (e.g., barbiturates, benzodiazepines,meprobamate), or anticonvulsivants (e.g., phenytoin). Subacute presentation butalso rapidly progressive are also frequent in cerebellar encephalitis associated withviral infection, paraneoplastic cerebellar degeneration, Wernicke’s encephalopathycaused by thiamine deficiency in chronic alcoholism or malnutrition, and transmis-sible spongiform encephalopathy. Nutritional disorders (e.g., vitamin B12 or vitaminE deficiency) may be expressed as a chronic disorder over weeks to months. Chronicand progressive disequilibrium syndrome over months to years is characteristic ofspinocerebellar degenerations, either hereditary or sporadic, and multiple systematrophy (MSA).

Age at onset has been a clinical criterion to orientate differential diagnosis ofataxias. Classically, early-onset ataxia, either familial or sporadic, has been associ-ated with autosomal recessive inheritance. However, in rare cases, X-linked, mito-chondrial, or autosomal dominant inheritance may underlay a sporadic patient.Apparent sporadic dominant cases may be the consequence of a de novo mutationincluding expansion of a dynamic mutation, but sometimes the sporadic appearanceis due to uninformative family history or false fatherhood. Late-onset ataxias use tostart after the age of 25 years. Whereas familial cases do not represent difficulties,finding the causes of sporadic cases is often a diagnostic challenge. Late-onsetsporadic patients can be divided in sporadic cases of hereditary ataxia, sporadicpatients due to identifiable exogenous causes, cerebellar type of MSA, or idiopathiclate-onset cerebellar ataxia when no cause is found.

Current research in natural history of disease and diagnostic and therapeuticaspects of ataxia have to be combined with the increasing knowledge on genetics(Bird 2019) and molecular mechanisms and pathways (Synofzik et al. 2019;Klockgether et al. 2019) underlying ataxia pathophysiology.

Autosomal Recessive Cerebellar Ataxias (ARCAs)

ARCAs are rare and encompass a group of genetic heterogeneous diseases (seeTable 1 for specific genetic and laboratory features of most frequent diseases). So fardifferent criteria have been used to classify ARCAs (Harding 1993; Di Donato et al.2001; Palau and Espinós 2006; Embiruçu et al. 2009; Manto and Marmolino 2009;Anheim et al. 2012). Awidely accepted classification considers the following groupsof diseases: (1) congenital or developmental ataxias; (2) metabolic ataxias; (3) ataxiawith DNA repair defects; (4) degenerative and progressive ataxias; and (5) ataxiawith additional features. However, diagnosis and therapeutics of ARCA requiresnew classifications, mainly based on understanding mechanisms inspired on theunderlying gene and pathways. This is an evolving field moving very rapidly.

Approach to the Differential Diagnosis of Cerebellar Ataxias 5

Table 1 Prevalence, involved genes, and laboratory tests of main ARCAs

Prevalence Gene Laboratory tests

Friedreich’s ataxia(FRDA)

Average prevalence 2–4/100,000 (Pandolfo2008); 4.7/100,000 inSpain (Polo et al. 1991,Lopez-Arlandis et al.1995)

FXN 98% of patients arehomozygous for anabnormal intronic GAAexpansion; 2% ofpatients are compoundheterozygous for GGAexpansion and a pointmutation

Ataxia Telangiectasia(AT)

Average prevalence1–2.5/100,000

ATM Elevation of serumα-fetoproteinKaryotypeReducedimmunoglobulins

Ataxia with oculomotorapraxia type 1 (AOA1)/early-onset ataxia withocular motor apraxiaand hypoalbuminemia(EAOH)

2nd cause of autosomalrecessive ataxia inPortugal (Barbot et al.2001)

APTX LDL cholesterolincreasedHypoalbuminemiaGenetic analysis of theexons 5, 6, 7

Ataxia with oculomotorapraxia type 2 (AOA2)/spinocerebellar ataxiaautosomal recessive 1(SCAR1)

2nd cause of autosomalrecessive ataxia in Alsace(France) (Anheim et al.2010)

SETX Creatine kinaseincreasedElevation of serumα-fetoprotein

Ataxia with isolatedvitamin E deficiency(AVED)

Founder mutations:c.513insTT in Europeand c.744delA in NorthAfrica (Di Donato et al.2010)

TTPA Undetectable serumvitamin EHigh serum cholesterol,triglyceride, and beta-lipoproteinDefective liver“tocopherol bindingprotein”

Abetalipoproteinemia(ABL)

<1/1,000,000 MTP Acanthocytosis on bloodsmearsDecreased lipids (LDL,triglycerides,apolipoprotein B)Identification ofsteatorrhea and truncatedapolipoprotein B afteroral lipid intakeDecreased liposolublevitamins (A, E, K)

Sensory ataxicneuropathy, dysarthria,ophthalmoparesis(SANDO)

POLGTwinkle

Red ragged fibers onmuscle biopsy

Cerebrotendinousxanthomatosis (CTX)

1:108 in MoroccanSephardic Jewish(Berginer and Abeliovich1981)

CYP27A1 Increased serumcholestanol

(continued)

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Finding common pathways for ARCAs and other ataxias is important to define newdiagnostic and prognostic biomarkers and to share molecular targets for differenttherapeutic approaches. In this way, it is becoming relevant to define clusters ofshared molecular themes such as mitochondrial metabolism and biology, DNArepair and genome stability, and complex lipid metabolism (Synofzik et al. 2019).

