Chapter 99 – Genetic and Metabolic Disorders of the White Matter

Introduction

 Over the past several decades, an increasing number of novel heritable disorders
affecting the white matter of the brain, or leukodystrophies, have been described,
often with identification of a causative gene (Table 99-1         
 Pathognomonic MRI patterns (Fig. 99-1 @)or clinical characteristics permitted
identification in a number of these disorders, and should guide the clinician's
molecular diagnosis for many conditions (see Figs 99-3, 99-5, and 99-6 @ for MRI
features).
 In addition, the recent advent of next generation sequencing approaches has
permitted a rapid increase in the number of novel diseases identified, as well as
improved diagnosis for individual patients.
 Challenges remain, however, for the neurologist, geneticist, or primary care provider
evaluating patients with suspected genetic or metabolic disorders of the white matter.
 Therefore the focus of this chapter is assisting the treating neurologist in the
diagnosis of inherited disorders of the white matter.

TABLE 99-1 Molecular Causes of Leukodystrophies

FIGURE 99-1 @ Diagnostic algorithm for use in patients with abnormal

myelination by MRI...

 The first challenge is distinguishing inherited disorders from acquired white matter
pathologies such as periventricular leukomalacia, acute demyelinating
encephalomyelopathy (ADEM), multiple sclerosis (MS) or neuromyelitis optica
(NMO), vasculitis, toxins, or infectious processes.
 This distinction is critical to patient management and genetic counseling, and
acquired etiologies should be excluded by clinical history, examination, and
laboratory testing before pursuing differential diagnosis of the heritable white matter
disorders.
 Special consideration should be given to endocrine dysfunction, as both congenital
and acquired thyroid and adrenal dysfunction have been associated with white matter
abnormalities, as have nutritional factors such as vitamin B12 deficiency.
 Furthermore, many inherited disorders such as inborn errors of metabolism or
disorders with primarily neuronal dysfunction can show CNS white matter
abnormalities on neuroimaging but are not considered classic leukodystrophies.
 This chapter will cover the classic leukodystrophies, as well as inborn errors of
metabolism and neuronal disorders relevant to differential diagnosis of the
leukodystrophies.
 A number of these will not be included in this review but should be noted as having a
component of white matter involvement (Table 99-
 Although history and clinical examination are critical to excluding acquired
leukoencephalopathies or disorders with secondary white matter manifestations,
 many classic leukodystrophies share clinical manifestations with these other
disorders.
 The hallmarks of CNS white matter disorders are progressive spasticity (often
associated with rigidity or ataxia), bulbar symptoms, and relatively preserved
cognitive function. Cranial nerve abnormalities such as optic nerve atrophy,
strabismus or nystagmus, and hearing loss can be seen.
 Peripheral nerve function may be preserved or lost to varying degrees depending on
the disorder.
 Seizures are less common and should alert the clinician to the possibility of an
underlying neuronal disorder, as should prominent dementia. These features do not,
however, exclude a leukodystrophy. Seizures, for example, are a prominent feature
of infantile Alexander disease.
 Given the heterogeneity and limited specificity in clinical findings, MRI pattern
recognition is the most useful tool for evaluating suspected leukodystrophy patients l
(Fig. 99-1 @).
 MRIs should be reviewed comprehensively, with attention to changes over time,
expected myelin development for the patient's age, and characteristics of T I-
weighted and T2-weighted signal abnormalities. Broadly, there are two groups of
leukodystrophies.
 Hypomyelinating leukodystrophies show increased white matter signal on T2 relative
to age, and often isointense or hyperintense white matter signal on T 1.
 Conversely, demyelinating leukodystrophies show increased white matter signal on
T2 relative to age and hypointense white matter signal on T 1.
 Additional radiologic features should be examined, such as white matter vacuolization
or cysts, best seen on FLAIR or similar imaging paradigms; and involvement of the
basal ganglia, brainstem, cerebellum or spinal cord; and abnormalities of cortical gray
matter.
 Finally, findings consistent with calcifications should be noted, and if clinically
indicated, a CT scan or calcium sensitive MRI sequences should be acquired to
exclude the presence of calcifications that might be missed on standard MR imaging.

 This chapter details a series of disorders for consideration in the differential diagnosis
of patients with white matter signal abnormality on neuroimaging. For each disorder,
genetic etiology, clinical features, mechanism of disease and diagnostic strategies
are reviewed.

 As this chapter's focus is diagnosis of heritable white matter disorders,

histopathologic markers are discussed where relevant to diagnostic evaluation and
pathophysiology.

 Symptomatic management remains the mainstay of care for the majority of these
conditions, and specific treatments are described only when disease-modifying
therapies are available or actively being researched.

Part I Hypomyelinating White Matter Disorders

 White matter disorders with hypomyelination are relatively frequent; hypomyelinating
leukodystrophies comprise 20% of leukodystrophies.
 They are characterized by a significant and permanent deficit of myelin.Even with
thorough genetic investigation, at least half of these hypomyelinating disorders lack
definitive diagnosis, prognostic information, and potential for prenatal diagnosis.
 Although most of these disorders show autosomal recessive inheritance, both X-
Iinked inheritance and de novo mutations are possible.
 Clinical manifestations common to hypomyelinating disorders are ataxia, spasticity,
and nystagmus.
 Other nonneurologic features such as hypodontia in 4H syndrome or cataracts in
hypomyelination with congenital cataracts can be valuable in diagnosis.
 The diagnosis of hypomyelination may be made if two MRIs at least 6 months apart
after the age of 12 months show little or no myelin development.
 Images in hypomyelinating leukodystrophies demonstrate a diffusely hyperintense
signal of the supratentorial white matter in T2-weighted images and an isointense or
hyperintense white matter signal on Tlweighted images.
 Certain areas such as the posterior internal capsule may have a more normal
appearing myelin signal.
 Myelin deposition in infratentorial structures is usually less affected.
 A definitive diagnosis of hypomyelination is not possible in young infants, as
myelination is incomplete.
 If no myelin deposition is visible on the first MRI of a child older than 24 months,
however, hypomyelination is highly probable.

 Delayed myelination is sometimes misdiagnosed as hypomyelination. In contrast to

hypomyelination, myelination progresses on serial MRI images to near normal myelin
development (Fig. 99-2 @).
 A typical example of a disease with severely delayed but progressing myelination is
the X-Iinked recessive condition thyroid hormone transporter (MCT8) deficiency, and
thyroid function should be tested in boys with severe myelination delay on MRI,
severe cognitive delay, and a pyramidal syndrome.
 Appropriate testing includes free T3 (which is elevated) and reverse T3 (which is
decreased) in the context of either normal or reduced T4 and normal or slightly
elevated TSH.
 Gray matter disorders with early onset often show hypomyelination, presumably a
result of defective axonal function.
 Features such as early atrophy and signal changes of cortex and basal ganglia may
help distinguish between primary hypomyelination and hypomyelination secondary to
neuronal dysfunction (Fig. 99-3)

FIGURE 99-3 Hypomyelinating leukodystrophies and their differential diagnosis.

A, MRI

 In cases of primary hypomyelination, the following disorders should be considered:

