REVIEW ARTICLE

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
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CITE AS:
CONTINUUM (MINNEAP MINN)
2018;24(1, CHILD NEUROLOGY):
130–149.
Address correspondence to
Dr Amy T. Waldman, Children’s
Hospital of Philadelphia, CTRB
10th Floor, Room 10012, 3501 Civic
Center Blvd, Philadelphia, PA
19104, waldman@email.chop.
edu.
RELATIONSHIP DISCLOSURE:
Dr Waldman serves on the
board of directors of the Child
Neurology Foundation and has
received personal compensation
for speaking engagements from
Johns Hopkins University, St.
Christopher’s Hospital for
Children, St. Peter’s University,
and SUNY Downstate Medical
T
Center. Dr Waldman receives
research/grant support from
Biogen, Elise’s Corner, the
National Institutes of Health
(K23NS069806, R01NS071463),
and the National Multiple
Sclerosis Society and receives
publishing royalties from
UpToDate, Inc.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Waldman discusses published
clinical trial results presenting a
lentiviral vector in combination
with hematopoietic stem cell
transplantation for
metachromatic leukodystrophy
and X-linked
adrenoleukodystrophy. These
data are presented to
demonstrate advances in
potential treatments for this
disorder and also help to
understand the pathology and
need for newborn screening.
© 2018 American Academy
of Neurology.
130
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Leukodystrophies
By Amy T. Waldman, MD, MSCE
ABSTRACT
PURPOSE OF REVIEW: The leukodystrophies, typically considered incurable
neurodegenerative disorders, are often diagnosed after irreversible central
and peripheral nervous system injury has occurred. Early recognition of
these disorders is imperative to enable potential therapeutic interventions.
This article provides a summary of the symptoms of and diagnostic
evaluation for leukodystrophies, along with the currently available
therapies and recent advances in management.
RECENT FINDINGS: The leukodystrophies are a rapidly expanding field because
of advances in neuroimaging and genetics; however, recognition of the
clinical and biochemical features of a leukodystrophy is essential to
accurately interpret an abnormal MRI or genetic result. Moreover, the
initial symptoms of leukodystrophies may mimic other common pediatric
disorders, leading to a delay in the recognition of a degenerative disorder.
SUMMARY: This article will aid the clinician in recognizing the clinical features
of leukodystrophies and providing accurate diagnosis and management.
INTRODUCTION
he leukodystrophies are inherited disorders that predominantly affect
the white matter of the central nervous system (CNS). Leukodystrophy
is a unifying term for diseases that affect glial cells, resulting in
myelin sheath and axonal damage; approximately 30 distinct
disorders have been classified as leukodystrophies (TABLE 6-1). 1
Leukodystrophies are distinguished from genetic leukoencephalopathies, which
may also have significant white matter involvement but whose pathology does
not primarily affect glia. Such conditions include systemic inborn errors of
metabolism and primary neuronal disorders (such as neuronal ceroid
lipofuscinoses, which are also lysosomal storage disorders). Altogether, more
than 91 leukodystrophies and genetic leukoencephalopathies have been
defined based on clinical, radiographic, and genetic data.
Clinically, a leukodystrophy is generally suspected in a child with regression in
developmental skills or failure to acquire new skills. Peripheral nervous system
disease also occurs in some of the leukodystrophies and may be a presenting feature;
therefore, a high index of suspicion is necessary to ensure a prompt diagnosis.
MRI is a key tool in differentiating leukodystrophies. On T2-weighted images,
symmetric hyperintensities occur in various regions depending upon the
underlying disorder.2 Typically the affected white matter is significantly
hypointense on T1-weighted images; however, a distinct subgroup, the
hypomyelinating leukodystrophies, are isointense or hyperintense (or sometimes
mildly hypointense) on T1-weighted images. The MRIs of patients with
FEBRUARY 2018
suspected leukodystrophies should be systematically reviewed to differentiate KEY POINTS
hypomyelinating from demyelinating disorders (using T1-weighted images),
● The leukodystrophies
determine the extent of white matter abnormality (confluent, isolated, comprise a heterogeneous
multifocal), categorize confluent disease by primary area of involvement group of disorders
(frontal, frontotemporal, parietooccipital, periventricular, subcortical, diffuse predominantly affecting
cerebral, or posterior fossa), and observe for the presence of MRI features unique the glial cell or myelin
sheath.
to certain disorders (eg, cysts, contrast enhancement, calcifications).2 Together,
these factors aid the clinician in narrowing the differential diagnosis. ● Genetic
Generally, the treatment of the leukodystrophies is supportive, with a leukoencephalopathies
multidisciplinary team to assist in managing the symptoms. Briefly, medications include metabolic
are used to treat seizures, spasticity, dystonia, autonomic dysfunction, and other disorders and primary
neuronal diseases that affect
symptoms, while equipment is used to optimize comfort, tone, and safety. Most the white matter through
children need further assistance with respect to nutrition and gastrointestinal mechanisms other than glial
function as well as pulmonary clearance and reserve. pathology.
The field of leukodystrophies is rapidly changing through gene discovery,
● X-linked
newborn screening, and novel therapy programs. This article focuses on a few adrenoleukodystrophy
of the leukodystrophies that highlight these advances, particularly those with should be considered in
recent clinical trials and treatment trials planned in the near future. Improved school-aged boys with the
neurologic outcomes occur with early treatment, which is predicated on prompt recent onset of attention
and behavioral difficulties,
recognition of the disorder.
especially for those who
demonstrate regression in
X-LINKED ADRENOLEUKODYSTROPHY cognition, fine motor skills,
X-linked adrenoleukodystrophy is a peroxisomal disorder caused by mutations or speech. While MRI may
be helpful in confirming
in ABCD1 on Xq28. ABCD1 encodes a peroxisomal membrane protein cerebral involvement, the
(ATP-binding cassette, subunit D) that is necessary for b-oxidation of saturated test of choice to confirm
unbranched very-long-chain fatty acids. As a result, very-long-chain fatty or exclude X-linked
acids accumulate in the brain, adrenal gland, and testes.3 adrenoleukodystrophy is
measurement of plasma
very-long-chain fatty acids.
Clinical Symptoms
Multiple phenotypes exist in X-linked adrenoleukodystrophy, with varying ● The adrenal function of
severity and clinical manifestations (TABLE 6-2 4 ). The earliest symptom in boys with X-linked
X-linked adrenoleukodystrophy is adrenal insufficiency, with affected boys adrenoleukodystrophy
should be monitored
coming to medical attention during an adrenal crisis. For approximately 10% of routinely by an
males, adrenal insufficiency is the only manifestation of disease (known as endocrinologist.
Addison only). The childhood cerebral form occurs in approximately 31% to 35%
of affected males and typically presents between 4 and 8 years of age with
attention difficulties, cognitive decline, and behavioral problems (CASE 6-1).
Changes in speech and handwriting occur, and school performance is affected.
Many children are initially thought to have attention deficit hyperactivity
disorder, and the delay in diagnosis precludes them from potential therapy. The
attention and behavioral problems may be present for several months, followed
by progressive loss of ambulation, speech, vision, and hearing over 6 months to
2 years. Adrenomyeloneuropathy (40% to 46% of affected males) occurs later in
life, manifesting as a distal axonopathy. Some females can develop symptoms in
adulthood, making the term carrier a misnomer.

