Download pdf - Tools for diagnosis of leukodystrophies and other disorders presenting with white matter disease

Tools for Diagnosis of Leukodystrophies and Other Disorders Presenting with

White Matter DiseaseAdeline Vanderver, MD

AddressDepartment of Neurology, Children’s National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010, USA. E-mail : [email protected]

Current Neurology and Neuroscience Reports 2005, 5:110–118Current Science Inc. ISSN 1528-4042Copyright © 2005 by Current Science Inc.

Advances in biochemical techniques, molecular genet-ics, and neuroimaging, particularly magnetic resonance imaging, have made possible the diagnosis of a significant proportion of leukodystrophies. A specific diagnosis allows the physician to give prognostic information, monitor for known complications, and ultimately may allow disease specific therapeutics. The purpose of this review is to familiarize the reader with pertinent tools in the diagnosis of leukodystrophies and other white matter disorders that may present with white matter disease. The first section discusses conditions that may mimic leukodystrophy and how to exclude them. Although not meant to be an exhaustive summary, several key disor-ders and their clinical, biochemical, and neuroimaging features are presented. The second section focuses on classically described leukodystrophies and their diagnosis. Finally, a third section provides a diagnostic algorithm to help the clinician in the diagnosis of the patient with leukodystrophy.

IntroductionHeritable disorders affecting the white matter can have dysmyelination as a predominant manifestation (leukodystrophy) or as part of a systemic disorder (leuko-encephalopathy). Individually, white matter diseases are rare, but as a group they have a prevalence of one in 5000 to 6000 live births. Several groups of metabolic disorders, notably, mitochondrial cytopathies, peroxi-somal disorders, amino acid disorders, urea cycle defects, organic acidemias, and lysosomal disorders, can result in classically described leukodystrophies or have associated leukoencephalopathy. A significant proportion of patients with white matter disease have yet unidentified disorders.

The combination of clinical, biochemical, neuro-imaging, and molecular genetic evaluations will allow the clinician to reach a diagnosis when the patient has a known white matter disease. Many of these same tech-niques are being used to classify novel leukodystrophies, and familiarity with them will allow the clinician to diagnose new disorders as they are identified.

Inborn Errors of Metabolism and Other Disorders with Associated LeukoencephalopathyThe term leukodystrophy is typically reserved for diseases with prominent disorders of central (and peripheral) myelin. Many disorders with systemic manifestations may have associated white matter abnormalities and these are usually referred to as leukoencephalopathies. Most often, the white matter findings are incidental in view of the devastating nature of these disorders. However, on occasion, in the disorders described here, white matter disease has been a prominent clinical or radiologic finding, with a paucity of other features to suggest the diagnosis. Therefore, these disorders enter the differential diagnosis in the evaluation of the patient with a white matter disease (Table 1). The summary in the following text is not meant to be exhaustive, merely indicative of the variety of disorders that can have associated white matter abnormalities.

Endocrinopathies or vitamin deficienciesTreatable disorders, such as endocrinopathies or vitamin deficiencies, should always be considered. White matter changes can be seen in autoimmune thyroid disease, and thyroid function studies should be tested in any undiag-nosed leukoencephalopathy. Vitamin B12 deficiency, while most often presenting with recognizable clinical features, has been reported to present with prominent central nervous system findings and should be excluded. Although animal models suggest that vitamin E and nutritional folate deficiency could present with white matter changes, the author found no reports supporting this diagnosis clinically. Biotinidase deficiency results

Diagnosis of Leukodystrophies and Other White Matter Disease Vanderver 111

in a clinical picture that includes seizures, hypotonia, ataxia, breathing problems, hearing loss, optic atrophy, skin rash, and alopecia. Patients have a diffuse leuko-encephalopathy, which is reversible after treatment with biotin, although neurologic sequelae remain.

A systemic disorder, Langerhan’s cell histiocytosis, can result in white matter parenchymal changes resem-bling a leukodystrophy [2]. However, these are associated with other recognizable manifestations, including lesions of the craniofacial bone and skull base, with or without soft tissue extension, and intracranial extra-axial changes that should help identify the disorder. If suspicion arises, careful review of neuroimaging features and skull films may be helpful.