1 Pelizaeus-Merzbacher Disease

 Pelizaeus-Merzbacher disease (PMD, OMIM 312080@) is the prototypic

hypomyelinating disorder and is caused by alterations in the proteolipid 1 (PLPI)
gene.
 Located on Xq22.2, this gene encodes the PLPI protein, which constitutes roughly
half of all myelin protein.
 The most common abnormality is a duplication of the entire gene, which is found in
60% to 70% of PMD cases and associated with the classic form of the disease.
 The lack of common breakpoints in these duplications results in varying sizes of the
duplicated area between patients. Missense mutations account for 10% to 15% of
cases.
 Several missense mutations affecting splicing or putative regulation of expression
also have been described.
 Deletions are also seen in a smaller number of cases.
 Triplications or even higher copy numbers are present in 1% to 2% of cases.
 More complex chromosomal rearrangements involving PLPI or its promotor region
have been described in individual cases.
 Deletions or null mutations are rare.
 Roughly 15% of cases fulfilling diagnostic criteria for PMD do not possess identifiable
PLPI mutations, suggesting the possibility of mutations in regulatory regions beyond
genetic assays.
 PLPI is a highly conserved, hydrophobic membrane protein with four transmembrane
domains and a large cytosolic loop between the second and third transmembrane
domain.
 The N- and C-termini are located in the cytoplasm. Different splicing of PLPI yields a
second, smaller isoform, DM20.
 Both isoforms are primarily expressed within the CNS. Although the function of PLPI
and DM20 remains poorly understood, mutations that leave DM20 intact are
associated with relatively mild phenotype.
 Mutations associated with severe phenotypes likely cause protein misfolding that
activates compensatory oligodendrocytic responses that ultimately cause
oligodendrocyte apoptosis.
 The pathogenicity of PLPI duplications is less well understood, although it has been
speculated that overexpressed PLPI in endosomal and lysosomal compartments
deplete myelin rafts of lipids necessary for the production of functional myelin
compounds.
 The clinical features of PMD were well described by Pelizaeus and Merzbacher.
 Typically, affected boys develop a pendular nystagmus at the age of several weeks,
similar to infants with congenital nystagmus.
 Shortly thereafter, delayed psychomotor development becomes apparent.
 These infants show axial hypotonia with difficult head control, titubation, exaggerated
tendon reflexes, and a combination of ataxia and extrapyramidal features.
 Nystagmus may improve or even disappear over time. Optic atrophy is common.
 In classic PMD, patients are unable to walk and often unable to sit without support.
 If they develop active speech, it is difficult to understand because of dysarthria and
scanning speech.
 Learning problems or intellectual disability is common, although motor impairment
tends to be more pronounced than cognitive disability.
 In connatal PMD, symptoms are evident shortly after birth and often include
congenital stridor, feeding difficulties, and profound hypotonia.
 Development is more impaired than in the classic form, and connatal PMD patients
do not learn to talk or sit without support and make very little developmental progress.
 Microcephaly is common.
 Transitional PMD is intermediate in severity to the connatal and classic variants.
 These three subtypes likely form a continuous spectrum.
 Epilepsy is rare in PMD, even in the severe connatal form, and has only been
described in exceptional cases.
 The clinical course in PMD is chronic.
 Until late childhood or early adolescence, patients may improve and make definite,
albeit slow, developmental progress.
 From this age, however, slow deterioration begins, with insidious progression of
neurologic symptoms and slow cognitive decline.
 Optic atrophy, if not yet present, develops.
 Although difficult to predict for individual patients, life expectancy is reduced and
depends on severity of neurologic deficits and additional complications.
 Connatal PMD patients often die within the first decade of life and classic PMD
patients in the second or third decade.
 PMD is allelic with a relatively mild disorder, X-Iinked spastic paraplegia type 2
(SPG2), also caused by PLPI mutations.
 In its pure form, the sole symptom associated with SPG2 is slowly increasing
spasticity, more of the legs than of the arms, that begins during childhood or
adolescence.
 In the complicated forms, additional symptoms such as nystagmus, ataxia, dysarthria,
and mild cognitive impairment are present. Life expectancy in this form is normal.
 Peripheral neuropathy is another possible finding with functional null mutations in
PLPI.
 A new clinical presentation with constant MRI abnormalities affecting especially early
myelination structures (hypomyelination of early myelinating structures, HEMS) has
recently been identified and is caused by PLPI mutations in exon 3B or intron 3,
affecting PLP1/DM20 splicing in favor of DM20.
 Altogether, alterations of PLPI mutations give rise to a spectrum of disorders, ranging
from the very severe connatal phenotype to mild spastic paraplegia with adolescent
onset.
 Genotype-phenotype correlations have been established for most PLPI alterations,
although clinical heterogeneity among patients with common genetic alterations
makes definitive characterization difficult.
 Symptoms do not correlate with duplication size, but high copy number appears to
predict increased clinical severity.
 Severe epilepsy, an otherwise uncommon feature of PMD, has been reported in
children with triplications.
 Point mutations are associated with the full spectrum of PLP1-associated disorders.
 Demyelinating neuropathy is associated either with null mutations or mutations in
PLP-specific regions.
 Patients with functional null mutations show relatively mild clinical course: they
usually achieve independent, albeit clumsy, ambulation, show mild cognitive
impairment, and demyelinating neuropathy.
 As spasticity increases after the first decade, patients become wheelchair-bound and
develop pseudobulbar palsy.
 Histopathologic investigations show evidence of length-dependent axonal
degeneration in these patients and in corresponding mouse models.
 Interestingly, female heterozygotes may develop symptoms. In cases of PLPI
duplications, symptoms are rare and include transient, PMD-like symptoms in young
girls.
 Symptom development in females tends to be associated with mutations causing mild
phenotypes in males.
 It has been suggested that severe mutations and duplications cause early apoptosis
in oligodendrocytes expressing the mutated allele in females.
 Oligodendrocytes expressing the wild-type allele proliferate to compensate for the
loss of mutant cells.
 Mild mutations, however, do not elicit oligodendrocytic apoptosis, and surviving
mutant cells cause impaired myelin formation and ultimate axonal degeneration.
Female carriers of these mutations develop slowly progressive spastic paraplegia
and cognitive decline later in life.
 MRI in PMD shows hypomyelination, indicated by diffusely elevated signal white
matter signal on T 2 (Fig. 99-3A       
 Myelination is arrested and fails to progress on repeated scans.
 Some patients show a more mottled, "tigroid" signal, perhaps due to small myelinated
areas surrounding blood vessels.
 In some patients, myelin deposition is seen in the posterior limb of the internal
capsule or the optic radiations.
 Myelination is usually present in the brainstem and sometimes in the cerebellar
hemispheres.
 Often—but not always—the pyramidal tracts in the brainstem show high T 2 signal. At
a young age, atrophy is not particularly prominent, especially in the cerebellum,
although white matter volume may be decreased.
 The corpus callosum is thin, reflecting lack of myelinated axons.
 As children grow older, generalized atrophy develops. Proton MR spectroscopy
reveals low choline, due to reduced membrane turnover in the absence of
myelinating oligodendrocytes, and normal-to-elevated Nacetylaspartate (NAA), due to
more densely packed axons.
 Patients with null mutations or deletions show more advanced supratentorial
myelination.
 In SPG2 patients, MRI abnormalities are variable, ranging from diffuse mild
hypomyelination to mild periventricular signal changes.
 Carrier females sometimes display small areas of elevated white matter signal, but
MRI is usually normal.
 Diagnosis of PMD is based on typical clinical presentation, radiologic evidence of
hypomyelination, and detection of PLPI alterations.
 Routine laboratory and metabolic tests, including CSF studies, are normal.
 As most PLPI alterations are duplications, simple sequencing must also be
accompanied by gene dose quantification by Southern blot, quantitative PCR, or,
more recently, multiple ligation-dependent probe amplification (MLPA).
 Recently elevation of the dipeptide N-acetylaspartylglutamate (NAAG) has been
described in several PMD cases, with NAAG level appearing to predict clinical
severity.
 The mechanism of NAAG elevation, however, remains unknown, and it is neither
specific to PMD, nor a marker of hypomyelination in general.

2 Pelizaeus-Merzbacher-Like Disease

 Pelizaeus—Merzbacher-like disease (PMLD, OMIM 608804 @) is phenotypically

similar to PMD, although its inheritance is autosomal-recessive instead of X-Iinked.
Children with hypomyelination on MRI but without the PMD phenotype are often
mischaracterized as PMLD.
 The primary clinical features include early nystagmus, ataxia and spasticity.
 PMLD is a genetically heterogeneous disease.
 In most cases, no gene has been identified. In a small subset of clinically identified
PMLD patients (fewer than 10%), mutations in GJC2 (also called GJA12), coding for
Connexin 46.6 (Cx47), have been found (OMIM 608804         and PMLD is now
mostly used for patients with GJC2 mutations.
 Located on chromosome Iq41q42, this gene was identified using a homozygosity
mapping approach in a large consanguineous family.
 Mutations were subsequently found in other, unrelated patients confirming GJC2 as
the responsible gene.
 Of note, several families with mutations in the GJC2 promoter region were published.
 The mutations found were predicted to attenuate GJC2 expression and negatively
influence binding of the transcription factor SOXIO.20-22 Connexins (Cx) are integral
to intercellular junctions.
 In the CNS, gap junctions are an essential component of the large glial syncytium
among astrocytes and oligodendrocytes.
 Oligodendrocytes express two connexins, Cx32 and Cx47, and GJC2 mutations
cause loss of Cx47 function, disturbing gap junction properties between
oligodendrocytes and astrocytes.
 The mechanistic link between these molecular genetic insults and hypomyelinating
phenotype remain unclear.
 Interestingly, other connexin genes have been implicated in white matter disorders.
 GJAI (Cx43) mutations are associated with oculodentodigital dysplasia, which is also
characterized by hypomyelination.
 GJBI (Cx3 2) mutations lead to Charcot-Marie-Tooth disease type I.
 Transient, sometimes fluctuating central neurologic symptoms may occur in this
disorder, often associated with mild infections. MRI reveals mild cerebral white matter
hyperintensities, likely reflecting myelin splitting and intramyelinic edema.
 As in PMD, patients typically present with nystagmus apparent after the first few
weeks of life. Motor development is delayed and children display ataxia during the
first few years.
 Pyramidal signs and frank spasticity often develop later.
 Compared with boys with classic PMD, motor and cognitive performance in PMLD is
better, especially during the first years of life, and children are often able to walk,
some without support.
 However, patients later show a more precipitous decline, with progressive spasticity,
prominent pseudobulbar signs, and facial weakness reminiscent of myopathic face.
 Patients become wheelchair-bound in their teens.
 Epilepsy starting in late school age has been reported in a substantial proportion of
cases and may be more severe in isolated cases, a very unusual feature for boys
with PMD.
 Mild demyelinating peripheral neuropathy revealed by nerve conduction studies has
been described in some patients, although it does not influence the overall clinical
manifestation.
 A recently described family carrying a homozygote missense mutation in GJC2
showed a phenotype of almost pure spastic paraplegia and minor cerebellar signs.
 There are no histopathologic data on PMLD.
 MRI shows hypomyelination and prominent signal abnormalities of the pyramidal tract
of the brainstem have been described (Fig. 99-3B Cerebellar atrophy is mild or
absent, at least in early stages; supratentorial atrophy with considerable white matter
loss is prominent in older patients.
 Brainstem atrophy is often seen in later stages. Routine metabolic investigations are
normal. In CSF, NAAG is elevated, as it is in PMD.

3 4H Syndrome

 This recently described leukoencephalopathy (OMIM 607694 @, 614381 @) is also

characterized by hypomyelination. Its name is derived from its three main clinical
findings: hypomyelination, hypodontia, and hypogonadotropic hypogonadism.
 About 90% of cases are caused by recessive mutations in either POLR3A or
POLR3B, encoding the two largest subunits of RNA polymerase Ill.29-31 4H
syndrome is the second most frequent hypomyelinating white matter disorders after
PMD.
 Initial development is normal, and affected children often start to walk without support
before 18 months.
 Their gait, however, does not improve as in healthy children, and by the age of 2 to 3
years, parents note that they walk clumsily and frequently fall.
FIGURE 99-4     Dental phenotype of children with 4H syndrome. Denta p
enotypeo two c...

 Hypogonadotropic hypogonadism can only be diagnosed in adolescence when

patients fail to enter puberty and is not obligate for the diagnosis. Low LH and FSH
levels indicate central hypogonadism, although the cause of reduced LH and FSH is
unknown.
 Other common symptoms include myopia, which may be high, and small stature
becomes evident around school age.

 MRI, as the name of the disease suggests, shows hypomyelinated white matter (Fig.
99-3C T2 signal in the supratentorial white matter is diffusely elevated, with the
exception of the pyramidal tracts in the posterior limb of the internal capsule and the
optic radiation.
 Tl white matter signal varies from hypointense to hyperintense, depending on the
amount of myelin deposited. Cerebellar white matter is usually myelinated on T2.
 The corpus callosum is of normal volume in the beginning but atrophies over the
course of the disease.
 There is also early and considerable cerebellar atrophy, more of the vermis than of
the hemispheres, in most patients.
 Whether clinical severity correlates with the amount of myelin deposited or the
degree of initial cerebellar atrophy has not yet been elucidated.
 Proton MR spectroscopy reveals low choline, as is usual in hypomyelination, and
often elevation of myoinositol compatible with gliosis.
 In later stages, considerable cortical atrophy and white matter loss develop, indicating
ongoing myelin loss.
 In patients of European descent, mutations in POLR3B are more common than in
POLR3A.
 There is one frequent mutation in POLR3B, c. 1568T>A, p.Va1523Glu present in the
heterozygous state in most individuals.
 In the homozygous state, this mutation causes an exceptionally mild form of 4H.
 In Quebec, the mutation c.2015G>A, p.Gly672Glu in POLR3A is frequent.
 Otherwise, patients carry mostly private mutations, making a genotype-phenotype
relationship difficult.
 Patients with POLR3A mutations are usually more severely affected than patients
with mutations in POLR3B.