Neuroimaging
Children with childhood cerebral X-linked adrenoleukodystrophy experience
inflammatory demyelination in the brain (confluent T2-hyperintense and
T1-hypointense lesions), typically beginning in the parietooccipital lobes (85% of

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LEUKODYSTROPHIES

cases) and posterior corpus callosum (FIGURE 6-1), although anterior

presentations can also occur. The Loes scoring system5,6 is universally applied to
quantify the extent of cerebral involvement. Regions of the brain (such as
parietooccipital white matter, anterior temporal white matter, visual pathway,
corpus callosum, auditory pathway, basal ganglia, projection fibers, and cerebellum)
are subdivided and scored based on the extent of disease (with a score of 0 if normal,
0.5 if unilateral involvement is present, and 1 if the lesion or atrophy is bilateral).
Global atrophy is also assessed. A normal MRI scan has a score of 0, and the
maximum severity score is 34. An enhancing rim is often seen at the border of the
T2-hyperintense area. Younger boys identified through newborn screening or
presentation with adrenal insufficiency have a normal brain MRI but require frequent

TABLE 6-1 The Leukodystrophiesa

Inborn Errors of Metabolism

u X-linked adrenoleukodystrophy

u Krabbe disease (globoid cell leukodystrophy)

u Metachromatic leukodystrophy

u Cerebrotendinous xanthomatosis

u Canavan disease

u Fucosidosis
u Peroxisomal biogenesis disorders (including Zellweger syndrome, neonatal
adrenoleukodystrophy, and infantile Refsum disease)

u Polyglucosan body disease

u Sialic acid storage disorders (Salla disease, infantile sialic acid storage disease, and
intermediate form)

u Single-bifunctional enzyme deficiencies of peroxisomal fatty acid b-oxidation (including

D-bifunctional protein deficiency, sterol carrier protein X [SCPx] deficiency, peroxisomal
acyl-coenzyme A [CoA] oxidase deficiency)
u Sjögren-Larsson syndrome

Disorders of RNA/DNA Transcription/Translation

u Aicardi-Goutières syndrome

u POL3-related disorders (hypomyelination, hypogonadotropic hypogonadism, and

hypodontia [4H syndrome])

u EIF2B-related disorder (vanishing white matter disease or childhood ataxia with central
nervous system hypomyelination [CACH])

u Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL)

u Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL)
u Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL)

u RNAse T2–deficient leukoencephalopathy

CONTINUED ON PAGE 133

132 FEBRUARY 2018

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MRI surveillance scans (every 6 months between 3 and 10 years of age) to promptly
recognize those who develop the cerebral form who may benefit from treatment.

Diagnosis
The diagnosis of X-linked adrenoleukodystrophy is confirmed by the presence of
elevated saturated unbranched very-long-chain fatty acids in plasma, red blood
cells, or cultured fibroblasts. The biochemical abnormalities among the
very-long-chain fatty acids include elevations in hexacosanoic acid (C26), the
hexacosanoic acid to docosanoic acid ratio (C26:C22), and the hexacosanoic
acid to tetracosanoic acid ratio (C26:C24). Variations in these three
measurements overlap with values for healthy controls; however, a

CONTINUED FROM PAGE 132

CONTINUED FROM PAGE 132

Genes Related to Proteins Critical for Myelin Development

u Pelizaeus Merzbacher disease (PMD)

u Pelizaeus Merzbacher–like disease (PMD)

u SOX10-associated peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy,
Waardenburg syndrome, and Hirschsprung disease (PCWH)

Cytoskeletal
u Alexander disease

u Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC)

u Autosomal dominant leukodystrophy with autonomic disease (ADLD)

Myelin Water Maintenance

u Chloride ion channel 2 (ClC2)–related leukoencephalopathy with intramyelinic edema

u Megalencephalic leukoencephalopathy with subcortical cysts (MLC)

Mechanism Not Yet Elucidated

u 18q deletion syndrome

u Adult-onset leukodystrophy with neuroaxonal spheroids and pigmented glia (including
hereditary diffuse leukoencephalopathy with spheroids [HDLS] and pigmentary type of
orthochromatic leukodystrophy with pigmented glia [POLD])

u Hypomyelination with congenital cataract (HCC)

u Oculodentodigital dysplasia

DNA = deoxyribonucleic acid; RNA = ribonucleic acid.

a
Data from Vanderver A, et al, Mol Genet Metab.1

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LEUKODYSTROPHIES

TABLE 6-2 X-linked Adrenoleukodystrophy Phenotypes and Frequenciesa

Phenotype Description Estimated Relative Frequency

Phenotypes in males with
X-linked adrenoleukodystrophy

Childhood cerebral Onset at 3–10 years of age; progressive behavioral, 31–35%

cognitive, and neurologic deficits, often leading to total
disability within 3 years; inflammatory brain
demyelination

Adolescent cerebral Like childhood cerebral; onset at 11–21 years of age; 4–7%
somewhat slower progression

Adrenomyeloneuropathy Onset 28 ± 9 years, progressive over decades; distal 40–46%

axonopathy that involves spinal cord mainly; inflammatory
response mild or absent; approximately 40% have or
develop cerebral involvement with varying degrees of
inflammatory response and more rapid progression