FRDA and ataxia-telangiectasia (AT) have been reported to be the two mostfrequent ARCAs. However, several ARCAs, such as ataxia with isolated vitamin Edeficiency (AVED), ataxia with oculomotor apraxia type 1 (AOA1) and type2 (AOA2), and Marinesco-Sjögren syndrome (MSS), although lesser frequent,have a relevant prevalence and should be considered in genetic testing irrespectiveof ethnic origins (Anheim et al. 2010). Other ataxia conditions are becomingincreasingly recognized, such as the autosomal recessive spastic ataxia ofCharlevoix-Saguenay (ARSACS, SACS gene) and spinocerebellar ataxia autosomalrecessive 8 (SCAR8, SYNE1 gene) that are not anymore restricted to the French-Canadian community but also worldwide distributed (Coutelier et al. 2018; Synofziket al. 2019). According to the type of mutation, only FRDA is caused by a dynamicexpansion, and the remaining ARCAs are due to conventional mutations. Theprogress in the knowledge has allowed the identification of more than 60 genesinvolved in ARCAs (Bird 2019; Neuromuscular Disease Center; http://neuromuscular.wustl.edu/ataxia/domatax.html).

FRDA is characterized by early disease onset, areflexia, dysarthria and signs ofposterior column dysfunction (Harding 1981a; Dürr et al. 1997). The triad ofabsence or hypoactive knee and ankle jerks, signs of progressive cerebellar dysfunc-tion, and preadolescent onset is commonly regarded as sufficient for diagnosis.However, patients with late onset after 25 years (De Michele et al. 1994; Dürr

Table 1 (continued)

Prevalence Gene Laboratory tests

Autosomal recessivecerebellar ataxia2 (ARCA2)/spinocerebellar ataxiaautosomal recessive9 (SCAR9)

3 families from Algeriaand 1 from USA (Lagier-Tourenne et al. 2008)

CABC1 Elevate lactate levelsCoenzyme Q10deficiency in muscle

Spinocerebellar ataxiatype 1 with axonalneuropathy (SCAN1)

TDP1 Increased LDLcholesterolHypoalbuminemia

Marinesco-Sjögrensyndrome (MSS)

<1/1,000,000 SIL1 Increased serum creatinekinase

Cerebellar ataxia withCoQ deficiency

COQ2,PDSS1,PDSS2,CABC1,COQ9

Reduction of CoQ levelsin muscle and/orfibroblasts

Approach to the Differential Diagnosis of Cerebellar Ataxias 7

et al. 1997) or presence of normal or brisk tendon reflexes (Palau et al. 1995; Cruz-Martínez et al. 1997; Dürr et al. 1997) have been reported and are not unusualphenotypes. FRDA patients are homozygous for the GAA expansion or compoundheterozygous for a GAA expanded allele and point mutation (Dürr et al. 1997;Cossée et al. 1999; De Castro et al. 2000). Patients with non-expanded GAA alleleshave not been reported; thus, analysis of the GAA repeat in the FXN gene isconclusive for diagnosis of the disease. AVED shows very similar clinical features.In some cases, they are identical to those of FRDA, although cardiomyopathy likethat of FRDA has not been reported in patients with AVED (Ben Hamida et al.1993). Other ARCAs with a highly particular clinical phenotype are AT, which ischaracterized by telangiectasias, immune defects and a predisposition to malignancy,and cerebrotendinous xanthomatosis, a lipid storage disease characterized byxanthomas, premature atherosclerosis, and cataracts. Cerebellar ataxia associatedwith primary coenzyme Q (CoQ) deficiency is characterized by the presence of avariable degree of CoQ reduction in muscle and/or fibroblasts and variable responseto CoQ supplementation (Artuch et al. 2006; Pineda et al. 2010). The disease is dueto mutations in some of the genes involved in the CoQ biosynthesis.

FRDA is the commonest ARCA worldwide with an estimated prevalence inCaucasian population of 1/25,000 to 1/50,000 (López-Arlandis et al. 1995; Pandolfo2008) and a carrier frequency of 1/85 (Fogel and Perlman 2007). The second mostfrequent ARCA is ataxia-telangiectasia (1–2.5/100,000). Other ARCA forms aremuch less common. The relative frequencies of the different ataxias vary widelyamong different ethnic and geographic groups, presumably due to founder effects.Thus, ataxia with oculomotor apraxia type I (AOA1) is the second most frequentform of ARCA in Portugal (Barbot et al. 2001). Autosomal recessive spastic ataxiaof Charlevoix-Saguenay (ARSACS) caused by mutations in the sacsin gene shows acarrier frequency of 1/21 in French Canadian of the Saguenay-Lac-Saint-Jean regionof northeastern Quebec (De Braekeleer et al. 1993), although mutations in the sacsingene have also been found responsible for early-onset ataxia in 37% of Dutchprobands (Vermeer et al. 2008).

