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NEUROLOGY BOARD REVIEW MANUAL
STATEMENT OF
EDITORIAL PURPOSE
The Hospital Physician Neurology Board Review
Manual is a study guide for residents and
practicing physicians preparing for board
examinations in neurology. Each quarterly
manual reviews a topic essential to the current practice of neurology.
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PRESIDENT, GROUP PUBLISHER
Bruce M. White
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PRODUCTION DIRECTOR
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PRODUCTION ASSISTANT
Metabolic Disorders in
Pediatric Neurology
Editor: Catherine Gallagher, MD
Assistant Professor of Neurology, University of Wisconsin Movement
Disorders Program, Staff Physician, Middleton VA Hospital,
Madison, WI
Contributors:
Gregory M. Rice, MD
Fellow in Clinical and Biochemical Genetics, Departments of Medical
Genetics and Pediatrics, University of Wisconsin, Madison, WI
David Hsu, MD, PhD
Assistant Professor of Neurology, Department of Neurology, University
of Wisconsin, Madison, WI
Table of Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Disorders Caused by Energy Failure . . . . . . . . . . . . . . . . . 2
Kathryn K. Johnson
Disorders of Amino Acid Metabolism. . . . . . . . . . . . . . . . 6
ADVERTISING/PROJECT MANAGER
Disorders of Carbohydrate Metablism . . . . . . . . . . . . . . . 9
Patricia Payne Castle
SALES & MARKETING MANAGER
Deborah D. Chavis
NOTE FROM THE PUBLISHER:
This publication has been developed without
involvement of or review by the American
Board of Psychiatry and Neurology.
Endorsed by the
Association for Hospital
Medical Education
Lysosomal Storage Disorders . . . . . . . . . . . . . . . . . . . . . 10
Peroxisomal Biogenesis Disorders . . . . . . . . . . . . . . . . . 11
White Matter Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 12
Gray Matter Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Other Metabolic Disorders . . . . . . . . . . . . . . . . . . . . . . . 14
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Cover Illustration by Kathryn K. Johnson
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Neurology Volume 9, Part 2 1
NEUROLOGY BOARD REVIEW MANUAL
Metabolic Disorders in Pediatric Neurology
Gregory M. Rice, MD, and David Hsu, MD, PhD
INTRODUCTION
This manual reviews metabolic diseases that affect
the nervous system, focusing on the usual presentations
from the perspective of a pediatric neurologist. Many of
these disorders also have milder presentations in later
life, which are not discussed here. This review presents
sufficient information to begin a workup and to institute initial interventions. A beginning neurologist will
need to learn more about each disorder as he or she
closes in on the definitive diagnosis. If a diagnosis is not
readily apparent by clinical presentation (Table 1), one
must resort to a more systematic approach.
In this review, disorders are generally grouped
according to defects of the various biochemical pathways (Figure 1). Metabolic disorders caused by energy
failure can involve defects in the mobilization of glycogen (ie, glycogen storage diseases) or fats (ie, fatty acid oxidation defects) or defects in the citric acid cycle or respiratory chain (ie, mitochondrial disorders). These disorders
tend to present as decompensations with stress or increased energy demand. Metabolic disorders caused by
defects in amino acid metabolism include the organic
acidemias, aminoacidopathies, and urea cycle defects. These
disorders tend to present in infancy as increasing lethargy and vomiting with initiation of feeds. Lysosomal disorders result in the accumulation of large carbohydrate–
lipid complexes and present as dysmorphism with
organomegaly, psychiatric symptoms, or white matter
disease. Aside from the glycogen storage disorders, the
disorders of carbohydrate metabolism are rather heterogeneous. Finally, some primarily white matter disorders are
suggested by clinical presentation, such as increasing
spasticity and abnormalities in white matter on magnetic resonance imaging (MRI), whereas primarily gray
matter disorders present as seizures and cognitive decline.
In the United States, most states screen newborns for
phenylketonuria, galactosemia, hypothyroidism, congenital adrenal hyperplasia, hemoglobinopathies, and
maple syrup urine disease. Some states employ tandem
mass spectroscopy, which gives amino acid and acylcarnitine profiles. These tests are useful for diagnosing
many metabolic disorders, as described below.
2 Hospital Physician Board Review Manual
DISORDERS CAUSED BY ENERGY FAILURE
GLYCOGEN STORAGE DISORDERS (GSD)
Glycogen is an important source of stored glucose
found primarily in liver and muscle. Defects in glycogen
mobilization can lead to energy failure during times of
fasting and exercise.
GSD Type II
GSD type II (Pompe’s disease) is caused by deficiency of
the lysosomal enzyme acid maltase (α-1-4-glucosidase).1
The infantile form presents as severe hypotonia and cardiomyopathy and is usually fatal before 12 months of age.
The childhood form affects only skeletal muscle and presents as progressive weakness. Creatine kinase (CK) levels
are markedly elevated, and muscle biopsy demonstrates
glycogen storage in muscle fibers and absence of acid maltase. Hypoglycemia is not seen in GSD type II.