Adult cerebral Dementia, behavioral disturbances; sometimes focal 2–5%

deficits, without preceding adrenomyeloneuropathy;
white matter inflammatory response present;
progression parallels that of childhood cerebral form

Olivopontocerebellar Mainly cerebellar and brainstem involvement in 1–2%

adolescence or adulthood

“Addison-only” Primary adrenal insufficiency without apparent Varies with age; up to 50%
neurologic involvement; onset common before in childhood
7.5 years; most eventually develop
adrenomyeloneuropathy

Asymptomatic Biochemical and gene abnormality without Diminishes with age; common
demonstrable adrenal or neurologic deficit; detailed <4 years; very rare >40 years
studies often show adrenal hypofunction or subtle signs
of adrenomyeloneuropathy

Phenotypes in female X-linked

adrenoleukodystrophy carriers

Asymptomatic No evidence of adrenal or neurologic involvement Diminishes with age; most

women <30 years
neurologically uninvolved
Mild myelopathy Increased deep tendon reflexes and distal sensory Increases with age;
changes in lower extremities with absent or approximately 50% >40 years
mild disability
Moderate to severe Symptoms and pathology resemble Increases with age;
myeloneuropathy adrenomyeloneuropathy but milder and later onset approximately 15% >40 years
Cerebral involvement Rarely seen in childhood and slightly more common in Approximately 2%
middle age and later
Clinically evident adrenal Rare at any age Approximately 1%
insufficiency

a
Modified with permission from Kemp S, et al, Hum Mutat.4 © 2001 Wiley-Liss, Inc.

134 FEBRUARY 2018

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discrimination function is applied that accurately distinguishes those with KEY POINT
X-linked adrenoleukodystrophy from healthy controls or those with
● Very-long-chain fatty
nonperoxisomal disorders.3 In a patient with elevated very-long-chain fatty acids, especially C26:0 and
acids, genetic sequencing of ABCD1 is performed. the ratios of C26:C22 and
Newborn screening for X-linked adrenoleukodystrophy has been implemented C26:C24, are elevated in
in some US states using various methodologies, such as the detection of all clinical phenotypes
of X-linked
1-hexacosanoyl-2-lyso-sn-3-glycero-phosphorylcholine (26:0-lyso-PC) in dried adrenoleukodystrophy,
blood spots using liquid chromatography–tandem mass spectrometry.7–9 The and these abnormalities
diagnosis of X-linked adrenoleukodystrophy through the newborn screening may be detected at birth,
program allows for proactive monitoring of adrenal function and neurologic facilitating a diagnosis prior
to symptom onset.
disease for affected boys and has further enabled the diagnosis of X-linked
adrenoleukodystrophy in family members (such as older siblings) who also
benefit from screening programs.

Disease-specific Therapy
The primary treatable manifestation of X-linked adrenoleukodystrophy is
adrenal insufficiency, which is the most common symptom of the disorder and
present in multiple phenotypes. Biochemical abnormalities in cortisol production
occur in 85% of all males with X-linked adrenoleukodystrophy; screening for
this should begin during infancy, with regular testing throughout the life of an
affected male. The need for cortisol supplementation and stress-dosed steroids or
both is determined in partnership with an endocrinologist.

A 6-year-old boy presented with attention and behavioral difficulties. CASE 6-1
According to his teachers, he had difficulty responding when his name
was called, following along during class activities, and following
directions, requiring reminders. His mother believed that he was often
lost in his thoughts and described him as a daydreamer. These symptoms
were first noted approximately 9 months before presentation.
Previously, he had no issues in preschool and was on target with his
peers. His brother died at 7 months of age “of an infection.”
On examination, he had difficulty with comprehension, often asking
for commands to be repeated, and abnormal expressive language. His
neurologic examination was also notable for difficulty with tandem gait,
brisk patellar reflexes, and extensor plantar responses. Brain MRI
revealed T2 hyperintensities in the parietooccipital lobes bilaterally with
an enhancing rim. Very-long-chain fatty acids revealed an elevation in
hexacosanoic acid (C26:0), an elevated hexacosanoic acid to docosanoic
acid ratio (C26:C22), and an elevated hexacosanoic acid to tetracosanoic
acid ratio (C26:C24).

This case illustrates the clinical variability of the presenting manifestations COMMENT
of X-linked adrenoleukodystrophy. This patient has childhood cerebral
adrenoleukodystrophy, whereas his brother likely died of an unrecognized
adrenal crisis in the setting of an illness.

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LEUKODYSTROPHIES

Hematopoietic stem cell

transplantation has been
successful in arresting or slowing
the progression of the cerebral
disease if initiated early in the
disease course (ie, Loes score less
than 10, no or minimal neurologic
symptoms, and preserved
cognition [Wechsler
Performance IQ higher than 80]).
In an experienced X-linked
adrenoleukodystrophy transplant
center, the 5-year survival rate
was 89% in those with a Loes
score of less than 10 (N = 30)
compared to 60% in boys with a
Loes score higher than 10
(N = 30). However, it is
FIGURE 6-1
important to note that even after
Childhood cerebral X-linked adrenoleukodystrophy. successful engraftment, the
Axial fluid-attenuated inversion recovery (FLAIR) neurologic progression may
MRI demonstrates confluent white matter signal continue for 12 to 18 months
abnormality in the bilateral parietal white matter
posttransplant, with disability
with involvement of the splenium of the corpus
callosum, posterior aspect of the thalami, progression occurring during this
and posterior limbs of the internal capsules. time. Therefore, many boys with
minimal evidence of neurologic
disease prior to transplant
develop worsening symptoms, such as visual and cognitive impairment or
behavioral problems, after the transplant. In addition, the transplant itself
confers significant morbidity. Hematopoietic stem cell transplantation is only
performed for the cerebral form of the disease and is not indicated in males
without evidence of active cerebral disease (detected by MRI). Active research
programs are investigating biomarkers of neurologic dysfunction and other
strategies (including reduced-intensity conditioning) to improve
transplantation outcomes.10
Gene therapy using a lentiviral vector in combination with hematopoietic
stem cell transplantation was performed in 17 boys with early cerebral X-linked
adrenoleukodystrophy who did not have a suitable match for transplant.11
Although MRI disease progression was evident in some participants 12 to
18 months posttransplant, 14 out of 17 participants had no (or minimal) clinical
symptoms at a median of 29.4 months posttransplant. One participant had a
seizure; thus, he did not meet predefined criteria for minimal disease progression
but otherwise did well. Two participants demonstrated disease progression, one
within 2 weeks of transplant, indicating a rapidly progressive course. The other
participant withdrew from the study and underwent an allogeneic transplant,
later dying from complications related to a viral infection. In summary, males
with early cerebral disease should be referred for an urgent hematopoietic stem
cell transplant; gene therapy in combination with transplant may be an option in
the future for those individuals without a sibling match. Males diagnosed
through newborn screening undergo serial neurologic examinations and imaging