The presence of multiple affected sibs in a single generation or consanguinity inthe parents supports the idea of an autosomal recessive mode of inheritance. InARCAs, as in other autosomal recessive diseases, carriers of only one disease-causing mutation in a gene (heterozygote) are not at risk of developing the disease.Both asymptomatic parents of an affected child are obligate carriers in heterozygosisof a mutation. At conception, each sib of a couple of carrier individuals has a 25%chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25%chance of being unaffected and not a carrier. Once an at-risk sib is known to beunaffected, the risk of his/her being a carrier is 2/3. Testing relatives at risk for thepurpose of early diagnosis and treatment require prior identification of the disease-causing mutations in the family. Similarly, prenatal testing or preimplantationgenetic diagnosis is usually offered to families with known disease-causing muta-tions. ARCAs frequently occur as sporadic disorders, the first case in the family, andtherefore, with a previous negative family history.

8 F. Palau and C. Espinós

Autosomal Dominant Cerebellar Ataxias (ADCAs)

More than 45 SCA loci/genes have been associated with ADCA phenotypes.Dentatorubropallidoluysian atrophy (DRPLA) is also included in this nosologicalgroup of genetic disorders (Bird 2019; Neuromuscular Disease Center; http://neuromuscular.wustl.edu/ataxia/domatax.html). Other autosomal dominant diseases withataxia, like adult-onset leukodystrophy or spastic ataxia syndromes, are heteroge-neous rare disorders. According to the type of mutation, dynamic mutations (CAGrepeats in exons or 50 untranslated regions, and penta- or hexanucleotides intronicrepeats) are responsible for 12 types of SCAs (types 1, 2, 3, 6, 7, 8, 10, 12, 17, 31,36, and 37) and DRPLA. In the last 10 years, a number of genes involved in otherless frequent types of SCAs have been described, so a diagnosis test is now availablebased mainly on massive genome sequencing searching for conventional mutations(Klockgether et al. 2019).

The phenotypic classification by Harding (1982) that categorized three groups ofADCAs may be useful to perform an accurate genetic testing. ADCA type I refers toataxia plus impairment of other neuronal systems, ADCA type II is ataxia plus retinaldegeneration, and ADCA type III is described as pure cerebellar ataxias as a non-life-limiting disease. For ADCA type I, the first genes to be tested are SCA1, SCA2,and SCA3. ADCA type II is almost exclusively associated with SCA7 mutations.And finally, for ADCA type III, SCA6 and SCA12 should be the first genes to beanalyzed. Moreover, regarding more specific clinical features, tremor is usuallyfound in patients with SCA2, SCA8, or SCA12, or dystonia and/or spasticity ispresent in patients with SCA3.

Epidemiology may also help to perform an accurate and rapid genetic diagnosis.Distribution and prevalence of SCAs assessed in population-based studies cases withan average of 2.7 cases per 100,000 inhabitants worldwide (ranged from 0 to 5.6)(Ruano et al. 2014). With respect to SCAs, SCA3 is the commonest subtypeworldwide and together with SCA1, SCA2, SCA6, and SCA7 are the most frequentforms, accounting for 50–80% of ADCA families. The remaining forms are thoughtto be<1%, and at least 20% of ADCA families do not carry any of the yet identifiedSCA genes (van de Warrenburg et al. 2002; Schols 2003). Frequency of eachtype can substantially vary depending on the geographical region and foundereffects. SCA2 has a prevalence of 43/100,000 in the province of Holguín (Cuba)(Orozco et al. 1989) and SCA3 of 714/100,000 in the Azorean island Flores(Stevanin et al. 1995). DRPLA is considered to be rare in Europe, whereas inJapan, where the prevalence of ADCAs has been estimated in 22/100,000,DRPLA is the second cause of ADCA accounting for 10% of the cases afterSCA6 (19%) (Shimizu et al. 2004).

A familial disorder affecting successive generation is suggestive of autosomaldominant cerebellar ataxias. As in other autosomal dominant disorders, each child ofan individual who suffer from an ADCA has a 50% chance of inheriting themutation. Prenatal diagnosis is usually offered to families in which the disease-causing mutation is known. Preimplantation genetic diagnosis is becoming a newdiagnostic option in reproductive medicine for patients suffering a dominant

Approach to the Differential Diagnosis of Cerebellar Ataxias 9

cerebellar ataxia. The patient should have a family history before testing the genes,although ADCAs can manifest as sporadic disorders with adult onset. Mutationscould be analyzed in sporadic cases despite a negative family history. Family historycould be uninformative because the patient is adopted or the parent died beforereaching the onset age. Nonpaternity or de novo mutations should be options to betaken into account as well. Too little data are available to estimate the proportion ofcases resulting from a de novo mutation. The frequency of positive tests in appar-ently sporadic ataxia patients ranged from 0.5% to 22% (Moseley et al. 1998; Pujanaet al. 1999; Schols et al. 2000; Dürr 2010).