Disorders of carbohydrate metabolismDisorders of carbohydrate metabolism may present with white matter findings. Galactosemia may present with diffuse hypomyelination. There are isolated reports of individual patients with congenital disorders of glyco-sylation having diffuse white matter hypodensities, stroke-like white matter changes, or small, focal white matter abnormalities. If systemic findings or structural brain abnormalities support the diagnosis, it is not unrea-sonable to pursue this diagnosis.

Amino acidopathiesAmino acidopathies may present with prominent leukoencephalopathy. Phenylketonuria is now usually diagnosed by newborn screening, and the classic symp-toms are rarely seen. Magnetic resonance imaging (MRI) studies in patients with phenylketonuria reveal symmetric, patchy, or band-like areas of white matter abnormality involving the posterior/periventricular white matter. Lesions may extend to the frontal and sub-cortical white matter, and include the corpus callosum. Dihydropteridine reductase deficiency is a rare cause of hyperphenylalaninemia, which is characterized by severe and progressive neurologic impairment, despite early and accurate dietary control of plasma phenylalanine. Imaging studies may show prominent white matter abnormalities [3].

Urea cycle disorders represent one of the most common groups of inborn errors of metabolism and may result in leukoencephalopathy. The most common of these, ornithine transcarbamylase deficiency, is an X-linked disorder that typically presents with neonatal hyper-ammonemic episodes that result in leukoencephalopathy due to brain injury from hyperammonemia [4]. In male patients with partial deficiencies and certain heterozygous female patients, presentation is less dramatic and of later onset [5–7]. In this situation, MRI may manifest focal white matter abnormalities and the diagnosis of a leuko-dystrophy may be considered (Table 2).

Maple syrup urine disease is caused by impaired metabolism of the branched-chain amino acids leucine,

isoleucine, and valine. In classic cases, infants present in the first week of life with poor feeding, vomiting, opisthotonus, seizures, and respiratory distress. In these cases, neuroimaging reveals white matter changes due to reversible edema [8]. The cerebellar white matter is markedly involved. In milder cases of maple syrup urine disease, the clinical picture may comprise mild to moder-ate mental retardation with a clinical history of periods of coma, acidosis, lethargy, and hypoglycemia. In these cases, a picture of delayed myelination or dysmyelination may be seen [9,10].

There are isolated reports of other amino acid disorders with associated white matter disease. Hyperprolinemia has been associated with a diffuse leukoencephalo-pathy. Nonketotic hyperglycinemia, in which significant plasma and cerebrospinal fluid (CSF) glycine elevations are seen, has been associated with supratentorial white matter abnormalities [11]. White matter abnormalities are also seen in gyrate atrophy of the choroid and retina, a disorder with hyperornithinemia.

Organic acid disordersGlutaric aciduria type 1 is caused by a deficiency of the enzyme glutaryl coenzyme A (CoA) dehydrogenase. It is characterized by symptom onset in infancy with macrocephaly, hypotonia, choreoathetosis, dystonia, and encephalopathic crises associated with an intercurrent illness or surgery. Rare adult-onset cases are described. Imaging findings include characteristic structural changes such as widening of the operculae, acute subdural hemorrhage, and signal changes of the basal ganglia, dentate nucleus, substancia nigra, and the pontine medial lemniscus [12]. White matter changes have been reported in the periventricular white matter [13].

Sjogren Larsson syndrome is an inborn error of lipid metabolism caused by a defect in fatty aldehyde dehydro-genase. Characteristic clinical findings include ichthyosis, mental retardation, spastic diplegia or tetraplegia, speech delay, short stature, and retinal abnormalities. On neuroimaging, white matter abnormalities are present in periventricular regions, the centrum semiovale, the corpus callosum, and frontal and parietal lobes [14]. There is sparing of subcortical U fibers.

Branched-chain organic acidurias such as propi-onic acidemia and methylmalonic acidemia have also rarely been associated with diffuse supratentorial white matter dysmyelination.