4 Hypomyelination Related to Cytoplasmic tRNA Synthetase Defects

 Recently two hypomyelinating disorders were described due to mutations in DARS or

RARS— coding for the cytoplasmic tRNA synthetases for aspartate (OMIM 615281
@) and arginine (OMIM616140@), respectively.
 Clinically, both entities are remarkably similar with onset in infancy in most cases, a
fine, rapid nystagmus, early severe spasticity and ataxia.
 Again, cognition is much less affected than motor abilities, with normal cognitive
abilities in a subset of the patients with DARS mutations.
 Two patients with subacute onset in late adolescence and DARS mutations have
been reported, mimicking multiple sclerosis, including presumed response to
steroids.
 MRI in RARS-related hypomyelination shows global, severe hypomyelination without
other specific features.
 MRI in patients with DARS mutations shows typical brainstem and spinal cord
abnormalities in addition to hypomyelination with T 2 -signal elevation of the superior
and inferior cerebellar peduncles, the anterior brainstem, the medial lemniscus, the
dorsal columns, and the lateral and anterior corticospinal tracts.
 These findings prompted the acronym HBSL (hypomyelination with brainstem and
spinal cord involvement and leg spasticity).
 Both tRNA synthetases are part of the multisynthetase complex, as is AIMPI
(aminoacyl-tRNA synthetase interacting multifunctional protein 1).
 Recessive mutations in the latter lead to a severe disorder with early onset,
hypomyelination, and brain atrophy, indicating primary neuronal involvement.
 The role of the multisynthetase complex in hypomyelination needs further elucidation.
 Additionally, AARS, encoding the cytoplasmic tRNA synthetase for alanine, has
recently been associated with a disorder characterized by congenital equinovarus,
microcephaly, epileptic encephalopathy, and persistently delayed myelination.
 Although the clinical features make it harder to attribute the disease manifestations to
a primary glial pathology, this disorder joins RARS-related hypomyelination, HBSL,
as well as EARS2, MARS2, DARS2, and AARS2-related disorders as conditions with
leukoencephalopathy or leukodystrophy caused by mutations in tRNA synthetase
genes.
 The role, canonical or not, that these multiple tRNA synthetases play in myelin
homeostasis, has not been elucidated.

5 Oculodentodigital Dysplasia

 Oculodentodigital dysplasia is another hypomyelinating disorder characterized by

dental abnormalities (ODDD, OMIM 164200 @).
 Its inheritance is autosomal dominant.
 Dominant mutations in another connexin gene on chromosome 6q21-23.2, GJAI
coding for connexin 43 (Cx43), cause ODDD.
 There is one family described with autosomal recessive mutations leading to the
same phenotype. Cx43 is expressed in the developing brain and teeth, as well as in
hands and feet.
 ODDD is likely not as frequent as 4H syndrome.
 Affected children are usually regarded as neurologically normal and are primarily
diagnosed based on the typical dysmorphic signs.
 These consist of ocular anomalies (microphthalmus, microcornea, iris abnormalities,
short palpebral fissures, epicanthus), facial dysmorphic signs (especially a thin nose
with hypoplastic alae, small anteverted nares and a prominent columella), hand and
foot abnormalities (syndactyly of third, fourth, and fifth fingers and second to fourth
toes, clinodactyly of fifth fingers), thin and brittle hair and sometimes microcephaly.
 Dental abnormalities have not been described in detail but are present in all patients.
Teeth are brittle and prone to decay.
 They show early discoloration, probably due to a defect in dentine. Microdontia and
hypodontia are other common findings.
 Neurologic symptoms are frequent although no large case series has been reported,
and as such, little is known about the exact time course and development of
neurologic abnormalities.
 In childhood and adolescence, coordination problems and mild ataxia are common.
 In adulthood, slow neurologic deterioration is seen, with development of pyramidal
tract lesions, ataxia, dysarthria, loss of bladder control and finally frank spasticity.
 Unsupported gait may become impossible in late stages. Optic atrophy and deafness
are possible. Cognition is preserved in most patients, although learning disabilities
have been reported. Whether and to what extent early cognitive deterioration occurs
await further study. e penp era nervous system appears una ecte
 MRI shows mild to moderate hypomyelination, supratentorial atrophy, and mild
cerebellar atrophy.
 Some authors describe hypointense signal of the basal ganglia and thalami.

6 Hypomyelination with Congenital Cataract

 Hypomyelination with congenital cataract (HCC, OMIM 610532 @) is a recently

described disorder with CNS hypomyelination reported in five families.
 The genetic locus of HCC is FAM126A, earlier called DRCTNNBIA, on chromosome
7p15.3.
 It encodes the hyccin membrane protein. Missense mutations, mutations affecting
splice sites, and a deletion of the entire gene have been identified, but its role in
myelination remains obscure.

 Affected patients present early with delayed motor development. Cognitive

development is mildly to moderately delayed.
 Most HCC-affected children learn to walk with support before their second birthday.
 Neurologic examination reveals dysarthria, moderate to severe spasticity with
elevated muscle tone, brisk reflexes, extensor plantar response, and cerebellar signs
such as intention tremor and dysmetria.
 Nystagmus is rare.
 As in other hypomyelinating disorders, progression of secondary neurologic
symptoms occurs, and children may be unable to walk with support by the end of the
first decade. An additional pathognomonic finding is congenital cataract.
 Several HCC cases have been published, and one patient failed to develop cataract
until age 9.
 A small subset of HCC patients suffers from occasional seizures.
 Peripheral neuropathy is seen in almost all patients, leading to loss of previously
exaggerated tendon reflexes and distal muscle wasting.
 It is not yet known whether a broad phenotypic spectrum exists in HCC, and clinical
presentation is heretofore remarkably homogeneous, with the exception of cataract
and peripheral neuropathy not present in all patients.
 There are no data yet about CNS pathology, nor experimental models to elucidate
hyccin function.
 Electrophysiologic studies show evidence of demyelinating neuropathy.
 Sural nerve biopsy in several patients revealed lack of myelinated nerve fibers, thin
noncompacted myelin surrounding the few myelinated axons, and, in some cases,
formation of small onion bulbs near Schwann cell processes.
 MRI shows hypomyelination, as evident from the diffusely elevated T 2 white matter
signal.
 In contrast to other hypomyelinating disorders, HCC patients show additional areas of
higher T 2 white matter signal and decreased signal intensity on corresponding T I-
weighted images, indicating elevated water content in these areas, particularly in
periventricular regions (Fig. 99-3E      Cerebellar atrophy is not seen.
 In early stages, normal myelin signal may be apparent in subcortical fibers and
corpus callosum.
 In late stages, white matter appears shrunken with increased apparent diffusion
quotients.
 Proton MR spectroscopy gives variable results depending on the disease stage.
 Choline may even be slightly elevated in early stages, which is unusual for a
hypomyelinating disorder, and decreased in later stages.

7 Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum

 Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC, OMIM
612438 @ is a rare disorder caused by dominant de novo mutations in the gene
coding for one of the beta-tubulins, TUBB4A.
 Several families with more than one affected child have been reported due to
mosaicism for a TUBB4A mutation in one of the parents.
 Disease severity ranges from severely affected infants presenting shortly after birth to
more mildly affected children with initially normal development.
 In severe cases, children fail to achieve motor milestones and linguistic development
and show profound axial hypotonia.
 Some have nystagmus, and optic atrophy is possible.
 Spasticity is common.
 Extrapyramidal symptoms such as dystonia, rigidity, and choreoathetosis are
uniquely common to H-ABC relative to other white matter disorders. Failure to thrive
and microcephaly are frequent.
 In mildly affected children, unsupported walking is achieved within the first few years
of life, sometimes on time, but is later lost.
 There is a combination of spasticity, extrapyramidal symptoms, and ataxia.
Intellectual impairment is mild, although patients tend to show cognitive decline in
addition to deteriorating motor functions.
 MRI shows hypomyelination.
 In some children, T 2 white matter signal is less hyperintense, indicating some myelin
deposition.
 The cerebellum is atrophic, more so the vermis than the cerebellar hemispheres.
Characteristic MRI features are atrophy or absence (in later stages) of the putamen,
apparent within the first year of life.
 The caudate is reduced in size and disappears entirely in some patients.
 Thalamic and pallidal volumes remain normal.
 Over time, white matter loss leads to supratentorial atrophy.
 The extent of basal ganglia and white matter atrophy predicts clinical severity.
 These MRI features are considered diagnostic.
 Recently it became obvious that the basal ganglia may be normal in this disorder.
 TUBB4A is therefore an important gene to consider in the differential diagnosis of
hypomyelination.
 The amino acid c. 745G>A (p.Asp249Asn) is the most prevalent mutation found in
classic H-ABC, located at the intradimer interface of the up-tubulin heterodimer.
 Patients carrying this TUBB4A change show a less rapid progressive course than H-
ABC patients with mutations affecting other residues, which are usually also located
at the intradimer interface."
 One mutation in TUBB4A has been shown to cause dystonia type 4 (whispering
dysphonia, OMIM 128101 @ ) with normal MRI.
 Additionally, numerous recent reports identify TUBB4A mutations in patients with
isolated hypomyelination and mild clinical course, suggesting that there is a spectrum
of both disease severity and MRI changes.
 Recently published neuropathologic findings from one H-ABC patient detail slightly
reduced white matter volume, reduced oligodendrocytes, severe myelin deficiency,
especially of deep white matter, and some white matter loss, as indicated by the
presence of macrophages in perivascular regions.
 Axons appeared relatively preserved. There was mild astrocytosis and strong
presence of microglia.
 The putamen was visible only as a small streak, and microscopy revealed substantial
neuronal loss.
 Cerebral cortex was normal, both macroscopically and microscopically.
 In the atrophic cerebellum, there was loss of granule cells.
 Pyramidal tracts appeared degenerated in the brainstem and spinal cord. Metabolic
investigations are normal in these children.