Episodic Ataxias

Episodic ataxias (EAs) are autosomal dominant disorders characterized by intermit-tent episodes of ataxias. Seven loci have been associated with episodic ataxias, andmutations in four genes have been reported. The most frequent types, EA-1 andEA-2, can be distinguished on clinical grounds. EA-1 manifests without vertigoand is associated with interictal myokymia, and EA-2 manifests with vertigo and isassociated with interictal nystagmus, and in these patients, acetazolamide oftendramatically stops the spells. Attacks of ataxia can last minutes in a patient withEA-1, whereas can last hours and even days, in a patient with EA-2. Both types ofEAs are due to mutations in ion channels. EA-1 is caused by mutations in theKCNA1 gene that encodes an α-subunit of a voltage-dependent potassium ionchannel, whereas EA-2 is caused by point mutations in the CACNA1A gene,which is translated in the α1A-subunit of the calcium voltage-dependent channel.Interestingly, point mutations in the same gene also caused familial hemiplegicmigraine (FHM), and CAG expansion in the COOH-terminal exon 47 causesSCA6. Thus, EA-2, FMH, and autosomal dominant cerebellar ataxia SCA6 areallelic disorders (Baloh and Jen 2000; Brunt 2000; Jen et al. 2007). More recently,mutations in the CACNA1A gene have been identified in patients with early infantileepileptic encephalopathy 42 (EEIE42) (Epi4K Consortium 2016).

X-Linked Cerebellar Ataxias

In X-linked diseases, males who inherit the mutation will be affected; femaleswho inherit the mutation will be carriers and may or may not be develop clinicalsymptoms. The severity of clinical findings in female may also dependent on theX-chromosome inactivation patterns (Lyonization). If the mother is a carrier,the chance of transmitting the mutation in each pregnancy is 50%, being carriermales affected. If the father is affected, he will necessarily transmit the mutation toall his daughters and never to his sons. Carrier testing for at-risk relatives andprenatal testing for pregnancies at increased risk are possible if the disease-causingmutation in the family is known.

10 F. Palau and C. Espinós

Few X-linked ataxias have been documented (Neuromuscular Disease Center;http://neuromuscular.wustl.edu/ataxia/domatax.html). The fragile X-associatedtremor/ataxia syndrome (FXTAS) is the most frequent (Zanni and Bertini 2011).The prevalence of FXTAS is estimated to be 1/4,000 in men and 1/7,800 in women(Hall and Jacquemont 2010). Prevalence in women is much lower because of theprotective effect of the second X chromosome. Other X-linked ataxias are Artssyndrome and X-linked sideroblastic anemia (XLSA). In these two disorders,female carriers may manifest some clinical findings usually in early adulthood.Some X-linked SCAs have been described (SCAX1 to SCAX5), and the causinggenes have been reported in the last years (see overview by Bird 2019). All theseX-linked forms are congenital ones, except the SCAX4 type. Other congenitalX-linked ataxias are syndromic forms associated with mental retardation, such asthe X-linked syndromic mental retardation Christianson type (MRXS-Christianson).Finally, an episodic ataxia is also described inherited as a recessive X-linked trait:the pyruvate dehydrogenase E1-α deficiency. All these X-linked forms are very raredisorders with estimated prevalence of <1/1,000,000.

Mitochondrial Cerebellar Ataxias

Mitochondrial disorders refer to a group of diseases associated with abnormalities ofthe mitochondrial energy metabolism, mainly the oxidative phosphorylation(OXPHOS), which can result from defects of mitochondrial proteins, either codedby the mitochondrial (mtDNA) or by the nuclear DNA (Chinnery 2014; Gormanet al. 2016). This section refers to ataxias caused by mutations on the mtDNA and,therefore, inherited through the maternal line. The mother of a proband usually hasthe mtDNA mutation and may or may not have symptoms, whereas the father is notat risk of having it. A male with an mtDNA mutation cannot transmit the mutation toany of his offspring. A female with the mutation (whether affected or unaffected)transmits the mutation to all of her offspring.

Disorders due to mutations in the mitochondrial genome are characterized byheteroplasmy, which makes the genetic counseling difficult. This can result invarying tissue distribution of mutated mtDNA. Mutations are usually detectedin mtDNA from leukocytes, but it can also happen that the pathogenic mutationmay be undetectable in mtDNA from leukocytes and may be detected only in othertissues, mainly skeletal muscle. Prenatal diagnosis for mitochondrial disorders ispossible if a mtDNA mutation has been detected in the mother. However, againheteroplasmy makes difficult genetic counseling. The mutational load in themother’s tissues and in the fetal tissues sampled (amniocytes, chorionic villi) maynot correspond to that of other fetal tissues. Moreover, clinical features in mitochon-drial disease are related to the mutational load within affected individuals (Chinneryand Turnbull 1997; Chinnery et al. 1998). Consequently, prediction of the clinicalphenotype from prenatal studies is not possible.