Mitochondrial cytopathiesMitochondrial disorders are caused by mutations of nuclear or mitochondrial DNA–encoded genes involved in oxidative phosphorylation. Mutations in these critical genes are associated with multisystem disorders that may manifest with neurologic, cardiac, endocrine, gastrointestinal, hepatic, renal, and/or hematologic involvement and may present with highly

112 Pediatric Neurology

variable symptomatology [16]. Abnormalities of white matter on neuroimaging include delayed myelina-tion, leukodystrophic pattern, and demyelination. Areas of abnormal myelin may include the cerebral hemispheres, the corpus callosum, and adjacent white matter. Infarct-like, often transient lesions not confined to the vascular territories are the imaging hallmark of mitochondrial encephalomyopathy–lactic acidosis–and stroke-like symptoms (MELAS) syndrome.

Lipid metabolismIsolated cases of white matter abnormalities have been described in Tangier’s disease. Cerebrotendinous xantho-matosis is a familial sterol storage disorder resulting in accumulation of cholesterol and cholestanol in multiple tissues, resulting in dementia, pareis due to spinal cord dysfunction, ataxia, multiple xanthomas, and cataracts. Neuroimaging reveals diffuse white matter changes, more prominently adjacent to the dentate nucleus, globus pallidus, and substancia nigra [17]. Diagnosis is suggested by cholestanol elevations in plasma. Other heritable lipid

disorders that lead to early atherosclerosis may lead to white matter changes due to a vascular mechanism.

Metal metabolismIsolated cases of Menke’s kinky hair disease have presented with prominent white matter disease on neuro-imaging. Molybendum cofactor deficiency may have periventricular white matter abnormality associated with caudate and thalamic abnormalities.

Peroxisomal disordersDefects in many of the enzymatic processes of the peroxi-somes have been demonstrated to cause disease. Diseases caused by the deficiency of a single enzyme within the peroxisome include Refsum’s disease (phytanoyl-CoA oxidase), X-linked adrenoleukodystrophy (fatty acid acyl-CoA synthetase) and -oxidation disorders (acyl-CoA oxidase, bifunctional protein, and thiolase) among others. These last three disorders, resulting from a defect in peroxisomal -oxidation, resemble the peroxisome biogenesis disorders. MRI is remarkable for diffuse

Table 1. Disorders resulting in leukoencephalopathy and their diagnostic tests*

Disorder Diagnostic test

Autoimmune thyroid disease Thyroid function studies

Vitamin disorders

Vitamin B12

B12

levels, methylmalonic acid

Biotinidase deficiency Biotinidase levels

Carbohydrate disorders

Galactosemia Fluorescent spot test for GALT activity, quantitative enzyme assays, Gal-1-P plasma levels

Congenital disorders of glycosylation Isosentric focusing of serum transferin

Amino acid disorders

Phenylketonuria and dihydropteridine reductase deficiency

This group of disorders may be diagnosed by plasma phenylalanine and tyrosine levels, as well as urine total biopterin and neopterin concentrations to exclude tetrahydrobiopterin metabolism abnormalities

Ornithine transcarbamylase deficiency Elevations of ammonia in blood and central nervous system, as well as eleva-tions of plasma and cerebrospinal fluid glutamine; urinary excretion of orotic acid is increased

Maple syrup urine disease Increased levels of plasma branched-chain amino acids and urinary branched-chain keto acids are seen

Hyperprolinemia Elevated praline

Gyrate atrophy of the choroids and retina

Hyperonritheinemia

Nonketotic hyperglycinemia Elevated cerebrospinal fluid and serum glycine

Organic acid disorders

Glutaric aciduria type 1 Elevated urinary, serum, and cerebrospinal fluid glutaric acid, confirmed by enzyme assay in fibroblasts

*This list is not meant to be exhaustive, but merely representative. GALT—galactose-1-phosphate uridyltransferase; MELAS—mitochondrial encephalomyopathy–lactic acidosis–and stroke-like symptoms; MERFF—myoclonus epilepsy with ragged red fibers.


white matter changes accompanied by malformations of cerebral development, such as polymicrogyria.

There is also a group of disorders resulting from a deficiency in the biogenesis of the peroxisome. These peroxisome biogenesis disorders are caused by defects in any of at least 14 genes whose products (peroxins) are required for the proper assembly of the peroxisome. This group includes the Zellweger spectrum, which is comprised of three disorders: 1) Zellweger syndrome (or cerebrohepa-torenal syndrome), 2) neonatal adrenoleukodystrophy, and 3) infantile Refsum disease. These patients have a multiorgan disease and prominent neurologic dysfunction. MRI imaging is remarkable for cerebral demyelination with sparing of subcortical fibers and pronounced central cerebellar demyelination, as well as features of disordered cerebral migration such as polymicrogyria [18,19•].