136 FEBRUARY 2018

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protocols as toddlers to identify cerebral disease early, which enables prompt KEY POINT
treatment and improved outcomes.
● Infantile Krabbe disease
Aside from transplant, dietary therapy has been explored for X-linked should be considered in a
adrenoleukodystrophy, with a reduction in fat intake and the use of Lorenzo’s oil child 6 months of age or
(4:1 mix of glyceryl trioleate to glyceryl trierucate). While this combination may younger with irritability,
correct the measurement of very-long-chain fatty acids in the blood, reduction in sterile pyrexia, and
elevated CSF protein. Other
dietary fat and supplementation with Lorenzo’s oil have not been effective in symptoms in this age group
alleviating symptoms of cerebral X-linked adrenoleukodystrophy (or other include extremity stiffness,
symptoms) once present.12 fisted hands, and
decreased oral intake.

GLOBOID CELL LEUKODYSTROPHY (KRABBE DISEASE)

Globoid cell leukodystrophy, or Krabbe disease, is an autosomal recessive lysosomal
storage disorder caused by mutations in GALC on chromosome 14q31. GALC
encodes the enzyme galactosylceramidase, which is essential in the degradation
of lipids (galactosylceramide and psychosine) during myelin turnover.

Clinical Symptoms
Four classic phenotypes are associated with galactosylceramidase deficiency
(TABLE 6-3). The most common is the early-onset infantile phenotype (85% to
90%), which presents prior to 6 months of age, with irritability, stiffness, arrest

Krabbe Disease (Globoid Cell Leukodystrophy) Phenotypes and Frequencies TABLE 6-3

Phenotype Description Frequency

Early-onset infantile Onset prior to 6 months, regression occurs over several months 85–90%a

Stage 1: Irritability; failure to thrive (decreased intake, vomiting), developmental arrest

and regression (decreased head control, loss of smiling); hypersensitivity to auditory,
tactile, or visual stimuli; stiffness and clenched fists; episodes of sterile hyperpyrexia;
seizures

Stage 2: Rapid neurologic regression with arm flexion, leg extension, and scissoring;
opisthotonos; seizures; hyperreflexia; optic atrophy; and abnormal pupillary responses

Stage 3: The “burnt-out” stage, characterized by decerebrate posturing, blindness,

deafness, and the absence of voluntary movement

Late-onset infantile Onset between 6 months and 3 years of age; early milestones are achieved, followed by 10–15%
psychomotor regression, notably affecting gross motor skills; ataxia, stiffness, and visual
impairment; disease progression is slower than the early-onset infantile form

Juvenile onset Onset between 3 and 8 years of age; initial presentation is visual impairment, followed Unknown
by hemiparesis and ataxia; initial symptoms occur rapidly, followed by a plateau or slow
progression with improved survival over other forms

Adult onset Heterogeneous group combining those who are asymptomatic in childhood and Unknown
develop neurologic symptoms (such as spastic paraparesis) as adults (typically older
than 20 years of age) and those who are mildly symptomatic in childhood but for whom
the disease was not recognized

a
Newborn screening results and longitudinal data will impact our understanding of GALC mutations, galactosylceramidase enzyme activity, and
the frequency of these clinical phenotypes in the future.

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LEUKODYSTROPHIES

of development, and failure to

thrive.13 Older patients generally
present with spasticity,
paraparesis, visual impairment,
and ataxia (TABLE 6-3). A
peripheral neuropathy is also
present in Krabbe disease, and a
loss of reflexes may be the
presenting symptom.14 The
clinical course is not determined
by the genotype; however, a few
variants have some predictive
value. A 30-kb deletion of GALC
(either homozygous or in
combination with another severe
variant) causes early-onset
infantile disease.
FIGURE 6-2
Krabbe disease. Axial T2-weighted MRI Neuroimaging
demonstrates confluent diffuse T2 high signal Krabbe disease is a demyelinating
involving the central white matter and corpus disorder (T1 hypointense) with
callosum. The white matter has a striated
and speckled appearance. confluent T2 hyperintensities
with a periventricular or
parietooccipital predominance
(FIGURE 6-2). 2 Of note, MRI abnormalities in early-onset infantile disease are
not always appreciated because of the myelination pattern of a newborn. For
example, bilateral symmetric T2-weighted hyperintensity is present in the
dentate hilum, surrounded by hypointensity in the peridentate area and
hyperintensity in the cerebellar white matter.15 This pattern may not be
appreciated as it is similar to the normal variability of these structures present in
a newborn.

Diagnosis
The diagnosis of Krabbe disease is confirmed by low galactosylceramidase
(0% to 5% of normal values) in white blood cells or cultured fibroblasts,
followed by GALC sequencing for mutations. Of note, deletions (and
duplications) are not detected through sequencing; therefore, anyone
presenting with clinical features consistent with Krabbe disease for whom a
heterozygous mutation is detected should have further testing for a deletion.
For an irritable infant presenting to medical attention, a lumbar puncture may
be performed to exclude infection or other etiologies. While not specific for
Krabbe disease, CSF protein is frequently elevated in early-onset infantile
disease (with a normal CSF cell count).16
Newborn screening for Krabbe disease is under way in several US states
to identify early-onset infantile disease for possible treatment.
Galactosylceramidase activity, which is measured in dried blood spots using
various methodologies, is typically employed as an initial screen; however,
significant overlap exists between affected patients, carriers, and healthy
individuals. Moreover, the lack of genotype-phenotype correlations precludes
the ability to accurately predict the onset of neurologic symptoms in an affected

138 FEBRUARY 2018

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individual; thus later-onset forms of the disease are identified through newborn KEY POINT
screening.17 As they may be asymptomatic for many years, these patients do
● The biochemical
not need an emergent transplant in the neonatal period. Some states use abnormality in Krabbe
psychosine as a second-tier test as elevated levels correlate with early-onset disease is an abnormal
infantile disease.18–20 Alternatively, some laboratories screen for the 30-kb galactosylceramidase level
deletion in GALC to identify early-onset infantile disease. In a child with a (typically 0% to 5% of
normal values) in white
positive newborn screen for Krabbe disease, the diagnosis is confirmed by low blood cells or cultured
galactosylceramidase followed by GALC sequencing/deletion analysis. fibroblasts.