Some of the examples of mitochondrial disorders manifesting with ataxia includeMELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis,

Approach to the Differential Diagnosis of Cerebellar Ataxias 11

stroke-like syndrome), MERRF (myoclonic epilepsy with ragged red fibers), NARP(neurogenic muscle weakness, ataxia, and retinitis pigmentosa), and KSS (Kearns-Sayre syndrome). The commonest form of these diseases is MELAS with anestimated prevalence of 1–5/10,000, followed by KSS and NARP whose prevalencevary between 1 and 9/100,000, and, finally, MERFF which is a very rare disorderwith a prevalence of 1–9/1,000,000 (Orphanet, www.orpha.net). In these four ataxiasas happens in other mitochondrial diseases, the vast majority of cases are producedby the same mutation. Thus, nearly the 80% of individuals who suffer from MELAScarry the m.3243A>G mutation in theMT-TL1 gene encoding leucine transfer RNAgene (tRNA-Leu) (Yasukawa et al. 2000). Other mutations in theMT-TL1 gene or inother mtDNA genes, particularly MT-ND5, can also cause this disorder. Them.8993T>G in the MT-ATP6 (subunit 6 of mitochondrial ATP synthase)gene accounts for nearly 50% of cases with NARP (de Coo et al. 1996; Whiteet al. 1999). In the same sense, 80% of patients with MERFF are carriers of them.8344A>G mutation in the MT-TK gene which encodes for lysine transfer RNAgene (tRNA-Lys) (Shoffner and Wallace 1992). KSS can result of point mutations,although by far the majority of patients carry a large deletion of mtDNA (Moraeset al. 1989).

Idiopathic Late-Onset Cerebellar Ataxias

Idiopathic late-onset cerebellar ataxias (ILOCAs), a term originally introduced byHarding (1981b), comprise a variety of cerebellar syndromes whose underlyingmechanisms are still unknown and that may present with a pure cerebellar syndromeor with additional non-cerebellar features. Prevalence estimates for ILOCA cases arelimited; a prevalence of 2.2 per 100,000 inhabitants was reported in Cantabria,Northern Spain (Polo et al. 1991), and later a prevalence of 10.8/100,000 has beenreported in the United Kingdom (Muzaimi et al. 2004). The cerebellar variant ofMSA is a pathologically and clinically well-defined ILOCA (Quinn 2020). To avoidmistakes, Klockgether has proposed the term sporadic adult-onset ataxia (SAOA) ofunknown etiology (Klockgether 2010). Thus the diagnosis of ILOCA is made bycarefully ruling out acquired and genetic causes of ataxia, as well as MSA. ClinicallyILOCA syndromes are heterogeneous; course and prognosis vary markedly betweenpatients. A wide spectrum of nongenetic and genetic causes have to be consideredwhen addressing the diagnosis of a sporadic ataxic patient with no familial history(see for review Klockgether 2010). Acquired forms of sporadic ataxia includechronic alcoholism and other toxic ataxias; paraneoplastic cerebellar degenerations;ataxias due to acquired vitamin deficiency as vitamin B1, vitamin B12, or vitamin E;superficial siderosis; ataxia in chronic infection (i.e., ataxia associated withCreutzfeldt-Jakob disease); and acute viral encephalitis, which is the most frequentsporadic nongenetic cause of ataxia in children. Natural history and anamnesisare very relevant to address the correct diagnosis of sporadic ataxia. Also importantin diagnosis are neuroimaging, especially MRI, and analysis of biomarkers.Autoantibodies are relevant diagnostic biomarkers for immune-mediated cerebellar

12 F. Palau and C. Espinós

degenerations associated with malignant tumors. Other immune-mediated ataxiasare those described in the polyglandular endocrine autoimmune syndrome in patientswith circulating antibodies to glutamic decarboxylase (GAD) and the controversialassociation between asymptomatic celiac disease and sporadic ataxia. With the aimof clarifying the nosology of sporadic adult-onset ataxia, several studies have beenperformed to develop tools which allow identifying genetic ataxias from nongeneticataxias with a limited success (Klockgether et al. 1990; Abele et al. 2002). Therefore,to diagnose accurately ILOCA cases, genetic ataxias should be excluded in patientsyounger than 50 years. First it is advised to screen for ARCA, mainly the FXN gene,and in males, for X-linked ataxias. Then, screening for SCA genes is alsorecommended. Many times, ILOCA patients are easily mistaken for SCAs becausethese patients can be interpreted as the resulting of de novo dominant mutations. Theyield of this mutational screening may be relatively low (2–19%) (Schols et al. 2000;Abele et al. 2002; Kerber et al. 2005) and although genetic counseling is difficult, thefinding of a mutation is extremely important for patients and their relatives.

Spastic Ataxias

The combination of cerebellar ataxia with spasticity (SPAX) is not infrequent andmay generate difficulties in the differential diagnosis (de Bot et al. 2012). This is anaspect that has to be very well defined in the neurological examination, with abalance between what is more prominent, ataxia, and uncoordinated movements orspasticity. Until now, six SPAX disorders have been reported. Spastic paraplegia 7 isan example of this combined phenotype caused but mutations in the paraplegingene SPG7 originally described in patients with hereditary spastic paraparesis(van Gassen et al. 2012). Mutations in the AG3L2 gene have been found in patientswith either spastic ataxia-neuropathy syndrome phenotype SPAX5 (Pierson et al.2011) or cerebellar syndrome SCA28 (Svenstrup et al. 2017; Tunc et al. 2019).

Molecular Genetics of Ataxias

Genetics and molecular genomics are relevant in the differential diagnosis of ataxias.When distinguishing between genetic ataxias and acquired ataxias, both inheritancepattern and molecular pathology are important tools, especially because of the widegenetic heterogeneity of hereditary ataxias.