Lysosomal disordersNiemann Pick disease type C is an autosomal recessive disorder resulting from defective cholesterol esterifica-

tion. The accumulation of unesterified cholesterol and gangliosides results in a systemic storage disorder, with hepatosplenomegaly, jaundice, on occasion liver failure in infancy, and severe neurologic manifestations. Diagnosis may be confirmed by demonstrating impaired ability of cultured fibroblasts to esterify exogenously supplied cholesterol. Neuroimaging has documented white matter changes described as diffuse [20] or on occasion as focal abnormalities [21].

GM1 gangliosidosis is an autosomal recessive disorder resulting in neurovisceral storage of gangliosides caused by a deficiency of the lysosomal enzyme galactosidase. Presentation is variable and age related. MRI in the infan-tile form shows delayed myelination or lack of normal myelination in the thalami, brainstem, and cerebellum [22]. In adult-onset patients, cortical gray matter and basal ganglia abnormalities predominate [23].

GM2 gangliosidosis is an autosomal recessive disorder of sphingolipid storage, with several biochemical vari-ants, including Tay Sachs and Sandhoff disease. Their

Table 1. Disorders resulting in leukoencephalopathy and their diagnostic tests*

Sjogren Larsson syndrome Diagnosis is made by demonstrating defective fatty alcohol oxidation directly in a skin biopsy using a histochemical staining method

Proprionic acidemia, methylmalonic acidemia

Urine organic acids

Mitochondrial cytopathies

MELAS, Leighs, MERFF, Kearns Sayre, and others

Serum lactate, pyruvate, lactate-pyruvate ratio, plasma amino acids (alanine levels), complete blood clount, electrolytes, carnitine, acylcarnitine profile, ammonia, and creatine phosphokinase

Lipid metabolism

Cerebrotendinous xanthomatosis Cholestanol elevation in plasma

Metal metabolism

Menke’s kinky hair disease Low serum ceruloplasmin, low serum copper, and abnormal fibroblast copper metabolism

Molybendum cofactor deficiency Abnormal urinary S sulfocysteine, xanthine, and hypoxanthine

Peroxisomal disorders

-oxidation disorders (acyl-coenzyme A oxidase, bifunctional protein, and thiolase) or Zellweger spectrum

Accumulation of very long-chain fatty acids, and/or abnormalities in plasmalogen, phytanic acid, and pipecolic acid

Lysosomal disorders

Niemann Pick type C Histology or fibroblast enzymatic analysis

GM1 gangliosidosis Deficiency of galactosidase assayed in lymphocytes or fibroblasts

GM2 gangliosidosis Deficiency of hexosaminidase A (and B) assayed in lymphocytes or fibroblasts

Mucopolysaccharidodis type 1 and 2 Analysis of urinary glycosaminoglycans and lysosomal enzyme assays can confirm a clinical suspicion

Fabry disease Lymphocyte lysosomal enzyme assay for a galactosidase A

Congenital muscular dystrophies

Merosin deficiency Creatine phosphokinase, muscle histology/histochemistry

*This list is not meant to be exhaustive, but merely representative. GALT—galactose-1-phosphate uridyltransferase; MELAS—mitochondrial encephalomyopathy–lactic acidosis–and stroke-like symptoms; MERFF—myoclonus epilepsy with ragged red fibers.

(continued)


clinical manifestations are similar. Infantile presen-tations result in progressive neurologic deterioration before 1 year of age with spasticity, blindness, seizures, and acquired macrocephaly. A cherry-red spot is seen on fundoscopic examination of the retina. Juvenile or adult-onset patients have prominent ataxia and dementia. Tay Sachs disease is due to deficiency of hexosaminidase A. Sandhoff disease is due to a deficiency of hexosamini-dase A and B. Neuroimaging findings are characterized by signal abnormalities of basal ganglia, thalamus, and diffuse white matter changes [24,25].