8 Sialic Acid Storage Disorders

 Salla disease OMIM 604369    and infantile sialic acid storage disease ISSD, OMIM
269920 @) are both caused by autosomal recessive mutations in SLCI 7A5 coding
for sialin, a lysosomal membrane protein transporting sialic acid from lysosomes.
 The gene is located on chromosome 6q14/15. Recently it was shown that sialin also
functions as a shuttle for aspartate and glutamate in synaptic vesicles.
 Free sialic acid accumulates in lysosomes of many cell types, including liver and
kidney cells and cultured fibroblasts.
 In leukocytes, this accumulation causes vacuoles visible at light microscopic
examination.
 Electron microscopy reveals membrane-bound vacuoles filled with fibrillogranular
amorphous material.
 The pathogenesis of free sialic acid storage disease and the role of sialic acid remain
unclear.
 Both diseases are characterized by elevated excretion of free sialic acid in urine.
Sialic acid is also elevated in other fluids such as CSF.
 Recently two siblings have been described lacking the characteristic sialuria; sialic
acid was elevated only in CSF.
 Prevalent in Finland, Salla disease is characterized by seemingly normal early
development followed by presentation with hypotonia and ataxia in the second half of
the first year of life.
 Nystagmus is also common.
 It may be evident in the neonatal period and frequently disappears.
 Many children also show strabismus.
 Spasticity develops slowly, and mild extrapyramidal symptoms are common in later
stages.
 Mean age at walking is 4 years, with roughly one third of patients who do not develop
independent ambulation.
 Language is severely affected and usually dysarthric; patients are at best able to
produce short sentences.
 Epilepsy with short, complex-focal seizures is relatively common.
 In some patients, there is evidence for peripheral hypomyelination with decreased
nerve conduction velocities.
 The disease is stable over a long period of time, with ultimate late progression.
 Additional symptoms may include short stature or hypogonadotropic hypogonadism.
Facial features become coarse in adulthood.
 Otherwise, there is no evidence for dysostosis multiplex or hepatosplenomegaly,
despite the presence of free sialic acid storage in liver and spleen. Life expectancy is
normal.
 ISSD is a much more severe disease, with neonatal presentation and rapid
progression.
 Hydrops fetalis is possible.
 Neonates may show hepatosplenomegaly and ascites.
 They have fair hair and coarse features.
 Milestones of normal development are not acquired, and death occurs within the first
couple of years.
 A phenotype with intermediate severity relative to Salla disease and ISSD has also
been identified.
 MRI in patients with Salla disease shows hypomyelination 0 (Fig. 99-3D         
 There is white matter volume loss. The corpus callosum may be stringlike, especially
in severe cases.
 There is usually cerebellar atrophy, and supratentorial atrophy is found in older
patients.
 Proton MR spectroscopy reveals a high N-acetylaspartate (NAA) peak, likely due to
elevated free sialic acid, whose N-acetyl peak coresonates with the N-acetyl peak of
NAA.

9 Fucosidosis

 Fucosidosis is another lysosomal storage disorder characterized by hypomyelination

(OMIM 612280 @).
 Enzymatic defects in a-L-fucosidase result in fucose accumulation in tissues.
 Type I fucosidosis shows early onset and rapid progression, although type Il develops
with more insidious onset, presenting with nonspecific psychomotor retardation.
 Dysostosis multiplex and coarse features are mild in type Il.
 Angiokeratomas are common and occur in 30% of patients under age 10. In type I,
sweat contains a high concentration of sodium chloride.
 Bone marrow transplantation has been performed in individual cases.
 Its efficacy has not yet been empirically established, but it may slow the progression
of the disease if performed early enough.
 MRI shows hypomyelination.
 A characteristic feature of fucosidosis is high Tl -signal and low T2 -signal in globus
pallidus, thalamus, and substantia nigra.
 Cerebral and cerebellar atrophy may be prominent in older patients.

10 Serine Synthesis Defects

 Serine is synthesized by a three-step biochemical pathway, and defects in any of the

three enzymes in this pathway have been shown to cause serine biosynthesis
defects: 3phosphoglycerate dehydrogenase (OMIM 601815 @), phosphoserine
phosphatase (OMIM 172480        and phosphoserine aminotransferase (OMIM
610992
 The biochemical hallmark of these disorders is low serine and glycine concentration
in CSF.
 In plasma, serine concentration is often also decreased but may be normal, making
CSF investigations an essential diagnostic tool for this group of disorders.
 Children with 3-phosphoglycerate dehydrogenase deficiency are born microcephalic,
and their development is grossly delayed.
 Epilepsy develops in the second half of the first year of life; West syndrome is one
possible manifestation.
 Supplementation with serine and glycine is effective in seizure management.
 If treatment is commenced prenatally, head circumference at birth and development
are normal.
 In untreated children, MRI shows hypomyelination and white matter volume loss.54
Corpus callosum is thin and short.
 Myelination improves under treatment.
 The first documented patient with phosphoserine aminotransferase deficiency
presented in the neonatal period with severe epilepsy resistant to medical treatment
and rapidly developing microcephaly.
 MRI showed supratentorial and brainstem atrophy. Supplementation with serine and
glycine did not attenuate the seizures.
 The same treatment, if started before the development of symptoms, was shown to
prevent epilepsy and enable normal development in the sibling of the proband.

11 Cockayne Syndrome and Trichothiodystrophy

 Cockayne syndrome (CS) is a rare disease combining neurologic and nonneurologic

features.
 This disorder and related disorders of DNA repair such as cerebro-oculo-facial
syndrome (COFS) and trichothiodystrophy (TTD) are genetically heterogeneous and
caused by mutations in CSA (CKNI or DNA excision repair protein ERCC-8,
responsible for 20% of the CS); CSB (CKN2 or ERCC-6, responsible for most of the
remainder of CS cases); XPB (ERCC3, OMIM 610651 XPD (ERCC2) or XPG
(ERCC5); ERCCI-XPF, TTDA, and TTDNI genes; and possibly others.
 The classic form, Cockayne syndrome type I, presents in the first year of life with
failure to thrive; weight is more affected than length ("cachectic dwarfism"), and there
is loss of subcutaneous fat, leading to a "wizened," bird-like, progeroid face.
 Microcephaly also develops, usually by the end of the second year. Children develop
contractures of the large joints, giving them a typical posture.
 Hands and feet are disproportionally large.
 Dental caries are prominent.
 Psychomotor development is also delayed resulting in mild to severe cognitive
impairment.
 Predominant neurologic features include ataxia and spasticity, which show slow
progression.
 In late stages, peripheral neuropathy leads to muscle wasting and loss of the initially
increased tendon reflexes.
 Over half develop sensorineural hearing loss.
 Most suffer from pigmentary retinal degeneration and cataracts. Autonomic
dysfunction (hypolacrimia, hypohydrosis, miosis, acrocyanosis) is possible.
 In Cockayne syndrome type Il, the clinical picture is much more severe with growth
failure already evident at birth.
 Loss or even absence of subcutaneous fat is striking. Joint contractures and kyphosis
develop rapidly.
 Hypotonia is prominent initially, followed by development of spastic tetraparesis.
 Psychomotor development is absent or extremely delayed with subsequent
deterioration and early death.
 Subcutaneous fat loss has been treated in both types by early hypercaloric tube
feeding, which allows reasonable growth in some children.
 Type Ill describes patients with milder forms.
 Cutaneous photosensitivity is also characteristic of Cockayne syndrome, occurring in
75% of all patients.
 In trichothiodystrophy (also called Tay syndrome), the hair is dry, thin, and brittle.
 Polarization microscopy of affected hair reveals a typical tiger-tail pattern.
 Structural hair abnormalities are due to a strong reduction in cysteine residues,
decreasing disulfide crosslinks in hair fibers.
 In some children, hair is lost after episodes with fever. Prominent cutaneous
photosensitivity is also present, and ichthyosis is possible. Nails are dystrophic.
Neurologic symptoms are variable, including psychomotor delay and mild cognitive
impairment, ataxia, pyramidal signs, frank spasticity, and nystagmus.
 As in Cockayne syndrome, cataracts and retinal degeneration may also be seen.
 Both syndromes are caused by defective nucleotide excision repair. Over 30 proteins
are involved in this process.
 It eliminates DNA lesions induced by ultraviolet light.
 There are two major subpathways of nuclear excision repair: transcription-coupled
repair dealing with reparation of transcribed genes and global genome repair
removing lesions in the entire genome.
 Defective DNA repair can be demonstrated by irradiating cultured skin fibroblasts with
ultraviolet light and subsequently measuring unscheduled DNA synthesis.
 This unscheduled DNA synthesis is diminished in trichothiodystrophy and xeroderma
pigmentosum patients.
 In Cockayne syndrome, this unscheduled DNA synthesis is not significantly
attenuated, but the otherwise rapid recovery of RNA and DNA synthesis after UV
irradiation is adversely affected, indicating that the global genome repair is still
functional.
 Additionally, reduction in basal transcription is also seen, an important signal for
apoptosis.
 These defects of transcription, perhaps combined with activation of apoptosis, are
thought to be mainly responsible for the neurologic symptoms in Cockayne
syndrome.
 Complementation assays in cultured cells could distinguish two different
complementation groups: Cockayne syndrome type I (OMIM 216400 @) caused by
mutations in the gene coding for group 8 excision-repair cross-complementing protein
(ERCC8); and type Il (OMIM 133540 @) due to mutations in ERCC6.
 Trichothiodystrophy is also heterogeneous, genetic defects having been identified in
at least three different genes.
 MRI of patients with Cockayne syndrome shows hypomyelination, its degree
corresponding to clinical severity.
 In severe cases with Cockayne syndrome type Il, hypoplasia of cerebellum and
brainstem is possible. Basal ganglia calcifications are common. Similar features are
seen in trichothiodystrophy, although calcifications are less common than in
Cockayne syndrome.
12 18q Minus Syndrome

 In this disorder (OMIM 601808 the distal region of the long arm of chromosome 18 is
deleted.
 It occurs de novo most commonly.
 The contiguous gene deletion usually involves the bands 18q22.3—qter.
 The gene for myelin basic protein (MBP), a component of healthy myelin, is located
within this region.
 It has been postulated that haploinsuffiency for MBP leads to the myelin
abnormalities observed in 18q minus syndrome.
 Heterogeneity in severity of clinical symptoms and hypomyelination between patients,
despite consistent loss MBP, is a focus of ongoing inquiry.
 There is a well-investigated mouse model, the shiverer mouse, with homozygous
rearrangements in the MBP gene, 60 which lead to CNS, but no peripheral,
hypomyelination.
 It is unknown why peripheral myelin is spared, despite MBP expression in peripheral
nerves.
 The disorder is stable with a variety of dysmorphic features (microcephaly,
hypertelorism, epicanthus, high or cleft palate, short neck, tapering fingers and
clinodactyly, external ear anomalies, cardiac malformations, foot abnormalities) and
neurologic abnormalities.
 Most patients show moderate to severe mental retardation, but cases with normal
intelligence have been seen. Many suffer from sensorineural deafness.
 Patients may also show hypotonia in infancy, ataxia, nystagmus, and epilepsy.
 IgA deficiency and partial growth hormone deficiency are common.
 MRI shows hypomyelination of variable, but usually mild, degree.
 The myelin signal in the cerebral hemispheres may be inhomogeneous with patchy
white matter abnormalities.
 Corpus callosum may be thin.
 There may be mild supratentorial atrophy.