Dynamic mutations. A number of SCAs (SCA1, SCA2, SCA3, SCA6, SCA7,and SCA17) and DRPLA are due to CAG repeat expansions in exons that encode apure repeat of the amino acid glutamine in the disease protein (Taroni and Di Donato2004; Orr and Zoghbi 2007; Paulson et al. 2017). A second group of SCAscomprises those due to repeat falling outside the coding region. These are SCA8due to a CTG expansion located at the 30untranslated region (Koob et al. 1999),SCA10 due to a massive expansion of an ATTCT pentanucleotide in intron 9 of theATXB10 gene (Matsuura et al. 2000), SCA12 caused by CAG expansions with more

Approach to the Differential Diagnosis of Cerebellar Ataxias 13

than 66 repeats placed at the 50 region of the PPP2R2B gene (Holmes et al. 1999),and SCA31 caused by an TGGAA repeat insertion within an intron of the BEANgene (Sato et al. 2009). To this latter group belong an ARCA, FRDA, and anX-linked ataxia, FXTAS. Close to 98% of patients with FRDA are homozygousfor an abnormal GAA expansion in intron 1 of FXN (frataxin) gene, and nearly 2%are compound heterozygous for the GAA expansion and a point mutation (Fogel andPerlman 2007). FXTAS is due to an abnormal CGG expansion in the 50 untranslatedregion of the FMR1 (fragile X mental retardation 1) gene (Leehey et al. 2003; Grecoet al. 2008). This abnormal expansion in the FMR1 gene was first associated with thefragile X mental retardation syndrome (Kremer et al. 1991).

Ataxias belonging to these two groups deserve separate mention because of theprivate features of dynamic mutations. In many diseases caused by repeat expan-sions, the age of onset is inversely correlated with repeat length. The abnormalexpended repeats are unstable and tend to expand further, which leads to earlier ageat onset and, therefore, a more severe phenotype in successive generations (antic-ipation). Thus, childhood onset is caused by extreme expansions and mostly withpaternal transmission. However, a precise correlation between age at onset and sizeof expansion cannot be given. These features require being especially cautious inpresymptomatic testing. Prenatal diagnosis must be undertaken with caution as thepositive predictive value of the expansions is mostly unclear. Prenatal diagnosis isalso a delicate issue due to the instability of the repeat during transmission mainly ifthe father is affected. Finally, genetic counseling is similarly difficult in individualswith alleles of intermediate repeat length. The length of the repeat may changeduring transmission and may expand into the pathological range.

In dynamic mutations, the trinucleotide repeat expansions are usually detected byPCR and capillary electrophoresis in a DNA sequencing analyzer. This methodallows establishing the size of the expansion independently if this expansion iscaused by a trinucleotide or a pentanucleotide repeat. The diagnosis of SCA8 alsohas some particular characteristics because the abnormal CTG repeat is adjacent to apolymorphic and stably transmitted CTA repeat, which makes it difficult to detectthe exact number of the repeats. In fact, the references ranges are based on thecombined (CTA•TAG)(CTG•CAG) repeat total. The disease-causing mutation asso-ciated with SCA31 is also worth a special mention because the abnormal expansionconsists of several complex pentanucleotide repeats (TGGAA, TAGAA, andTAAAA), with a long TGGAA stretch (Sakai et al. 2010). The TGGAA repeats inthe insertion are related to the pathogenesis, but it remains unclear whether a largeinsertion without the TGGAA repeats is nonpathogenic.

Point and small mutations. A number of SCAs are caused by conventionalmutations (e.g., missense, nonsense, frameshift, deletion, or insertion) in specificgenes such as β-III spectrin (SPTBN2) in SCA5; tau tubulin kinase 2 (TTBK2) inSCA11; voltage-gated potassium channel (KCNC3) in SCA13; protein kinase C γ(PRKCG) in SCA14; inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) inSCA15; prodynorphin (PDYN) in SCA23; fibroblast growth factor 14 (FGF14) inSCA27; and ATPase family gene 3-like 2 (AFG3L2) in SCA28. With respect to EAs,conventional mutations in four genes have been described in association with

14 F. Palau and C. Espinós

potassium voltage-gated channel gene KCNA1 in EA-1; calcium ion channel geneCACNA1A in EA-2; calcium voltage-dependent channel gene CACNB4 in EA-5;and SLC1A3 gene, a glutamate transporter, in EA-6. Most of them have beenobserved in a few families as SCA28 associated with five families (Di Bella et al.2010) or EA-6 described in two families (Jen et al. 2005; de Vries et al. 2009).