Disease-specific Therapy
Hematopoietic stem cell transplantation may alter the neurologic progression in
asymptomatic early-onset infantile Krabbe disease, but the overall impact
on morbidity in this disorder remains in question. The outcomes of umbilical
cord blood transplantation for 11 children with asymptomatic disease (identified
prenatally or in the neonatal period through previously affected siblings) were
compared to 14 children diagnosed between 4 and 9 months of age.21 In the
asymptomatic group, the transplant occurred between 12 and 44 days of life,
compared to between 142 and 352 days in the symptomatic group. Survival was
100% in the asymptomatic group at a median of 36 months compared to 43%
of the symptomatic group (P=.01). In the asymptomatic group, brain MRIs
showed normal maturation of myelin, with decreased hyperintensity of affected
areas. In addition, transplant outcomes were significantly improved for the
asymptomatic children with respect to gross motor, fine motor, language, and
cognitive function. Many achieved developmental milestones; however, all
ultimately developed gross motor impairments of varying degrees (spasticity,
gait abnormalities, or needing assistance to stand or walk). In comparison, the
symptomatic children who survived lost all gross and fine motor skills. The
outcomes for many of these children were included in a subsequent publication
with longitudinal follow-up data (range 4 to 15 years). Of the 18 children with
Krabbe disease who were transplanted within 7 weeks of life, five ultimately
died (three died of transplant-related complications, one died of a surgical
complication unrelated to Krabbe disease, and one died of disease progression).
Surviving children had variable deficits in gross motor function, neurocognitive
skills, language, and adaptive behavior.22 These results, while encouraging for
early transplantation, suggest that additional modalities of therapy will likely be
necessary in Krabbe disease to achieve symptomatic control.
The state of New York has published its experience in screening over 2 million
infants for Krabbe disease and other disorders as part of its newborn screening
program since 2006.17 On the initial screen, approximately 10,200 infants were
identified with galactosylceramidase activity less than or equal to 20% of normal
activity. On repeat testing, 620 newborns who had galactosylceramidase activity
less than or equal to 12% of normal subsequently underwent genetic sequencing,
and 348 infants had at least one pathogenic GALC mutation. Ultimately, 14
children had very low galactosylceramidase activity (0 nmol/h/mg to
0.15 nmol/h/mg protein, considered high-risk), but only five were confirmed
through further evaluations (MRI, lumbar puncture, nerve conduction studies,
and brainstem auditory evoked response) to have early-onset infantile Krabbe
disease. One family declined treatment, and that child is deceased. Four of the
patients underwent umbilical cord blood transplantation: two died of
transplant-related complications, one is unable to walk independently and has

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LEUKODYSTROPHIES

KEY POINTS
● Metachromatic
leukodystrophy should be
considered in a toddler with
regression in gross motor
skills, a peripheral
neuropathy, or gall
bladder polyps.
● Gall bladder disease
should be considered in
patients with metachromatic
leukodystrophy who
experience feeding
intolerance.
●Arylsulfatase A
pseudodeficiency is
common; therefore, the
diagnosis of metachromatic
leukodystrophy is confirmed
by low arylsulfatase A
activity along with an
elevation in the urinary
excretion of sulfatides.
failure to thrive but receptive language appropriate for age, and one has severe
delays and failure to thrive.
For older individuals, the assessment of transplantation outcomes is
challenged by differences in phenotypes, unpredictable disease onset, and
variability in disease duration. Transplantation does not improve peripheral
nervous system disease for most patients.
METACHROMATIC LEUKODYSTROPHY
Metachromatic leukodystrophy is also an autosomal recessive lysosomal storage
disorder caused by an enzyme deficiency of arylsulfatase A, which is encoded on
the ARSA gene on chromosome 22q13.3-qter. Sulfatides accumulate in the central
and peripheral nervous systems, kidneys, testes, and visceral organs (gall bladder).
Clinical Symptoms
The clinical phenotypes and frequencies of metachromatic leukodystrophy are
presented in TABLE 6-4. Of note, the peripheral neuropathy may present prior
to the onset of speech or other CNS abnormalities (CASE 6-2). In fact, several
patients with metachromatic leukodystrophy have been diagnosed with other
disorders (eg, Guillain-Barré or spastic diplegia) because of the perceived
absence of CNS disease (clinically and radiographically).23,24 Any child with
normal early milestones followed by a decline in motor skills at any age should be
evaluated for metachromatic leukodystrophy through leukocytes and
urine sulfatides.
Unique to metachromatic leukodystrophy, the gall bladder is also involved,
likely due to sulfatide accumulation and irritation of the epithelium.25 Gall
bladder disease may be asymptomatic, detected through an ultrasound revealing
a polyp or thickening of the wall, or cause abdominal pain, vomiting, or biliary
colic. Asymptomatic gall bladder polyps were detected incidentally in two
patients (undergoing trauma evaluations) who later exhibited neurologic
symptoms 12 to 15 months after the polyps were detected.26,27 Neuroimaging was
available (as part of the trauma evaluation) for one of these patients, and the

TABLE 6-4 Metachromatic Leukodystrophy Phenotypes and Frequencies

Phenotype Description Frequency

Late infantile Onset <30 months; early milestones are often achieved, followed by regression in gross motor 50–60%
skills (especially gait) and speech; weakness and hypotonia evolve to spasticity, tonic spasms,
and decerebrate posturing; a peripheral neuropathy may be present prior to central nervous
system symptoms