Changes of the white matter mimicking a leuko-dystrophy may mark the course of mucopolysaccharidosis type I (-iduronidase deficiency or Hurler), and also mucopolysaccharidosis type II (Hunter) [26,27,28•]. These disorders are usually pathognomic in their clinical presentation with multisystem organ involvement. Another lysosomal disorder that may result in white matter abnormalities is Fabry disease ( galactosidase A), with diffuse frontoparietal deep white matter lesions or lesions associated with cerebrovascular accidents.

Muscular dystrophiesCongenital muscular dystrophy with merosin deficiency is an important etiology of a leukoencephalopathy on MRI. It is due to a laminin-2 deficiency. These children often have quite dramatic and unexpected white matter findings with mild hypotonia, gross motor delay, peripheral neuro-pathy, and minimal cognitive findings. The MRI reveals diffuse white matter abnormality that is more marked in older age groups and spares the U fibers [29].

OtherXeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy are rare autosomal recessive inherited

human disorders that are associated with impaired nucleo-tide excision repair activity. Xeroderma pigmentosum and Cockayne syndrome have neurologic burden of disease, including microcephaly, spasticity, hyporeflexia/areflexia, ataxia, chorea, sensorineural deafness, supranuclear ophthalmoplegia, progressive neurologic degeneration, neuronal loss, mental retardation, and dementia. Diagno-sis is suggested by clinical characteristics, and confirmed by biochemical and cellular evidence of nucleotide excision repair abnormality (eg, fibroblast DNA repair characteris-tics). Neuroimaging may show diffuse or periventricular white matter abnormality, but other findings are more characteristic, including symmetric calcifications in the cerebellum and basal ganglia with a hyperintense rim in Cockayne syndrome [30].

Very rare disorders may present with leukoencephalo-pathy and may require subspecialist evaluation to exclude. L-carnitine deficiency is a rare metabolic disorder leading to cerebral infarctions, hypoglycemia, and myopathy and can rarely be associated with nonspecific periventricular white matter abnormalities [31]. Carnitine levels can be tested on patients’ serum to exclude this diagnosis. Patients with a deficiency of ribose-5-phosphate iso-merase (RPI) may present with leukoencephalopathy and peripheral neuropathy [32]. Deficient activity of RPI, one of the pentose-phosphate-pathway enzymes, can be demonstrated in fibroblasts.

Classic LeukodystrophiesLysosomal disordersMetachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A, or cerebroside sulfatase activator (saposin B), causing the storage of the sphingolipid sulfatide. The disease is

Table 2. Initial approach to the diagnosis of white matter disease suspected to be a leukodystrophy

Review of MRI to exclude those diagnoses with characteristic MRI findings and no definite biochemical marker: Pelizaeus-Merzbacher disease*, Alexander’s disease*, MLC*, VWM/CACH *, Aicardi Goutierres, LBSL, and H-ABC

Organelle based approach based on associated features of the disorder

Peroxisomal: VLCFA, phytanic acid, plasmalogens for ALD, Zellweger syndrome, single enzyme peroxisomal defects

Lysosomal: enzyme assay on leukocytes for MLD, Krabbe, multiple sulfatase deficiency, MPS, GM1 and 2 gangliosidoses, Nieman Pick C disease, Fabry’s disease

Mitochondrial: lactate/pyruvate ratio and mDNA studies for mitochondrial cytopathies

Organic aciduria: urinary organic acids for Canavan’s, glutaric aciduria type 1

Amino acidopathies: plasma amino acids for PKU, MSUD, urea cycle disorders

Other: also consider CPK, cholestanol, vitamin B12

, TFTs, isoelectric focusing of transferrin, and other studies based on specific clinical situations

*These disorders can be confirmed with mutation analysis. ALD—adrenoleukodystrophy; CACH—childhood onset ataxia and central nervous system hypomyelination; CPK—creatine phosphokinase; H-ABC—hypomyelination with atrophy of the basal ganglia and cerebellum; LBSL—leukoencephalopathy with brainstem and spinal cord involvement and elevated white matter lactate; MLC—megalencephalic leukoencephalopathy with subcortical cysts; MLD—metachromatic leukodystrophy; MPS—mucopolysaccharidosis; MRI—magnetic resonance imaging; MSUD—maple syrup urine disease; PKU—phenylketo-nuria; TFT—thyroid function studies; VLCFA—very long-chain fatty acid; VWM—vanishing white matter.