13 SOXIO-Associated Disorders

 These rare syndromes are caused by mutations in SOX 10 on chromosome 22q13,

which encodes a transcription factor for various genes, some such as GJBI (connexin
32) involved in myelin formation and metabolism.
 These disorders are characterized by a white hair lock and hypomelanotic spots,
sensorineural deafness, and Hirschsprung disease.
 Patients are affected with varying severity, ranging from antenatal onset with
congenital arthrogryposis multiplex and severe neurologic abnormalities to more
mildly affected patients, lacking neurologic manifestations (Waardenburg-Shah
syndrome, WS4, OMIM 277580 @ ).
 The severe variant has been designated peripheral demyelinating neuropathy, central
dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease
(PCWH, OMIM 609136 @).
 Consistent with a neurocristopathy, many features of this disease can be explained
by defective differentiation or migration of neural crest cells.
 In the severe cases, MRI reveals hypomyelination.
 The milder phenotype of WS4 is explained by SOX 10 haploinsufficiency, whereas
the severe form, PCWH, is thought to be caused by a dominant negative mechanism.
 Mutations found in children with PCWH are all truncating and located in the last exon.
 These mutations, unlike SOXIO mutations leading to WS4, escape nonsense
mediated decay and can therefore exert their dominant negative effect on protein
level.
 Neurologic symptoms of children with PCWH include delayed development,
nystagmus, spasticity, and ataxia. In severe cases, neonates are already
symptomatic with profound hypotonia, seizures, or congenital arthrogryposis due to
hypomyelinating neuropathy.
 Other possible symptoms are reduced tear and saliva production, anhidrosis, and
severe failure to thrive, in addition to the classic syndromes of WS4.
 Neuropathologic investigations of a severely affected infant have shown absence of
central and peripheral nervous system myelin at the age of 3 months.
 Detailed MRI features have not been reported for many patients, but preliminary
cases suggest mild to severe hypomyelination and possibly atrophic brainstem.

Part Il White Matter Disorders with Demyelination

 If MRI is not consistent with hypomyelination, if there is white matter hypointensity on

Tl instead of isointensity or hyperintensity, and if there is hyperintensity on T 2, then
the imaging pattern fits the demyelinating leukodystrophies.
 They comprise the leukodystrophies with primary demyelination, leukodystrophies
with white matter vacuolization and intramyelinic edema, calcifying
leukoencephalopathies, cystic leukoencephalopathies, leukoencephalopathies with
brainstem involvement, and most adult-onset leukoencephalopathies.
 In assessing patients with these leukodystrophies, careful attention should be paid to
specific neuroimaging features, including basal ganglia or brainstem signal
abnormalities, contrast enhancement, cysts, calcifications, contrast enhancement, or
specific FLAIR imaging abnormalities (Fig. 99-3, 99-5, and 99-6 @) to assist in the
differential diagnosis.

Primary Demyelinating Leukodystrophies

 These conditions comprise several of the "classic" leukodystrophies and include

Alexander disease, X-Iinked adrenoleukodystrophy, metachromatic leukodystrophy
and Krabbe disease, as well as other less common disorders.

1 Alexander Disease
 Alexander disease (AxD, OMIM 203450@) 67 is associated with mutations in the gene
encoding the glial fibrillary acidic protein (GFAP).
 GFAP mutations are thought to confer gain of function, and a mutation on a single
allele is sufficient to cause disease. In most cases, mutations are sporadic, although
familial cases are described in adult or juvenile onset cases.
 In familial cases, inheritance is autosomal dominant.
 There is usually concordance in presentation within a family, such that a family with
adult-onset presentation and subsequent infantile presentation has not been
reported.
 There is no definite genotype-phenotype correlation, with the exception of the two
most common mutations, R79 and R239. R239, in particular, is associated with
earlier onset and poor prognosis.
 Type I AxD typically presents before the fourth year of life and with typical MRI
features.
 In very rare cases, patients present in the neonatal period with macrocephaly and
delay in milestones, with both cognitive and motor deficits.
 Patients may present with seizures, often febrile, although these are rarely refractory
to classic anticonvulsants.
 Pyramidal and sometimes extrapyramidal features develop and children often lose
motor skills in the first decade of life.
 Bulbar features, such as intractable vomiting, swallowing difficulties and respiratory
compromise, can be present early on or only develop over time.
 Hydrocephalus can become a significant clinical issue, and serial CT scans, in
particular when abrupt clinical decompensation is noted, may help in clinical
management.
 In some cases, surgical placement of a ventricular drainage system has provided
benefit. With aggressive supportive care, these children can enjoy periods of clinical
stability, although the disease is relentless.
 Lifespan is variable.
 Type Il AxD (older than 4 years at onset) usually is associated with atypical MRI
abnormalities, often sparing the supratentorial white matter and affecting
predominantly the brainstem.
 These patients present with predominant motor dysfunction, often with progressive
gait disturbance or fine motor difficulties, and clinically evident spasticity.
 Bulbar symptoms, in particular palatal myoclonus, can be very suggestive of the
diagnosis.
 Over time, dysphonia and dysphagia can become increasingly debilitating.
Dysautonomia is frequent.
 Sleep apnea is a commonly reported problem, and sleep history should be
monitored.
 In juvenile patients undergoing significant statural growth, scoliosis often evolves.
 In the older subjects, disease progression is slower than in the infantile cases, and
many subjects continue to benefit from school and social activities for many years.
 In rare cases, juvenile and adult patients can present with atypical clinical
manifestations such as focal brainstem abnormalities that can be mistaken for
brainstem gliomas.
 Incidence and prevalence of AxD are not known.

 GFAP mutations are thought to result in decreased solubility of the glial fibrillary
acidic protein, and accumulation of GFAP along with vimentin, uß-crystallin, and heat
shock protein 27, resulting in Rosenthal fiber (RF) aggregation. RFs, accumulating in
astrocytes, are thought to obstruct normal glial cell function and result in myelin
destruction.
 RF accumulation in the ventricular collecting system is believed to cause the
hydrocephalus seen in the clinical setting.
 Studies to improve pathophysiologic understanding of this disease and possible
treatment strategies are ongoing in an existing murine model of AxD. AxD is typically
suspected based on clinical presentation and characteristic MRI features.
 Typical AxD imaging features include frontal predominance of white matter
abnormalities, basal ganglia and/or brainstem involvement, a periventricular rim of
altered signal on Tl- and T2-weighted imaging, and contrast enhancement of specific
intracranial structures (Fig. 99-5A @).
 The presence of four of five of these features makes diagnosis of AxD very likely and
should prompt mutation testing. 69 In very young infants and in the juvenile or adult-
onset cases, MRI imaging may be less typical and involve only restricted brain
regions.
 Additional features described in AxD imaging include predominant or isolated
involvement of posterior fossa structures, multifocal tumor-like brainstem lesions,
brainstem atrophy, and garland-like abnormalities along the ventricular wall. \
 MRS can be helpful in the diagnosis if it shows a lactate peak in affected tissues but
may also lead to inappropriate evaluations for mitochondrial cytopathies.
 There have been reports of findings of elevations of GFAP protein in CSF, but this
test is not used as a clinical tool.