GSD Type V
GSD type V (McArdle’s disease) is caused by deficiency of myophosphorylase and presents in adolescents
as cramps and muscle fatigue shortly after initiating
exercise. A “second wind” effect can occur (ie, renewed
ability to continue exercising if patients rest briefly after
the onset of fatigue). Laboratory studies show elevated
CK levels, post-exertional myoglobinuria, and a failure
of the normal rise in lactate levels with exercise. The
forearm ischemic test is the classic exercise test but is difficult to perform reliably. Muscle biopsy shows glycogen
storage in muscle and absence of myophosphorylase.
Moderate exercise with careful warmup is advisable.
Dietary treatments have been disappointing.
FATTY ACID OXIDATION DISORDERS
Fatty acid oxidation disorders consist of autosomal
recessive defects in either the transport of fatty acids into
mitochondria or in the intramitochondrial β-oxidation
of fatty acids. A prolonged fast or significant stress (eg, illness, surgery) may deplete liver stores of glycogen. If fatty
stores fail to be mobilized for fuel, the result is the classic
laboratory finding of hypoketotic hypoglycemia.2 A mild to
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Metabolic Disorders in Pediatric Neurology
Table 1. Clinical Presentations and Differential Diagnosis of Metabolic Disorders
Stroke/stroke-like episodes
Cardiomyopathy
Progressive myoclonic epilepsies
Mitochondrial myopathy, encephalomyelopathy, and lactic acidosis with stroke-like
episodes (MELAS)
VLCAD deficiency
Myoclonic epilepsy with ragged red fibers
(MERRF)
Homocystinuria
Propionic acidemia
Methylmalonic acidemia
Isovaleric acidemia
Glutaric acidemia type I
Urea cycle disorders
Congenital disorders of glycosylation
Menkes’ syndrome
Fabry’s disease
Leigh disease
Electron transport chain defects
Pyruvate dehydrogenase complex deficiency
Biotinidase deficiency
Reye-like syndrome
Fatty acid oxidation disorders
Urea cycle disorders
Organic acidemias
LCHAD deficiency
Unverricht-Lundborg disease (Baltic
myoclonus)
Carnitine transporter deficiency
Infantile CPT2 deficiency
Neuronal ceroid lipofuscinosis
GSD II (Pompe’s disease)
Lafora’s disease
GSD III (Cori’s disease)
Sialidosis type 1
Mitochondrial disorders
Psychiatric/behavioral change
Cherry red spots on the macula
Wilson’s disease
Tay-Sachs disease
Neuronal ceroid lipofuscinosis
Sandhoff’s disease
X-Linked adrenoleukodystrophy
GM1 gangliosidosis
Juvenile- and adult-onset metachromatic
leukodystrophy
Niemann-Pick disease
Sialidosis
Late-onset GM2 gangliosidosis
Multiple sulfatase deficiency
Lesch-Nyhan syndrome
Rhabdomyolysis/myoglobinuria
Porphyria (episodic)
GSD type V (McArdle’s disease)
Urea cycle disorders (episodic)
Adult CPT2 deficiency
VLCAD deficiency
Sanfilippo’s syndrome (mucopolysaccharidosis III)
LCHAD deficiency
Hunter’s syndrome (mucopolysaccharidosis II)
Carnitine transporter deficiency
Mitochondrial disorders
CPT = carnitine palmitoyl transferase; GSD = glycogen storage disease; LCHAD = long-chain hydroxy acyl coenzyme A dehydrogenase; VLCAD =
very-long-chain acyl coenzyme A dehydrogenase. (Adapted from Nyhan WL, Ozand PT. Atlas of metabolic diseases. New York: Chapman and Hall;
1998; and Clarke JT. A clinical guide to inherited metabolic diseases. 2nd ed. New York: Cambridge University Press; 2002.)
moderate hyperammonemia may also be seen. Organs
especially sensitive to fatty acid oxidation defects include
the brain (which depends on ketones for fuel in the fasted state), the heart and muscles (due to high metabolic
demand and because fatty fuels spare proteolysis), and
the liver (which relies on energy derived from fatty acid
oxidation for gluconeogenesis and ureagenesis). Management for all fatty acid oxidation disorders includes
avoiding prolonged fasts and aggressive use of dextrosecontaining fluids during decompensations.