characterized by a progressive demyelination, which results in progressive neurologic dysfunction, includ-ing pyramidal signs, polyneuropathy, bulbar symptoms, ataxia, or even psychiatric symptoms in adult presenta-tions. Metachromatic leukodystrophy is biochemically diagnosed by abnormal arylsulfatase A activity measured by enzyme assay in leukocytes or fibroblasts. The saposin B–deficient variant may be diagnosed by direct enzyme assay or indirectly by measuring urinary sulfatides. MRI shows diffuse signal abnormality in the cerebral white matter, initially of periventricular white matter and the centrum semiovale white matter. Other common mani-festations include involvement of the corpus callosum, the internal capsule, and the corticospinal tract. Disease progresses to involvement of the arcuate fibers and the cerebellar white matter [33]. The signal abnormality is sometimes described as a “tigroid” or “leopard-skin” appearance of the deep white matter similar to that seen in Pelizaeus Merzbacher disease [34].

Multiple sulfatase deficiency (MSD) is an autosomal recessive disorder with deficiencies in all known sulfa-tases. The clinical presentation is much like infantile MLD, but biochemical studies reveal abnormal urinary oligosaccharides, and mucopolysaccharide and glyco-peptide profiles. Neuroimaging is similar to MLD.

Krabbe disease (globoid cell leukodystrophy) is an autosomal disease caused by genetic defects in the lyso-somal enzyme galactosylceramidase (galactosyl ceramide -galactoside deficiency [GALC]). Clinical manifesta-tions are a result of central and peripheral white matter destruction. The diagnosis is made by leukocyte assay for activity of galactosylceramidase (ie, GALC). Deficiency of one of the sphingolipid activator proteins, saposin A, has been associated in mice with this disorder, but not identified in humans. Neuroimaging shows white matter abnormality without contrast enhancement of the pos-terior periventricular white matter and corticospinal tracts, sparing U fibers. This is followed by a significant decrease of white matter volume, generalized atrophy, and abnormal high signal in all white matter areas except the anterior limbs of the internal capsules. There are a few cases where optic nerve enlargement has been noted to be a prominent feature [35]. Spinal nerve and cranial nerve enhancement may be a prominent, even isolated, finding and may mimic other disorders such as Guillain-Barre syndrome [36,37].

Peroxisomal disordersAdrenoleukodystrophy is a rare, X-linked, recessive, inher-ited metabolic disorder affecting cerebral white matter and adrenal cortex, leading to progressive neurologic disability and death. Patients classically present with behavioral disorders, followed by a progressive dementia, spastic paraplegia, incoordination, dysarthria, dysphagia, and neurosensory loss. Very long chain fatty acid patterns on serum are diagnostic. Mutations are seen in the ABC

transporter gene. Cerebral X-linked adrenoleukodystro-phy is typified by white matter demyelination that often starts in the parieto-occipital regions bilaterally and then extends across the corpus callosum. The disease then progresses anteriorly and laterally as a confluent lesion to involve white matter of the temporal, parietal, and frontal lobes, with relative sparing of the subcortical arcuate fibers [38]. The border of progressing myelin destruction shows contrast enhancement. Subcortical U fibers and cerebellar white matter are typically spared.

Organic acid disordersCanavan disease is an autosomal recessive disorder caused by aspartoacylase deficiency. The deficiency of asparto-acylase leads to increased concentration of N-acetylaspartic acid in the brain and body fluids. This causes disruption of myelin, resulting in spongy degeneration of the white matter of the brain. The clinical features of the disease are hypotonia in early life, which evolves to spasticity, macrocephaly, head lag, and progressive severe mental retardation. Elevated urinary N-acetylaspartic acid is used in the diagnosis of this disorder. Aspartoacylase can be assayed in cultured skin fibroblasts. Mutations are found in the gene for aspartoacylase (ASPA). Neuroimaging classically reveals early involvement of the arcuate fibers (U fibers). In most cases, the entirety of the cerebral white matter is then progressively affected, with relative sparing of the putamen [39].