Juvenile Onset between 30 months and puberty; early milestones are achieved, followed by 20–30%
psychomotor regression, mental status changes, and behavioral disturbances; declining
school performance, personality changes, or gait abnormalities may prompt medical attention

Adult Onset >12–14 years; psychiatric manifestations (such as behavioral changes and emotional 15–20%
lability or substance abuse) may lead to diagnoses of bipolar disorder and dementia prior
to the recognition of motor and cognitive symptoms; other adults may present with a
peripheral neuropathy

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brain MRI was normal at the time of the trauma. Fifteen months later, the MRI
was repeated because of regression in motor skills and was consistent with
metachromatic leukodystrophy.26

Neuroimaging
Metachromatic leukodystrophy is a demyelinating disorder (T1 hypointense)
with confluent T2 hyperintensities surrounding the frontal and parietal
periventricular white matter (FIGURE 6-3). 2 In patients with diffuse disease,
a striped (tigroid) appearance may be seen, in which normal white matter
alternates with hyperintense lesions (also seen in other leukodystrophies, such
as Pelizaeus-Merzbacher disease).28

Diagnosis
The diagnosis is suspected if a low arylsulfatase A level (less than 10% of normal
values) is detected in white blood cells or cultured fibroblasts; however,
arylsulfatase A pseudodeficiency is relatively common. Individuals with
arylsulfatase A pseudodeficiency have arylsulfatase A levels ranging from 5% to
20% of normal values without clinical or radiographic disease. Therefore, a
diagnosis of metachromatic leukodystrophy in individuals with low arylsulfatase A
must be confirmed by the detection of elevated sulfatides in the urine and ARSA
sequencing for mutations.29

A full-term infant boy was noted to have slow development of motor CASE 6-2
milestones. He walked around 18 months but continued to be unsteady.
He was referred for early intervention, and hypotonia was suspected. His
speech and cognition were normal for his age. At 2 years, he had
persistent gait unsteadiness and was referred to neurology. An EMG was
consistent with a demyelinating polyneuropathy. Subsequently, his gait
further regressed and a walker was needed. He could not push up into a
prone position or crawl. His speech regressed with decreased speech
production. His examination was notable for increased tone in the lower
extremities, decreased dorsiflexion, and absent patellar reflexes. He was
only able to walk with assistance. Brain MRI was performed at 2 years,
7 months, and diffuse T2 hyperintensities were seen throughout the white
matter. Arylsulfatase A level in leukocytes was low, and urine sulfatides
were elevated.

This case illustrates a delay in the diagnosis of metachromatic leukodystrophy. COMMENT

Late infantile metachromatic leukodystrophy typically presents between 1 and
3 years of age with gross motor delay or regression. In this patient, a peripheral
neuropathy, rather than symptoms localizing to the central nervous system,
was the initial manifestation of disease. Metachromatic leukodystrophy
should be considered in any child presenting with a peripheral neuropathy.
As the typical central nervous system involvement may develop later,
brain MRI findings may be subtle or unremarkable. Biochemical testing
(arylsulfatase A, urine sulfatides) is the diagnostic test of choice.

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LEUKODYSTROPHIES

A high index of suspicion for

FIGURE 6-3
Metachromatic leukodystrophy. Axial MRI in
metachromatic leukodystrophy demonstrates
confluent diffuse T2 hyperintense signal involving
the central white matter and corpus callosum, similar
to Krabbe disease. The striped “tigroid” appearance
is not specific for metachromatic leukodystrophy
but characteristic of leukodystrophies.
metachromatic leukodystrophy
must exist for children presenting
with a peripheral neuropathy or
gall bladder abnormality in the
absence of other neurologic
features. The MRI may not reveal
pathology early in the disease
course; therefore, a normal MRI is
not sufficient to exclude
metachromatic leukodystrophy.
The diagnosis of metachromatic
leukodystrophy should be
excluded through a normal
arylsulfatase A level and the
absence of urinary sulfatides.
Legislation mandating newborn
screening for metachromatic
leukodystrophy has not been
approved at the state or federal
level. The required methodology
for metachromatic leukodystrophy
newborn screening is still under
development30 and is further
challenged by the frequency of
arylsulfatase A pseudodeficiency
in the population.

Disease-specific Therapy
Hematopoietic stem cell transplantation may be beneficial in asymptomatic
children with metachromatic leukodystrophy (diagnosed because of an affected
sibling) or early symptomatic juvenile-onset disease. Cohorts have included
those receiving bone marrow–derived cells,31 umbilical cord blood,32 or both.33
For late-infantile disease, four of ten in one cohort32 and two of four in a different
cohort died.33 Of the six children who died, five of the deaths occurred within the
first year posttransplant. One patient in each group was asymptomatic at the
time of transplant. In patients with juvenile disease, the 5-year survival
posttransplant is estimated to be 59% (N = 27),33 79% (N = 24),31 and 82.4%
(N = 17)32 across various studies. While disease stability may occur, many
patients experience decline posttransplant with respect to MRI involvement,
gross motor function, cognitive skills, nerve conduction velocities, and other
metrics, although outcomes are frequently better compared to affected siblings
or natural history cohorts.32,33
In a phase 1/2 clinical trial, gene therapy in combination with autologous
hematopoietic stem cell transplantation was performed in 20 children with
metachromatic leukodystrophy (asymptomatic late-onset infantile disease,
juvenile disease, and early-onset juvenile disease [less than 6 months from
symptom onset]).34,35 For this open-label study, hematopoietic stem cells were
removed from the patient, transduced with a lentiviral vector encoding ARSA
ex vivo, and returned to the patient after myeloablative conditioning. Two