The genetic heterogeneity related to ARCAs is extremely wide with more than50 genes/loci (Neuromuscular Disease Center; http://neuromuscular.wustl.edu/ataxia/domatax.html). Genetic complexity is greater since some ARCAs are allelic.Thus, AOA1 and coenzyme Q10 (CoQ10) deficiency with cerebellar ataxia are dueto mutation in the APTX (aprataxin) gene. Several types of mutations (insertions,deletions, missense) have been detected in patients with AOA1 (Date et al. 2001;Moreira et al. 2001), whereas the described patients with ataxia and CoQ10 defi-ciency are homozygous for a nonsense mutation (p.W279X) in the APTX gene(Quinzii et al. 2005; Le Ber et al. 2007). Sensory ataxic neuropathy, dysarthria,and ophthalmoparesis (SANDO) is caused mainly by mutations in the POLG(polymerase DNA gamma) gene, but SANDO syndrome can also be produced bydominant mutations in the twinkle/C100RF2 (chromosome 10 open reading frame 2)gene. The twinkle gene is also associated with infantile-onset spinocerebellar ataxia(IOSCA), an ataxia caused by a founder mutation in the Finnish population (Nikaliet al. 2005). On the other hand, mutations in the POLG gene have been reportedassociated with several diseases: male infertility (Rovio et al. 2001), progressiveexternal ophthalmoplegia (PEO) (Van Goethem et al. 2001), Alpers syndrome(Naviaux and Nguyen 2005), and mitochondrial gastrointestinal syndrome (VanGoethem et al. 2003).

Some genes have been identified involved in X-linked ataxias. Arts syndrome iscaused by mutations in the PRPS1 (phosphoribosylpyrophosphate synthetase 1)gene and XLSA in the ALAS2 (delta-aminolevulinate synthase 2) gene. Othercongenital X-linked ataxias are syndromic forms associated with mental retardationand related to the genes SLC9A6, OPHN1 (oligophrenin-1), CASK (calcium/cal-modulin-dependent serine protein kinase),DKC1 (dyskerin) and CUL4B (cullin 4B).Finally, the episodic pyruvate dehydrogenase E1-α deficiency is due to mutations inthe PDHA1 (pyruvate dehydrogenase E1-α) gene.

The full spectrum of mutations in the vast majority of these genes remains largelyunknown. In the vast majority of these genes’ mutations are distributed throughoutthe gene without any consistent hot spots. The screening mutation studies arepreferentially focused in analyzing the coding sequences (exons) and their intronicflanking sequences. This is why deletions, duplications, and cryptic mutations inuntranslated or intronic regions important for gene expression could exist, but theyhave barely been described so far. Thus, large deletions have been described inpatients with EA-2 using a quantitative multiplex PCR (polymerase chain reaction)of short fluorescent fragment test (Riant et al. 2010).

Approach to the Differential Diagnosis of Cerebellar Ataxias 15

Multiple methods are available to detect a conventional mutation. When thenumber of cases to be analyzed is very low, the most classical method by PCRamplification of the interest fragments and subsequent automated Sanger sequencingis still an option. However, mutation or genetic variant analysis is currently based onmassive parallel sequencing using next-generation sequencing (NGS) technologies.NGS allows analysis of the protein-coding exons of genes (whole exome sequenc-ing, WES) and the entire genome (whole genome sequencing, WGS), and it is beingapplied on a daily basis in many centers that take care and treat patients with ataxia(Nemeth et al. 2013; Iglesias et al. 2014; Olgiati et al. 2016; Coutelier et al. 2018).

Genetic Testing

Modern genomic approaches for the diagnosis of hereditary ataxias are currentlyaddressed in reference genetics departments and laboratories by using NGS. Due tothe complexity of genetics of ataxias, to be efficient in the genetic diagnosticsapproach, it is important that physicians and neurologists propose clinical suspicionand inform about the main symptoms and signs. This become more relevant inpatients with complex neurological expression that may affect not only cerebellumand cerebellar tracts but also other central or peripheral nervous structures. In thissense, the assignment to each main symptom of a code such as HPO (HumanPhenotype Ontology) (Robinson and Mundlos 2010) can help geneticists definethe most likely gene among those that show genetic variants.

The considerations for genetic testing are driven by the patient’s best interest.Genetic testing is a useful tool in clinical diagnosis, but there are other clinicalsettings where genetic testing depends on the patient’s or relative at-risk individualrequirement. In such cases, genetic testing should only be performed at the patient’srequest. Genetic information is private and is directly related to an individual’sidentity. Several forms of genetic testing can be considered: predictive or pre-symptomatic testing, carrier detection, prenatal diagnosis, preimplantation geneticdiagnosis, and newborn screening. Genetic testing implies identification of thegenetic status in the individual. Decision is personal as the result may change thefuture and the style of life. Thus, genetic testing may raise ethical implications, andtherefore, it should be accompanied by pre- and posttest counseling, as well asongoing psychological support.

The family history is very useful to infer a genetic origin and to reveal theinheritance pattern of the disorder or, on the contrary, to define the patient asa sporadic case. This is best achieved by drawing up a family tree or pedigree.A clearly drawn pedigree provides an unambiguous and permanent record of thegenetic information in a particular family. Genetic testing has to be oriented from theclinical background. Because the number of genes involved in ataxias is relevant,prioritization of genes to be analyzed may be recommended in specific cases.

16 F. Palau and C. Espinós

Although most ataxia disorders present with a clinical syndrome of cerebellardysfunction, the clinical signs add relevant information, and in fact, mutations insome genes have been associated with specific phenotypes. However, if these privateclinical manifestations are absent, the relative frequency of different ataxias inspecific populations or the patient’s ethnicity gains relevance for the genetic analysisapproach.