Disorders characterized by MRI and known genetic defectAlexander disease is a progressive disorder of white matter whose onset is usually in infancy or early childhood, with features of macrocephaly, spasticity, and histologic accumulation of Rosenthal fibers in astrocytes. It is assoc-iated with mutations of the glial fibrillary acidic protein (GFAP) gene. There are no clinically useful biochemical markers, although the cerebrospinal fluid can show an elevation of B-crystallin and heat shock protein. Diag-nosis is based on suggestive neuroimaging, confirmed by mutation sequencing of the GFAP gene. Imaging features have been found to be variable depending on age of presentation. The classic presentation in infancy or child-hood is associated with such typical MRI findings that before identification of mutations in GFAP, MRI findings were considered to be diagnostic. These findings include the following: extensive cerebral white matter changes with frontal predominance and caudal progression; a peri-ventricular rim with high signal on T1-weighted images and low signal on T2-weighted images; abnormalities of basal ganglia and thalami; brain stem abnormalities; and periventricular gray and white matter enhancement [40••]. In the adult type, MRI has been shown to be much more heterogeneous.

Vanishing white matter (VWM) disease or childhood onset ataxia and central nervous system hypomyelination


(CACH) is an autosomal recessive neurodegenerative disease, most often beginning in early childhood with a chronic progressive course punctuated by episodic dete-rioration in the context of febrile illness or mild head trauma. The patients demonstrate progressive ataxia, spastic quadriplegia, and relatively preserved mental capacities. Initially, the diagnosis was based on clinical and radiologic findings with no specific biochemical marker [41–43]. The only known biochemical marker described is the elevation of glycine in CSF and urine in patients with VWM/CACH [44]. Discovery of mutations in the five genes encoding the epsilon subunits of the translation initiation factor eIF2B have led to diagnostic confirmation by mutation analysis [45••]. eIF2B is a com-plex that is essential to the regulation of translation. Cree leukoencephalopathy, previously thought to be a distinct disorder, is now known to be allelic with VWM disease.

Magnetic resonance imaging characteristics are felt to be typical. Hemispheric involvement of cerebral white matter that may include U fibers is seen, with gradual rarefaction resulting in a signal change isointense with CSF/ventricles on all images. Gradual cavitation results in the appearance of threads of residual tissue left in a space in which the white matter has otherwise “vanished.” White matter space appears mildly swollen with thicken-ing of the gyri. Basal ganglia and the internal capsule are generally preserved.

Pelizaeus Merzbacher disease (PMD) is an X-linked recessive leukodystrophy that is caused by a mutation in the proteolipid protein (PLP) gene on chromosome Xq22. The clinical spectrum is extremely variable and ranges from severe neonatal cases to relatively benign adult forms and X-linked recessive spastic paraplegia type 2. Classic findings on physical exam include transitory nystagmoid eye movements with rotatory movements of the head, spastic quadraparesis, ataxia, parkinson-ism, and dementia. Imaging and gross pathology reveal a characteristic “tigroid” appearance of affected white matter. There is no biochemical marker for the disorder, and diagnosis is based on typical neuroimaging and clinical findings, confirmed by duplication and dele-tion studies of the PLP gene. There remain a number of patients with the PMD phenotype who do not have documented mutations in the PLP gene. Some of these patients may have mutations of extra exon sequences of the PLP gene [46]. Others may have mutations in other genes, such as the recently described mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6), responsible for a PMD–like disorder [47].

On neuroimaging, severe hypomyelination is a hall-mark of PMD. Affected white matter may have a tigroid or leopard-skin appearance caused by patchy areas of myelin deposition. Hypoplasia and abnormal myelination of the cerebellum and brainstem may be present [48].

Megalencephalic leukoencephalopathy with sub-cortical cysts (MLC) is an autosomal recessive disorder

characterized by acquired macrocephaly, developmen-tal motor delay of varying degrees, slowly progressive cerebellar and pyramidal signs, sometimes intractable epilepsy, and initially preserved intellectual function [49]. It is related to different mutations in MLC1 gene [50]. There is no biochemical marker for the disorder. Diagnosis is based on suggestive neuroimaging and clinical findings, confirmed by mutation analysis.