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publications describe the outcomes of the first nine patients enrolled in the KEY POINTS
study.34,35 The onset of MRI abnormalities in asymptomatic individuals was
● Aicardi-Goutières
delayed compared to sibling controls, and many showed age-expected gains syndrome should be
in gross motor function and cognition. However, not all children remained considered in young
asymptomatic, and some disease progression occurred. The unique aspect of children with developmental
regression, acquired
this therapy is the ability of the transduced cells to make supranormal levels of
microcephaly, spasticity,
arylsulfatase A, which was detected as early as 1 month in blood and 6 months in and dystonia. Chilblains,
CSF. Data from the trial are still being analyzed to determine the future role of glaucoma, cardiomyopathy,
gene therapy for this disorder. stroke, and comorbid
autoimmune conditions are
present, with variability in
AICARDI-GOUTIÈRES SYNDROME the presence and frequency
of these symptoms by
Aicardi-Goutières syndrome is an inflammatory disorder caused by mutations genetic mutation.
in any one of seven genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C,
SAMHD1, ADAR, or IFIH1), all of which encode proteins involved in nucleic ● In Aicardi-Goutières
acid metabolism and signaling.36 The pathophysiology involves the accumulation syndrome, a CT scan may
be performed to
of nucleic acids (for all genes except ADAR and IFIH1) that activate the innate demonstrate calcium
immune response with increased expression of type I interferon–stimulated deposits in the basal
genes. The symptoms and imaging features of Aicardi-Goutières syndrome ganglia and other areas of
mimic TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus the brain.
infection, and herpes simplex) and other in utero infections.
● Patients with
Aicardi-Goutières
Clinical Symptoms syndrome may have a CSF
lymphocytic pleocytosis,
In 1984, Jean Aicardi and Françoise Goutières described the syndrome that elevated interferon alfa, or
now bears their names.37 Among five families, eight infants had a progressive elevated neopterin or
encephalopathy presenting shortly after birth with feeding difficulties or biopterin.
manifesting as subacute neurologic deterioration after a period of normal
development, typically before 1 year of age. Ultimately, the affected children
developed appendicular spasticity and dystonia, truncal hypotonia, and acquired
microcephaly. These children were all found to have basal ganglia calcifications
on head CT and a persistently elevated CSF white blood cell count (lymphocytic
predominance) on serial measurements. Since the initial description, the clinical
phenotypes (TABLE 6-5) have evolved.
In addition to the neurologic manifestations, other symptoms provide clues to
the diagnosis of Aicardi-Goutières syndrome, and some trends in clinical
manifestations based on genetic mutations have been identified among 374
patients with Aicardi-Goutières syndrome.36 Chilblains, which are small purple-red
or white blistering lesions on the toes, fingers, helix, or pressure areas, occur in
approximately one-third of all patients with Aicardi-Goutières syndrome
(FIGURE 6-4 38 ). 39,40 They are most common after 1 year of age and increase in
cold weather.41 Chilblains have been reported with mutations of each of the seven
genes; however, they most frequently occur in children with SAMHD1 mutations
(approximately 54%, or 26 of 48 children) and rarely occur in ADAR mutations.
Glaucoma also occurs in approximately 20% of children (10 of 48) with SAMHD1
mutations, typically in the first 6 months of life, although it can occur at an older
age. Stroke due to large vessel disease has also been reported in SAMHD1
mutations (9 of 9 children). While infrequent, infantile-onset hypertrophic
cardiomyopathy may occur, especially in infants with a TREX1 mutation (9 of 12
infants with cardiomyopathy had mutations in the TREX1 gene). These
relationships may inform genetic testing of single genes but should not be used to

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LEUKODYSTROPHIES

exclude a diagnosis of Aicardi-Goutières syndrome, as overlap of genetic

syndromes does occur.
Although rare, other autoimmune diseases, including hypothyroidism,
diabetes mellitus, autoimmune gastritis, autoimmune hepatitis, panniculitis,
Crohn disease, systemic lupus erythematosus, and antiphospholipid antibody
syndrome, have been described in patients with Aicardi-Goutières syndrome.

Neuroimaging
The pathognomonic feature of Aicardi-Goutières syndrome on neuroimagingis
intracerebral calcifications, which are present in approximately 90% of
individuals (N = 121) using MRI (FIGURE 6-5) and CT.42 The calcium deposits
are frequently present in the basal ganglia, deep white matter, thalamus, and
dentate nuclei of the cerebellum. They can be visualized on MRI using
T1-weighted, gradient recalled echo (GRE), or susceptibility-weighted images;
however, a head CT may be necessary to confirm their presence. The cerebral
white matter is also affected (present in 120 of 121 children), with T2
hyperintensities or white matter rarefaction with a frontotemporal predominance or
diffuse involvement.42 In the same study, one patient had isolated bilateral striatal
necrosis, which has been reported in ADAR1 mutations.43 Other distinguishing MRI
features in infants with Aicardi-Goutières syndrome (median age 0.7 months)
include cerebral atrophy (with ventricular enlargement), temporal lobe swelling,
temporal horn dilation, and temporal cysts.44 A normal brain MRI and nonspecific
white matter changes have been reported in children with severe dystonia (but
preserved cognition) who have mutations in various Aicardi-Goutières syndrome
genes. As such, a normal or nondiagnostic brain MRI does not exclude the
diagnosis of Aicardi-Goutières syndrome.

Diagnosis
A diagnosis of Aicardi-Goutières syndrome should be considered in young
children with the clinical or radiographic features described. A lumbar puncture

TABLE 6-5 Aicardi-Goutières Syndrome Phenotypes and Frequenciesa

Phenotype Description Frequency

Prenatal Presents at birth with poor feeding, irritability, abnormal tone and movements, seizures; 11.4%
onset thrombocytopenia and hepatosplenomegaly at birth support the prenatal onset

Perinatal Presents at birth with similar features to the prenatal onset form but without the systemic 11.4%
involvement

Infancy Onset <1 year of age; may meet early milestones, followed by psychomotor regression, spasticity, 68.6%
dystonia, and acquired microcephaly; seizures and visual impairment may also occur
Childhood Variable symptoms and disease onset, although the oldest known age at symptom onset is 8.6%
5 years of age (subacute dystonia); glaucoma developed in a 6-year-old patient with
known disease

a
Data from Crow YJ, et al, Am J Med Genet.36

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may provide supportive evidence. The KEY POINT
CSF may reveal a lymphocytic pleocytosis.
● Infants with persistent
Elevated CSF neopterin and biopterin and jaundice or chronic diarrhea
reduced folate have been reported in and children with bilateral
patients with normal CSF profiles cataracts should be tested
(including cell counts, interferon, and for cerebrotendinous
xanthomatosis, even in the
interleukin levels).45 absence of neurologic
symptoms, through
Disease-specific Therapy measurement of serum
cholestanol and urine and
No therapies are currently approved for
serum bile alcohols.
Aicardi-Goutières syndrome; however,
active research studies and clinical trials
are investigating treatments that
target the interferon pathway and
autoantibody production in children with
Aicardi-Goutières syndrome.46

CEREBROTENDINOUS XANTHOMATOSIS
Cerebrotendinous xanthomatosis is an
autosomal recessive disorder caused by
mutations in the CYP27A1 gene, which
encodes sterol 27-hydroxylase. The
deficiency of this enzyme results in the
accumulation of cholesterol and cholestanol
and the formation of xanthomas in
tendons, CNS, skin, and other organs.