2 X-Linked Adrenoleukodystrophy

 X-Iinked adrenoleukodystrophy (XALD, OMIM 300100 @) is associated with

mutations in the ABCDI gene 73 encoding a peroxisomal membrane transporter.
 This disorder follows X-Iinked inheritance, and often when male children are
diagnosed with the childhood-onset cerebral form, disease manifestations are
recognized in obligate female carriers or male relatives of the proband.
 Differences in disease manifestations are known to occur with identical genotype and
even within a sibship, underscoring the likely effect of other genetic factors on clinical
presentation.
 Genotype does not predict very long chain fatty-acid levels or specific clinical
prognosis.
 Genetic changes reported include missense mutations, nonsense mutations,
framshift mutations, small deletions/insertions, and large deletions.
 XALD is characterized by three predominant phenotypes.
 The best known is the childhoodonset cerebral form (3 5% of affected individuals), in
which male children of school age (usually 4 to 8 years) present with a prior history of
behavioral or cognitive changes.
 These are often initially misdiagnosed as attention deficit disorder, or hyperactivity.
 The progressive nature of the symptoms, overlaid with progressive motor difficulties,
deteriorating school function and handwriting, altered perception of speech, and
worsening behavior problems, usually brings the child to medical attention, and
neuroimaging frequently is highly suggestive of the diagnosis.
 Disease course is variable, but complete symptom development occurs over a range
of 6 months to 2 years.
 Over time, significant motor involvement develops with a spastic quadriplegia.
 In addition, bulbar dysfunction becomes problematic and often necessitates
gastrostomy tube feeding.
 Adrenal insufficiency is a life-threatening complication of XALD, and studies suggest
that a large number of subjects with the childhood-onset cerebral form have adrenal
insufficiency at time of diagnosis.
 Adrenal function should be tested at diagnosis and monitored thereafter to permit
symptomatic management.
 A second frequent type of presentation is adrenomyeloneuropathy (AMN; 40% to
45% of affected individuals), characterized by onset in young adult males (20s to
middle age) of progressive gait abnormalities, sexual dysfunction, and abnormalities
of sphincter control.
 In some cases, predominant spinal cord symptoms are associated with significant
abnormalities on MRI of the brain, and in a subset of these, relentless neurologic
deterioration will occur.
 In the remainder of the subjects, the disease appears slowly progressive.
 Adrenal insufficiency should be sought at diagnosis and at follow up, although it is
less frequent than in the childhood cerebral-onset form.
 A third type is isolated adrenal insufficiency.
 On occasion, patients with XALD may first present with an Addisonian crisis, and no
neurologic features or abnormalities on neuroimaging.
 XALD should be on the differential diagnosis of isolated adrenal insufficiency in a
male subject.
 Finally, approximately 20% of female carriers may have symptoms of progressive gait
disturbance and spastic paraparesis similar to that seen in subjects with AMN. Onset
is usually in middle age.
 Female carriers were long thought to be asymptomatic, but recent research
demonstrated that the vast majority do develop symptoms and signs by the age of 60
years, especially progressive spastic paraparesis and urinary incontinence.
 Of note, an allelic disorder, with a neonatal presentation of cholestasis, hypotonia,
and developmental delay is caused by a contiguous gene deletion syndrome
involving the 5 ' end of ABCD 1.
 This disorder is called CADDS (contiguous ABCDI DXS1357E deletion syndrome)
and is clinically distinct from XALD.
 The estimated prevalence of XALD is estimated to be at 1 in 20,000 to 1 in 50,000.
 The estimated prevalence of hemizygotes (affected males) and heterozygotes
(carrier females) is estimated at 1 in 16,800.
 The pathophysiology of XALD is believed to arise from accumulation of saturated
very long chain fatty acids (SVLCFA) within the brain.
 This accumulation is thought to result from defective peroxisomal fatty-acid oxidation
of SVLCFA caused by defective transport by the mutated ABCDI, possibly due to
altered ATP binding.
 Diagnosis is based on characteristic clinical presentation and suggestive MRI
features.
 MRI shows a predominance of occipital findings (Fig. 99-5 C @), although frontal and
corpus callosum variants are recognized.
 The affected white matter appears hyperintense on T2 and hypointense on T 1.
 Characteristically, there is a rim of enhancement around the abnormal tissue that can
be very helpful in establishing the diagnosis, as few other leukodystrophies, with the
exception of Alexander disease, show significant contrast enhancement.
 When XALD is suspected, appropriate clinical tests include fasting very long chain
fatty-acid (VLCFA) testing on plasma, which shows an excess in saturated VLCFAs
with specific abnormalities in C 26 to 0, C24 to O/C22 to 0 and C26 to O/C22 to 0
ratios.
 Mutation testing of the ABCDI gene provides molecular confirmation of the diagnosis,
with attention to the 7% of cases with deletions or rearrangements.
 Treatment with Lorenzo's oil or diets rich in oleic and erucic acids in addition to
VLCFA restriction can alter VLCFA levels.
 As treatment strategies for XALD evolve, interest in newborn screening is growing.
 This can be done using liquid chromatography-tandem mass spectrometry
(LC-MS/MS) to test for the analyte I-hexacosanoyl-2 -lyso-sn-3-
glycerophosphorylcholine (26 to 0-1yso-PC).80,81 Testing for XALD is gradually
being adopted in newborn screening platforms.
 Treatment of XALD depends on the stage and type of disease manifestations and is
still research-based.
 Treatment with Lorenzo's oil, which decreases hexacosanoic acid (C26 to 0), does
not appear to stop or reverse cerebral disease once it has begun, although there are
reports of improved long term stability in presymptomatic patients in open label
studies with no placebo control.
 The use of Lorenzo's oil is investigational and should be performed in the context of a
clinical research protocol.
 Bone marrow transplantation (BMT) is indicated in children with the early stage
cerebral form of XALD, as evidenced by active disease on MRI imaging.
 Family members of an affected proband should be tested by VLCFA and monitored
for early MRI evidence of cerebral involvement to identify candidates for BMT.
 These patients should be evaluated by clinicians with specific expertise in this
disorder.
 Gene therapy is a potential future tool and research studies are underway.
 Supportive care can improve comfort and quality of life for XALD patients.
 Careful monitoring and treatment of adrenal insufficiency should be part of
therapeutic management.

3 Other Peroxisomal Disorders

 In addition to XALD, disorders of peroxisome biogenesis and single peroxisomal

protein deficiencies can also result in significant white matter abnormalities.
 It is important to note that, although they are covered in this section, in some cases
they can present with prominent brainstem abnormalities (see later in this chapter).

Peroxisome Biogenesis Disorders (PBD)

 PBD are abnormalities of peroxisome biosynthesis caused by mutations in a series of

PEX genes (at least 15 in humans) encoding various peroxins.
 A variety of clinical presentations exist. Rhizomelic chondrodysplasia punctata,
characterized by skeletal deformities, facial dysmorphisms, and developmental
abnormalities, is associated with hypomyelination or focal white matter signal
abnormalities.
 A second clinical phenotype is characterized by the Zellweger spectrum, in which
patients can present at variable ages with facial dysmorphisms, hypotonia, seizures,
liver dysfunction, and developmental delay.
 Neuroimaging can show cerebral malformations such as polymicrogyria and both
hypomyelination and demyelination in cerebral and cerebellar white matter (Fig. 99-
5F    Metabolic testing reveals abnormalities of plasmalogens and VLCFA.

Single Enzyme Deficiencies of Peroxisomal Fatty-Acid ß-Oxidation

 Three of the four disorders of peroxisomal fatty-acid ß-oxidation, acyl-CoA oxidase

deficiency (OMIM 264470 @ ), D-bifunctional protein deficiency (OMIM 261515 @),
and peroxisomal thiolase deficiency are clinically and radiologically similar to the
peroxisomal biogenesis disorders.
 Patients show abnormalities of plasmalogens, phytanic, pristanic acid and VLCFAs
on metabolic testing.

4 Metachromatic Leukodystrophy

 Metachromatic leukodystrophy (MLD, OMIM250100   is caused by mutations in the

ARSA gene encoding arylsulfatase A 88,89 on chromosome 22q13.31 and is
inherited in an autosomal recessive manner.
 It is one of the most prevalent inherited white matter disorders.
 Homozygous or compound heterozygous ARSA mutations impair arylsulfatase A
degradation of sulfatides, causing sulfatide accumulation within the brain and
peripheral nervous system.
 Complete loss of arylsulfatase A activity ("I" or "O" alleles) is typically associated with
earlyinfantile MLD.
 Partial loss of arylsulfatase A activity ("R" or "A" alleles) is typically associated with
juvenile or adult-onset MLD.
 Compound heterozygosity with an I and A allele usually results in juvenile-onset
MLD.
 Rarely, subjects with microdeletions of 22q13 and deletion of the ARSA gene with an
MLD-causing mutation on the other allele have been diagnosed with MLD.
 Additionally, there are common polymorphisms of ARSA (referred to as "PD" alleles),
which result in sufficient residual activity to avoid sulfatide accumulation.
 These cause arylsulfatase pseudodeficiency rather than MLD.
 These polymorphisms, either homozygous or compound heterozygous with MLD-
causing ARSA mutations, do no cause MLD.
 Enzymatic evidence of low arylsulfatase activity must be accompanied by abnormal
urine sulfatides analysis or demonstration of pathogenic ARSA mutations before
establishing a diagnosis of MLD.
 MLD is characterized by three clinical subtypes, defined primarily by age at
presentation. Lateinfantile MLD patients usually present by age 30 months, after a
period of apparently normal development. Initial clinical manifestations include gait
disturbance, ataxia, dysarthria, or cranial nerve features such as strabismus.
 Initially symptoms may be slowly progressive or plateau, sometimes followed by a
rapid loss of motor skills over a few weeks, during which time the diagnosis is
commonly made.
 In the beginning, demyelinating peripheral neuropathy may be prominent, causing
misdiagnosis as chronic inflammatory demyelinating polyneuropathy.
 Tonic spasms, with pyramidal and extrapyramidal dysfunction, and loss of peripheral
reflexes are striking.
 Eventually, the disease progresses to severe motor impairment with loss of volitional
movements, bulbar dysfunction, loss of vision and hearing, and seizures.
 The time course of deterioration is highly variable, and, with maximal supportive care,
death often occurs much later than reported in older texts.
 The disease, however, is relentlessly progressive after the initial period.

 Juvenile MLD patients present between age 30 months and 16 years (12 to 14
years). Patients presenting after this age are classified as having adult-onset MLD.
 Patients often present with cognitive and behavior difficulties. Younger juvenile-onset
patients often show early motor involvement and may also show rapid decline.
 Clumsiness, gait problems, dysarthria, incontinence, and worsening behavioral
problems occur later in the course, and often prompt etiologic evaluation and
diagnosis. Patients may have seizures, most often complex partial seizures.
 Progression is similar in juvenile MLD as described in infantile MLD, with a slower
course.
 Adult-onset MLD patients may present with motor symptoms common to earlier
presentation. More commonly, they develop severe neuropsychiatric symptoms, often
leading to misdiagnosis until motor features evolve.
 Patients may initially present with predominant peripheral neuropathy, or with
seizures.
 Arylsulfatase A deficiency results in impaired breakdown of sulfatides (cerebroside
sulfate or 3-0-sulfo-galactosylceramide).
 Sulfatides comprise approximately 5% of myelin within the central and peripheral
nervous system.
 They are also found at high concentrations in the kidneys and testes.
 Sulfatide accumulation in glial cells is thought to eventually lead to myelin destruction,
glial cell death and the resultant neurologic phenotype.
 The only other organs known to show manifestations are the kidneys (with excretion
of large amounts of sulfatides in urine but no clinical symptoms), the gall bladder, and
testes.
 Microscopic pathology is characterized by myelin loss, paucity of oligodendroglia,
reactive astrogliosis, and metachromatically staining material in the white matter.
 MLD diagnosis is often suspected based on clinical manifestations of central motor
impairment with a peripheral neuropathy.
 Typical MRI features include sparing of the arcuate fibers and a rim of subcortical
white matter with involvement of periventricular and deep white matter in the
supratentorial CNS (Fig. 99-5B @).
 Involved white matter takes on the appearance of radiating stripes that can be highly
suggestive of the disorder and reflects accumulation of sulfatides in perivascular
macrophages.
 These radiating stripes are also present in other disorders, however, including
Krabbe disease.
 In early stages or in adult cases, incomplete neurologic findings can complicate
diagnosis, and early involvement of the corpus callosum may provide a clue.
 Occasionally, isolated involvement of cranial or peripheral nerves has been seen in
the early stages of disease.
 When the diagnosis is suspected, enzymatic assessment of peripheral leukocytes for
arylsulfatase A activity is often performed.
 If abnormal, confirmatory evidence of disease such as excess urinary sulfatides
should be sought to avoid the diagnostic pitfall of pseudodeficiency.
 To offer appropriate genetic counseling and carrier testing for family members,
molecular confirmation should be sought by sequencing the ARSA gene.
 In view of evolving treatment studies, some states are now providing newborn
screening that included lysosomal disorders such as MLD.
 This practice is highly debated due to lack of evidence of complete penetrance and
perfect genotype-phenotype correlation and uncertainty regarding management of
affected patients.
 MLD is the focus of intensive research exploring approaches to restore partial
enzymatic activity.
 Hematopoietic stem cell transplantation (HSCT) has been performed in patients with
MLD, but its success is dependent on the age and stage of disease progression and
does not appear to completely halt disease progression.
 Candidates for HSCT should be evaluated by persons with particular expertise in this
disorder to best weigh risks versus potential benefits.
 Enzyme replacement therapy delivered directly to the intrathecal compartment is
currently being researched as a therapeutic option.
 The advent of possible treatments has reinforced the need for early and appropriate
diagnosis, especially in siblings of index patients.
 Additionally, symptomatic treatment can greatly influence quality of life. In addition to
usual management of spasticity, attention to possible extrapyramidal symptoms and
to painful neuropathy should guide therapy.
 Possible seizures should be evaluated and treated as appropriate.