The neuroimaging findings are characteristic for a discrepancy between the mild-appearing clinical picture and severe lesions on MRI. Cerebral hemispheric white matter appears diffusely swollen, obliterating the subarachnoid spaces. Cysts develop in the tips of the temporal lobes and frontoparietal subcortical area. The cerebellum is only mildly involved. The corpus callosum, internal capsule, and brainstem are relatively spared.

Disorders characterized by characteristic MRI features but no known genetic defectAicardi Goutieres syndrome is a leukodystrophy charac-terized by a progressive encephalopathy associated with microcephaly, spastic quadriplegia, dystonia, refractory seizures, visual loss, abnormal eye movements, and pro-found retardation [51]. A raised level of CSF interferon and chronic CSF lymphocytosis are the only known biomarkers [52]. Recent genomic studies have linked the entity in some cases to gene locus 3q21, but there is no definitive genetic association [53]. In a subset of patients, abnormal CSF findings include extremely high neopterin and biopterin combined with lowered 5-methyltetrahydrofolate concentrations, but this may represent a distinct disorder [54]. Computed tomo-graphy is very important in the diagnosis of Aicardi Goutieres syndrome, demonstrating clearly the pres-ence of calcifications in basal ganglia, specifically the lenticular nuclei. MRI reveals diffuse leukodystrophy and progressive cerebral atrophy [55].

Hypomyelination with atrophy of the basal ganglia and cerebellum is a distinct leukodystrophy identified based on MRI characteristics. Patients may present in infancy with optic atrophy, spasticity, rigidity, dystonia, and choreoathetosis, and lack of significant develop-mental outcome, or may present later with a very mild phenotype [56••]. There is no known biochemical marker for this disorder, no known mechanism of inheritance, and diagnosis is based on MRI findings. MRI shows severely delayed myelination and progres-sive atrophy and even disappearance of the caudate and putamen. The globus pallidus and thalamus remain normal. Corticospinal tracts are hypomyelinated. The cerebellum becomes progressively atrophic. Over time, cortical white matter becomes atrophic, with resultant increase in ventricular size. The basic defect in this disorder is unknown.

Leukoencephalopathy with brainstem and spinal cord involvement and elevated white-matter lactate is


another distinct leukodystrophy defined based on MRI characteristics. This disorder is suspected to be autosomal recessive. In these patients, initial development is normal, followed by a slowly progressive disorder with an onset in childhood or adolescence, characterized by progres-sive spasticity involving legs more than arms, peripheral neuropathy, minimal cognitive decline, and, on occasion, seizures [57••,58,59]. There is no specific biochemical marker for this disorder, and the mechanism of genetic transmission is unknown. MRI reveals a periventricular distribution of white matter abnormality, with extension peripherally but sparing the U fibers. White matter signal abnormalities may appear homogenous or spotty. The corpus callosum is characteristically involved. Within the brainstem and spinal cord, there is selective involvement of pyramidal tracts/lateral cortical spinal tracts, medial lemniscus/dorsal columns, cerebellar peduncles, anterior spinocerebellar tracts at the level of the medulla, and mesencephalic trigeminal tracts. The cerebellum devel-ops white matter signal abnormalities and atrophy. On proton magnetic resonance spectroscopy, there is abnor-mal elevation of lactate in nearly all the patients. The underlying defect in this disorder is unknown.

ConclusionsThe patient with white matter disease can be approached in a systematic function to arrive at possible diagnoses. First, MRI should be reviewed for features of the classic leukodystrophies and confirmed with genetic tests when possible. Subsequently, an organelle-based approach, excluding leukodystrophies and other disorders with associated leukoencephalopathy, can be performed. Tests for disorders of amino acid, organic acid, and lyso-somal, mitochondrial, and peroxisomal metabolism should be conducted based on clinical characteristics because MRI is rarely pathognomic in these disorders. Reversible causes of leukoencephalopathy, includ-ing endocrine disorders, vitamin deficiencies, and acute neurologic damage, should be excluded. Finally, it is important to remember that a number of leuko-dystrophies remain unclassified and these patients may benefit from referral to a center with special interest in these disorders in the hope of increasing the number of described syndromes.

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