Clinical Symptoms
The earliest manifestation of
cerebrotendinous xanthomatosis is
neonatal cholestatic jaundice,47 which
persists beyond the first week of life with
chronic diarrhea and is associated with FIGURE 6-4
elevated transaminases and bilirubin. In Chilblains in Aicardi-Goutières
syndrome. Chilblains are vasculitis
childhood and adolescence, juvenile lesions (purple-red discolorations) of
bilateral cataracts occur, but they are often the skin typically located on the fingers,
thought to be “idiopathic,” and most toes, or other dependent areas (such
clinicians do not appreciate the possibility as elbows or earlobes); necrosis of these
lesions can occur.
of cerebrotendinous xanthomatosis. Reprinted with permission from Abe J, et al,
Xanthomas occur in the Achilles and other Rheumatology (Oxford).38 © 2013 The Authors.
tendons, especially over extensor surfaces,
in adolescence or adulthood. They can also
develop in the brain, lungs, and bones. The neurologic symptoms develop
predominantly in adulthood, with cognitive impairment, ataxia, and pyramidal
features (such as spasticity). Psychiatric symptoms can also occur.

Neuroimaging
The cerebellum is preferentially affected in cerebrotendinous xanthomatosis;
notably, T1 hypointense and T2 hyperintense lesions are seen in the bilateral

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LEUKODYSTROPHIES

dentate nuclei as well as T2

hyperintensities in the cerebellar
white matter.48 Cerebellar and
cerebral atrophy are also present.
The periventricular white matter,
globus pallidus, posterior limb of
the internal capsule, substantia
nigra, and cerebral peduncles
may also be affected.49

Diagnosis
A high index of suspicion is
needed for the diagnosis of
cerebrotendinous xanthomatosis
as serum cholesterol levels and
hepatic function testing are
normal. The diagnosis is
confirmed through elevated
FIGURE 6-5
Aicardi-Goutières syndrome. Axial T1-weighted
serum cholestanol, which
MRI demonstrates hyperintensity in the bilateral is 5 to 10 times normal values, and
basal ganglia, predominantly the putamen (arrows), the excretion of bile alcohols in
representing mineralization in a patient with the urine and serum.
Aicardi-Goutières syndrome.
Testing for cerebrotendinous
xanthomatosis has not been
incorporated into newborn
screening programs in the United States; however, a methodology
to detect a bile acid precursor in dried blood spots has successfully differentiated
infants with cerebrotendinous xanthomatosis from unaffected controls.50 In
Victoria, Australia, urine bile alcohols have been added to a urine metabolic
screening panel (including amino acids, organic acids, and others) and enabled
the diagnosis of four patients with cerebrotendinous xanthomatosis among
23,000 urine samples.51,52

Disease-specific Therapy
Chenodeoxycholic acid inhibits cholesterol and cholestanol synthesis by
downregulating CYP7A transcription.53 Treatment with chenodeoxycholic acid
does not improve neurologic deficits once present but, if started early, prevents
neurologic deterioration. For example, patients whose treatment with
chenodeoxycholic acid began before 25 years of age (N = 10) had improved
ambulation with significantly less pyramidal involvement and fewer cerebellar
deficits compared to those who started after 25 years of age (N = 6).54 Dysarthria
was not noted in any of the treated younger patients. Cholic acid is FDA approved
for children and adults with cerebrotendinous xanthomatosis and has fewer side
effects than chenodeoxycholic acid, especially in infants and children, whose
diarrhea worsens on chenodeoxycholic acid.55

TRENDS
Newborn screening programs for leukodystrophies are being implemented
for Krabbe disease and X-linked adrenoleukodystrophy, while testing for

146 FEBRUARY 2018

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metachromatic leukodystrophy and cerebrotendinous xanthomatosis are under KEY POINT
development. Such programs are providing new challenges for disease prediction
● Cholic acid is a US Food
models. Genotype-phenotype correlations for many disorders do not predict age and Drug Administration–
of onset or functional decline; therefore, it is not clear when to introduce a approved treatment for
therapy, such as hematopoietic stem cell transplantation, or how to determine its cerebrotendinous
efficacy. Gene therapy trials in some of the leukodystrophies provide hope for xanthomatosis and, when
initiated early, delays the
families; however, more data are needed on their efficacy and safety profiles. onset of neurologic
Novel therapeutic strategies are needed for peripheral nervous system symptoms.
involvement of leukodystrophies such as Krabbe disease and metachromatic
leukodystrophy, as hematopoietic stem cell transplantation has a limited benefit
in the treatment of these symptoms.

CONCLUSION
The leukodystrophies are a group of complex disorders with variable
clinical features and presentations by age. Many of these disorders have
extra-CNS manifestations before the onset of neurologic symptoms
or MRI abnormalities, such as adrenal insufficiency in X-linked
adrenoleukodystrophy or chronic diarrhea and cataracts in cerebrotendinous
xanthomatosis. Both metachromatic leukodystrophy and Krabbe disease can
present with a peripheral neuropathy, and, in such cases, the brain MRI is
often normal or reveals subtle findings. Therefore, knowledge about the
typical disease presentations and a high index of suspicion are crucial to
confirming the diagnosis before the worsening of CNS symptoms and disease
progression on MRI. Biochemical testing, such as enzyme levels in Krabbe
disease and metachromatic leukodystrophy; very-long-chain fatty acids in
X-linked adrenoleukodystrophy; CSF cell counts, neopterin, and biopterin in
Aicardi-Goutières syndrome; and serum cholestanol in cerebrotendinous
xanthomatosis, are the tests of choice to screen suspected individuals for
these disorders.

ACKNOWLEDGMENT
This work was supported by a career training grant (K23NS069806) from the
National Institutes of Health.

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