5 Metachromatic Leukodystrophy-Like Variants

 In some cases, there is strong clinical suspicion of MLD, including presence of

urinary sulfatides, but ARSA sequencing is normal.
 Two disorders should be considered in this clinical situation.
 In cases with excess urinary sulfatides and clinical picture consistent with MLD/but
normal arylsulfatase A activity, deficiency of arylsulfatase activator protein (Saposin
B) (OMIM 249400 @ ) should be tested.
 Diagnostic confirmation requires studies of sulfatide metabolism in fibroblast cultures
or sequencing of the prosaposin gene.
 Another variant with overlap with MLD is multiple sulfatase deficiency (MSD) (OMIM
272200   in which a defect of the formylglycine-generating enzyme (FGE) causes a
deficiency in the function of multiple sulfatases, including arylsulfatase A, but also
arylsulfatase B, arylsulfatase C, iduronate sulfatase, and heparan-N-sulfamidase in
leukocytes.
 In these subjects, excess sulfatides in the urine are accompanied by abnormal
mucopolysaccharides. Subjects have clinical manifestations of MLD in addition to
mucopolysaccharidoses. MRI findings in both of these disorders are similar to MLD.

6 Krabbe Disease or Globoid Cell Leukodystrophy

 Krabbe disease (OMIM 245200 is caused by autosomal recessive mutations in the

gene encoding galactosylceramidase (GALC) on chromosome 14q31.
 Two recurring mutations are associated with specific phenotypes.
 One common 30-kb deletion results in the classic infantile form in the homozygous
state or when compound heterozygous with another mutation associated with severe
disease.
 The 809G>A mutation is associated with the lateonset form of Krabbe disease, even
when associated with mutations associated with severe disease.
 There is limited genotype-phenotype correlation for other mutations, however, and
different disease courses have been seen in the same family.
 Krabbe disease has two main forms. In the classic infantile form, onset is within the
first 6 months, typically after a few months of apparently normal development.
Patients present with irritability, hypertonia, and peripheral nerve involvement (stage
I).
 CSF protein is elevated.
 Symptoms will often lead to neuroimaging, and MRI suggests the diagnosis.
 This stage is followed by rapid deterioration and extreme irritability, leading to
decerebrate posturing and almost opisthotonic positioning of the head and neck
(stage Il).
 Optic atrophy develops, and pupillary light reflexes are abnormal. Seizures often
occur at this stage.
 This period is often followed by a longer period of slow deterioration in infants in a
near vegetative state (stage Ill).
 Infants often succumb to respiratory infections in the first years of life, although
supportive care has been known to extend life.
 Late-infantile-onset forms (after 6 months of age) present with symptoms of vision
loss, developmental regression, and spasticity.
 Juvenile (after 4 years of age) and adult-onset cases present with variable symptoms,
including gait dysfunction, loss of vision, seizures, or cognitive-behavioral changes.
 The rapidity of decline appears to correlate with age at onset, with younger patients
(late infantile and juvenile) progressing more rapidly than the adult-onset cases.
 Prevalence has been reported to be about 1 in 100,000 births in the United States
and Europe.
 In Krabbe disease, deficiency of galactosylceramidase results in psychosine
accumulation, which is thought to be either directly toxic to glial cells or to cause
indirect injury via microglial activation and the creation of multinucleated giant cells,
also known as globoid cells.
 On pathology specimens, microscopic evaluation demonstrates accumulation of
globoid cells, multinucleated giant cells, in affected central white matter and deep
gray nuclei.
 Peripheral nerve demyelination may also be demonstrated.
 The diagnosis is suspected based on combined motor and peripheral nerve
involvement.
 Neuroimaging can also guide diagnosis, with CT demonstrating highly suggestive
hyperdensity of the thalami, caudate, corona radiata, and, in some cases, cerebellum
and brainstem.
 MRI is less pathognomonic than in other disorders; however, early involvement of the
brainstem and cerebellar white matter, in particular the hilus of the dentate nucleus,
can be helpful in establishing the diagnosis (Fig. 99-5G        
 Thickening of the optic nerves and chiasm has been reported.
 Over time, the most significant involvement occurs in deep and periventricular white
matter, with relative early sparing of U-fibers.
 The corpus callosum is affected.
 Radiating stripes can be seen within the affected white matter. There is often
prominent atrophy of the brain.
 Late-onset forms may present with similar MRI patterns or less typical ones such as
changes limited to the corticospinal tracts in adult-onset cases.
 In some instances, enhancement of the gray-white matter junction, cranial nerves, or
spinal nerve roots can be seen.
 When Krabbe disease is suspected, GALC enzyme activity (using radiolabeled
natural substrate galactosylceramide [gal-cerl) can be measured in vitro in leukocytes
and cultured skin fibroblasts. Individuals with Krabbe disease have very low GALC
enzyme activity (0% to 5% of normal activity).
 Carrier screening using GALC activity is unreliable.
 Newborn screening using GALC enzyme activity has been established and is in use
in some states.
 Abnormal GALC enzyme activity can be followed up by molecular testing using
targeted analysis for the most common mutations followed by sequencing and
deletion studies.
 Disease-modifying treatments have focused on the use of hematopoietic stem cell
transplantation; however, risks for this procedure are great, and treatment must be
initiated before onset of significant clinical symptoms and in the infantile form may be
of limited utility.
 Decisions regarding pursuit of this type of therapy for Krabbe should be made in a
center with a large clinical experience in this disorder.
 Newborn screening may allow earlier detection, but age of onset and disease severity
is unpredictable for the late onset cases, stirring debate as to its merits.
 Research into other treatment modalities, including gene therapy, enzyme
replacement therapy, neural stem cell transplantation, substrate reduction therapy,
and chemical chaperone therapy are being explored in animal models but are not yet
established for use in clinical trials.

7 Saposin A Deficiency

 An infant with abnormal myelination resembling Krabbe disease was found to have a
mutation in the saposin A region of the prosaposin (PSAP) gene (OMIM 611722
Prosaposin is one of several known sphingolipid activator proteins and interacts with
the enzyme GALC to catalyze the hydrolysis of lipids.

8 Sjögren-Larsson Syndrome

 Sjögren-Larsson syndrome (OMIM 270200 is an autosomal recessive disorder

characterized by ichthyosis, spastic diplegia or tetraplegia, and mental retardation.
 The disorder is caused by mutations in the fatty aldehyde dehydrogenase (FALDH)
gene, which result in impaired oxidation of long-chain aliphatic aldehydes derived
from fatty alcohol metabolism.
 Neuroimaging reveals white matter disease in most patients with mild periventricular
signal abnormalities on 2-welghte Images. 1 revea sc aractensåc elevation of lipids
around 1.3 ppm.

 B White Matter Disorders with White Matter Vacuolization and Intramyelinic Edema
 Among the specific radiologic features associated with white matter disease, white
matter vacuolization is very helpful in the differential diagnosis of leukodystrophies.
 The disorders most likely to present with white matter vacuolization are Canavan
disease and elF2B-related disorders, also known as vanishing white matter disease
and CACH (childhood-onset ataxia and central nervous system hypomyelination),
although these disorders are clinically and radiologically distinct.
 One other disorder, not considered a leukoencephalopathy or leukodystrophy but
which may have vacuolization on MRI, is Lowe disorder.
 The oculocerebrorenal syndrome of Lowe (OCRL; OMIM 30900) is a multisystem
disorder with major abnormalities in the eyes, the nervous system, and the kidneys.
 OCRL is an X-Iinked disorder caused by mutations in OCRLI, encoding a
phosphatidylinositol -4,5- bisphosphate 5 -phosphatase.
 The pathophysiology of this disorder remains unclear.
 Affected patients may have patchy white matter abnormalities in the centrum
semiovale on Tl- and T2 -weighted images, with vacuolization on FLAIR or PD
images. 99 Diagnosis is based on the constellation of cataracts, renal tubular
acidosis, and neurologic features.
 Molecular testing is the mainstay of diagnosis.
 Symptomatic management of renal, ophthalmologic, and neurologic abnormalities is
indicated.
 In addition to disorders with white matter vacuolization, a new category of disorders is
emerging, related to intramyelogenic edema.
 These include megalencephalic leukoencephalopathy with subcortical cysts (MLC),
which is detailed in the section on cystic leukodystrophies, as well as the
mechanistically related CIC-2 (chloride channel-related leukoencephalopathy.