Conclusions and Future Directions

Diagnosis of ataxias requires a comprehensive approach that has to be based onclinical and genetic criteria. Recognition of clinical signs and symptoms in thepatient interview, anamnesis, and clinical and neurological examinations are funda-mental to establish the age at onset of the disease, chronobiology, focal versusdiffuse extension of the disorder, and the specific topology of the pathology(de Silva et al. 2019a, b; Poretti and Boltshauser 2016; Bürk 2016). A major pointin anamnesis is drawing three-generation pedigree with family history. In the last30 years, positional cloning and gene characterization have improved the knowledgeabout molecular genetics of hereditary ataxias. Now genetic and genomic analyseshave become a basic tool for the classification of ataxias and for genetic testing andcounseling in patients and families. This is true not only for hereditary ataxias butalso to exclude a genetic cause in sporadic ataxias. In nongenetic ataxias, recognitionof specific disorders is sometimes based on neuroimaging, biochemical, and labo-ratory tests. Modern classification and diagnosis of ataxias has to be based on fourmain clinical and biological criteria (Fig. 1): (1) natural history, age at onset, andclinical (neurological and systemic) features; (2) pathophysiological aspects alongwith biochemical markers, neuroimaging, and electrophysiological information;(3) familial versus sporadic case and inheritance pattern; and (4) genetic testingand mutation detection in patients and relatives, especially when genetic or hered-itary ataxia is suggested by the pedigree. In hereditary ataxia, such a genetic testingstarts with the study of dynamic mutation repeats and then NGS to analyze conven-tional variants of ataxia genes.

As has been the case in many medical disciplines, the field of ataxia is movingtoward precision or personalized medicine, which represents the bridge betweengeneral medical and scientific knowledge and the specific needs of the particularpatient. Precision medicine is a proactive model of care that allows addressing theperson’s health and disease in the context of the own individuality and the publichealth. It is a process that affects the complete cycle of life and, therefore, fromchildhood to adulthood (Palau 2020). The analysis of the genome by NGS allowsreaching the diagnosis in a large number of patients in all the clinical disciplines,which includes hereditary ataxias. In addition, genomics opens up new paths topersonalized advanced therapies and the integration of other omics to the manage-ment and care of patients affected by ataxia.

Approach to the Differential Diagnosis of Cerebellar Ataxias 17

Cross-References

▶Autosomal Dominant Spinocerebellar Ataxias and Episodic Ataxias▶Autosomal Recessive Cerebellar Ataxias▶Cerebellar Motor Disorders▶Clinical Scales of Cerebellar Ataxias▶Diagnosis of Neoplastic and Paraneoplastic Cerebellar Ataxia▶Genes and Cell Type Specification in Cerebellar Development▶Mitochondrial Disorders▶Multiple System Atrophy (MSA)▶Neuropathology of Ataxias▶Novel Therapeutic Challenges in Cerebellar Diseases▶X-Linked Ataxias

Age at Onset versus Inheritance matrix[with some examples of disease]

ecnatirehnIfoedo

M

Age at Disease Onset

Progression rate

• focal •non focal, diffuse

Non-genetic:•symptomatic

• idiopathic

JBSRareXLAS/ALS UC defectsCS

Congenital (<2 yr)

Late-onset(LO>25 yr)

Early-onset (EO<25 yr)

Cerebellar localization

•acute, rapid•chronic, slowly progressive•chronic, stationary

FRDAEO_SCAs

MELAS, MERFFAVED, CTXAT

Viral cerebellar encephalitis

Rare

Hereditary:•AR•AD•X-linked•Mitochondrial•Metabolic*•DNA repair*

LO_FRDASCAs, EAsFXTASMELAS (<40yr), KSSRareRare

Paraneoplasticcerebellar degeneration

Cerebellar MSA

Extension and Evolution

Diagnosis Features of Cerebellar Ataxia

clinical/neurological examination – electrophysiology – neuroimaging – biochemistry –genetic testing: dynamic repeats mutations plus WES or WGS

Other nervous system structures

•Basal ganglia, midbrain •Spinal cord, posterior columns•Sensory nerves

Fig. 1 Diagram of clinical diagnostic criteria in cerebellar ataxias. The draw is designed intointegrate age at onset with the mode of inheritance, involvement of the nervous system, and diseaseevolution. AR autosomal recessive; AD autosomal dominant; EO early onset; LO late onset;AT ataxia telangiectasia; AVED isolated ataxia with vitamin E deficiency; CTX cerebrotendinousxanthomatosis; CS Cockayne syndrome; EAs episodic ataxias; FRDA Friedreich’s ataxia;FXTAS fragile X-associated tremor/ataxia syndrome; JBS Joubert syndrome; KSS Kearns-Sayresyndrome; LS Leigh syndrome; MELAS mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes;MERFFmyoclonic epilepsy with ragged red fibers; SCAs spinocerebellar ataxias;UCdefects urea cycle disorders; XLAS/A X-linked ataxia syndrome with anemia. Mitochondrialinheritance refers to disorders involving mitochondrial DNA genes that affect oxidative phosphor-ylation. �Both metabolic and DNA repair disorders are also genetic pathologies usually inherited asan autosomal recessive pattern. (Modified from Palau and Arpa 2016)

18 F. Palau and C. Espinós

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