1 Canavan Disease

 Canavan disease (CD; OMIM 271900@), previously known as spongy degeneration

of the CNS of the Van Bogaert-Bertrand type, is caused by a deficiency of
aspartoacylase, encoded by ASPA.
 This disorder has been documented since at least the 1950s, but a biochemical
marker was not identified until nearly 30 years later.
 Inheritance is autosomal recessive. Incidence is increased in patients of Ashkenazi
Jewish descent, with two common mutations,
 Glu285Ala and p.Tyr231 X, responsible for 98% of disease alleles, facilitating carrier
screening in this population.
 In addition, p.Ala305Glu is responsible for 40% to 60% for the disease causing alleles
in non-Jewish populations and is responsible for 1% of disease-causing alleles in the
Ashkenazi Jewish population.
 A final splice site mutation, c.433-2A>G is responsible for 1% of disease-causing
alleles in the Ashkenazi Jewish population.
 Beyond these, there are many pathogenic mutations with no clear genotype-
phenotype correlation, and affected siblings may have a variable course despite
identical genotypes.
 Although less common, deletions and duplications can be disease causing alleles.
 Most patients with CD present with the infantile form.
 These children appear normal until approximately 3 to 6 months of life, when
hypotonia with loss of head control, irritability, loss of milestones, and head
circumference growth become notable.
 Over time, spasticity replaces hypotonia, and optic atrophy, extrapyramidal
movement disorders, seizures, and autonomic disturbances develop.
 In time, a more chronic vegetative state develops, which can evolve over years.
 Tonic extensor spasms are often described.
 More rarely, a congenital variant is seen in which poor feeding, irritability and
hypotonia become evident within days after birth, followed by rapid deterioration and
death.
 Some patients with prolonged development of early milestones have been
characterized as having juvenile onset; however, the course generally overlaps the
infantile form, and it is unclear whether this is truly a distinct variant.
 CD is caused by aspartoacylase deficiency, resulting in accumulation of N-
acetylaspartic acid (NAA) in the brain, and its excretion in the urine.
 The synthesis and role of NAA and the related compound N-acetylaspartylglutamate
(NAAG) within the brain remain poorly understood and are the subject of active
research.
 NAA accumulation is thought to cause myelin vacuolization and astrogliosis, although
the mechanism is unclear.
 Hypotheses include altered neurotransmission, osmotic disturbances, and abnormal
synthesis of myelin lipids.
 Histopathologic studies have documented myelin loss and innumerable small
vacuoles, predominantly in the deep cortex and subcortical regions, giving the brain
the spongiform appearance that first resulted in its name "spongy degeneration."
Myelin loss is accompanied by astrogliosis and, in the cortex, swollen astroglial cells.
 Biochemical testing is diagnostic in CD, with NAA elevations detectable in urine,
plasma, and CSF, and decreased aspartoacylase activity in cultured fibroblasts.
 Proton MRS demonstrates highly elevated NAA throughout the brain.
 Targeted mutation analysis is often used as a first line diagnostic strategy.
 Panels testing the four most common disease-causing alleles will diagnose almost
100% of affected Ashkenazi Jewish patients and 40% to 60% of affected nonJewish
patients.
 Full sequencing and detection of deletions or duplications is used to identify the
remainder of subjects with CD.
 Diagnosis may also be suggested by MRI features such as confluent involvement of
subcortical white matter extending in severe cases to the central and periventricular
white matter in a centripetal fashion, as well as signal abnormalities of the globus
pallidus and thalamus with sparing of the caudate and putamen.
 Signal abnormalities of the brainstem and cerebellar white matter can be seen.
 Over time, extensive white matter atrophy leads to ventriculomegaly.
 No disease-specific treatment is available for CD at this time, although supportive
care is very important. Several therapeutic trials are ongoing, including the use of
gene therapy.
2 elF2B-Related Disorder (Vanishing White Matter)

 The elF2B-related disorder and its various allelic clinical subtypes (vanishing white
matter OMIM 603896 106 or CACH, 107 Ovarioleukodystrophy,108,109 and Cree
leukoencephalopathy 110) are caused by mutations in one of the five genes (EIF2B1-
5) encoding a complex, elF2B.
 The elF2B disorder, or eukaryotic translation initiation protein 2B, is the guanine
nucleotide exchange factor for elF2, another critical protein in translation initiation.
 The elF2B-related disorders are inherited in an autosomal recessive manner, with
65% of mutations found on the gene EIF2B5.113,114 Mutations across the five
genes are numerous and, in most cases, are private mutations with a compound
heterozygous presentation, although some patients are homozygous for the more
common mutations. No phenotype is known to exist for heterozygous carriers.
 There is known genotype-phenotype correlation for certain more common genotypes,
including homozygous RI 13H mutation positive subjects, 115 who have an adult
onset with milder phenotype, and the homozygous R195H mutation positive subjects,
who have a more severe early-onset presentation.
 Patients with elF2B mutations may present with a variety of clinical syndromes.
 The bestknown presentation is the infantile or early childhood presentation with
"vanishing white matter."
 These children, previously healthy, present with acute neurologic decompensation
after events of physiologic stress, including fever, falls or fright.
 The precipitating event is usually followed after several hours by acute motor
dysfunction, typically hypotonia or ataxia, and even coma.
 The child may die during the acute event or survive with neurologic sequelae and be
vulnerable to future events of decompensation.
 On occasion, no acute event is noted, but loss of skills is gradual and relentlessly
progressive.
 Over several years, progressive motor dysfunction results in spastic quadriparesis,
cranial nerve involvement, including ophthalmoparesis and optic nerve atrophy, and
severe bulbar dysfunction.
 At opposite ends of the phenotypic spectrum, elF2B mutations can also present in a
connatal form, where neurologic disability is evident from birth (with additional
findings such as ovarian dysgenesis, cataract, or hepatomegaly) or present in an
adult form with progressive spastic paraparesis.
 Allelic disorders include Cree leukoencephalopathy, whose name derives from the
Cree Indian population in Quebec and Manitoba, Canada, with the R195H founder
mutation resulting in aggressive early-infantile presentation, with rapid progression
and early death.
 Another allelic disorder is ovarioleukodystrophy, in which adult women present with
primary ovarian failure and minimal, if any, neurologic features.
 Incidence and prevalence of elF2B-related disorders are not known.
 An elF2B-related disorder is thought to be caused by alterations in the cellular
response to endoplasmic reticulum stress and alterations in protein translation.
 elF2B plays a crucial role in the initiation of protein translation, acting as the guanine
nucleotide exchange factor for elF2alpha, another translation initiation factor.
 When a cell undergoes physiologic stress, protein translation is altered and misfolded
proteins often accumulate within the endoplasmic reticulum.
 Cell salvaging pathways include elF2B as a critical modulatory element.
 It is unknown, however, how alterations in a ubiquitously expressed housekeeping
gene result in a primarily glial cell phenotype.
 Diagnosis of elF2B-related disorder is based on appropriate clinical history,
neuroimaging and molecular genetics. Common MRI features include diffuse signal
abnormality of the supratentorial white matter, with less constant signal abnormalities
in the cerebellar white matter, brainstem, thalamus, and globus pallidus.
 In supratentorial white matter, T2 FLAIR shows low signal intensity, isointense with
CSF, suggestive of white matter rarefaction and cystic degeneration.
 On sagittal T I-weighted images, a pattern of radiating tissue strands may be seen,
compatible on pathology with preserved tissue (Fig. 99-5C @).
 MRI findings of elF2Brelated disorder are nearly pathognomonic, except in very early-
or late-onset cases.
 In appropriate clinical conditions, molecular studies of the elF2B genes is appropriate,
usually beginning with elF2B5 which harbors 65% of identified pathogenic mutations.
 If molecular testing does not clarify the diagnosis, biomarkers such as CSF glycine
121 and decreased CSF asialotransferrin 122 can help further investigate the
likelihood of elF2B-related disorder.
 There is currently no disease-modifying therapy for elF2B-related disorder.
 Avoidance of head trauma and infectious triggers is suggested, but no data on the
success of these strategies exit.
 Supportive therapy, including careful attention to orthopedic and pulmonary
complications in patients with severe spastic quadriparesis, is the only management
option currently available for elF2B-related disorder.

3 Megalencephalic Leukoencephalopathy with Subcortical Cysts

 Megalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM604004

is an autosomal recessive disease associated with mutations in the gene encoding
MLCI protein, thus named because locus heterogeneity was anticipated. Recently
mutations in HEPACAM, encoding GlialCAM, have been identified in MLC patients.
 Synonyms for MLC include leukoencephalopathy with swelling and discrepantly mild
course, cysts, infantile leukoencephalopathy and megalencephaly, van der Knaap
disease, and vacuolating leukoencephalopathy.
 There is a founder effect in the Agarwal community in India, with a common genotype
for MLCI protein (p.Cys46LeufsX34), as well as some more common mutations in
individual populations, including persons of Libyan Jewish descent, Turkish Jewish
descent, and Japanese descent.
 Postnatal macrocephaly is the predominant presenting symptom, noted in the first
year although macrocephaly may be present at birth.
 No molecularly confirmed cases of MLC without megalencephaly have been
identified.
 This is of diagnostic importance because a number of other disorders can present
with temporal lobe subcortical cysts, including AicardiGoutieres syndrome (AGS),
CMV infection, and RNAseT2-deficient leukoencephalopathy, among others.
 Stabilization of head growth rate often occurs after age 1, and ultimate head size can
be up to four to six standard deviations higher than normal.
 Patients may have normal early development or mild delays in motor and cognitive
milestones. Later in life, patients develop a spastic ataxia of variable severity.
 Epilepsy, often easily controlled, is common. Cognitive deterioration is usually late
and mild.
 Dysarthric speech can be particularly debilitating in MLC.
 In dominant HEPACAM mutations, there is a discrepantly mild course, with
improvement over time of both the clinical and radiologic manifestations.
 Pathophysiology in MLCI protein-related MLC is thought to involve altered cellular
trafficking in mutated MLCI and its ligand, GlialCAM, in astrocytes.
 These are localized with the dystrophin glycoprotein complex in astrocytic endfeet in
perivascular, subpial, and subempendymal regions.134,135 In MLC, abnormal MLCI
and GlialCAM are thought to result in dysregulated maintenance of ion and water
homeostasis in myelin.
 Diagnosis of MLC is based on clinical manifestations and typical MRI features.
 These include a swollen appearance of subcortical white matter; diffuse white matter
signal abnormality with relative preservation of central structures such as the corpus
callosum, internal capsule, brainstem, and cerebellum; and development of
subcortical cystic structures, most prominently in the anterior temporal and
frontoparietal regions (Fig. 99-5F Over time, severe white matter structural atrophy
can ensue.
 No disease-specific treatment for MLC currently exists, although supportive services
for speech and gait difficulties and medical management of seizures are important for
maintenance of quality-of-life.