Carnitine must bind to long-chain fatty acids for fatty
acid transport across the mitochondrial double membrane. Carnitine enters the cell through a carnitine
transporter. It is bound to the fatty acyl group by carnitine palmitoyl transferase 1 (CPT1) at the outer mitochondrial membrane. Acylcarnitine is then transported
to the inner mitochondrial membrane by acylcarnitine
translocase. At the inner mitochondrial membrane, acylcarnitine is disassembled into acyl coenzyme A (CoA)
and free carnitine by carnitine palmitoyl transferase 2
(CPT2). Acyl CoA then enters β-oxidation while free
carnitine is recirculated to the cell cytoplasm. The first
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Carbohydrates
Glucose
Glycogen
Galactose
Glucose-6-P
Fatty acids
Amino acids
Fructose
Urea
NH3
Pyruvate
Lactate
Urea
cycle
Acetyl CoA
Krebs
cycle
Ketones
β-oxidation
ATP ADP
Mitochondrion
Cytosol
Respiratory chain
Figure 1. Basic pathways of intermediary metabolism. Glucose6-P = glucose-6-phosphate. (Adapted with permission from
Hoffmann GF, Nyhan WL, Zschocke J. Inherited metabolic diseases. Philadelphia: Lippincott Williams & Wilkins; 2002:6.)
Neurology Volume 9, Part 2 3
Metabolic Disorders in Pediatric Neurology
Table 2. Carnitine-Associated and Fatty Acid Disorders
Deficiency
Total
Transporter
Free (F)
Esters (E)
E:F Ratio
Serum
Acylcarnitine
Profile
Age of
Onset
Tissue
Affected
H/M/L
↓↓
↓
↓↓
< 0.3 (nl)
↓All esters
I/C
CPT1
↑
↑
↓↓
< 0.2
↓C16, C18
I/C
L
Translocase
↓
↓
↑
> 0.4
↑C16, C18
N
H/L
CPT2 (liver)
↓
↓
↑
> 0.4
↑C16, C18
N/I
H/L
CPT2 (muscle)
↓
↓
↑
> 0.4
↑C16, C18
C/A
H/M
MCAD
↓
↓
↑
> 0.4
↑C6, C8, C10:1
I/C
L
LCHAD
↓
↓
↑
> 0.4
↑C16-OH, C18-OH
I/C
H/M/L
A = adult; C = child; CPT = carnitine palmitoyl transferase; H = heart; I = infant; L = liver/Reye syndrome; LCHAD = long-chain hydroxy acyl
coenzyme A dehydrogenase; M = skeletal muscle; MCAD = medium-chain acyl coenzyme A dehydrogenase; N = neonate; nl = normal. (Adapted
from Nyhan WL, Ozand PT. Atlas of metabolic diseases. New York: Chapman and Hall; 1998.)
step in β-oxidation is performed by acyl CoA dehydrogenases, which are distinct depending on the acyl group
chain length.
Carnitine also acts as a scavenger of potentially toxic
acyl CoA metabolites, forming acylcarnitine esters that
are excreted in the urine. A secondary carnitine deficiency results when urinary acylcarnitine loss is excessive. Blood carnitine levels then show an elevated
acylcarnitine ester-to-free carnitine ratio (ie, > 0.4).2 Valproic acid therapy can cause secondary carnitine deficiency in this way by forming valproyl carnitine ester.
Screening laboratory tests include plasma free and
total carnitines, plasma acylcarnitine profile, and urine
acylglycines. Laboratory findings are summarized in
Table 2. Interpretation of urine acylglycines is complex
and is omitted in this review.
Carnitine Disorders
Carnitine transporter deficiency leads to total body
carnitine depletion secondary to increased renal loss.
Symptoms include muscle weakness and cardiomyopathy. Carnitine given in high doses reverses symptoms
and can be lifesaving.2
CPT1 deficiency presents as a Reye-like syndrome,
with progressive encephalopathy, seizures secondary to
hypoglycemia, hepatomegaly, moderate hyperammonemia, and elevated liver enzymes. Skeletal and cardiac
muscle are not involved. Acylcarnitine profile shows decreased long-chain acylcarnitines (C16, C18). Chronic
treatment with medium-chain fatty acids may be of benefit.
CPT2 deficiency has an infantile (liver) and adult
(muscle) form. The infantile form presents as hepatomegaly, liver failure, cardiomegaly, arrhythmias, and
seizures, with hypoketotic hypoglycemia. The adult
4 Hospital Physician Board Review Manual
form presents in the teens to twenties as episodic rhabdomyolysis and myoglobinuria with elevated CK levels
following prolonged exercise, cold exposure, infection,
or fasting.
Disorders of β-Oxidation and Ketogenesis
Medium-chain acyl CoA dehydrogenase (MCAD)
deficiency is the most common of the fatty acid oxidation disorders. MCAD helps metabolize medium-chain
fatty acids to ketones, which are used as fuel during
times of stress and fasting. Acute presentation consists
of lethargy, vomiting, seizure, and progressive encephalopathy after fasting or physical stress. An initial attack
may result in sudden infant death. Management includes moderate dietary fat restriction and carnitine
supplementation.
Very-long-chain acyl CoA dehydrogenase (VLCAD)
deficiency and long-chain 3-hydroxy acyl CoA dehydrogenase (LCHAD) deficiency are associated with
cardiomyopathy, skeletal myopathy, post-exertional
rhabdomyolysis, and hypoketotic hypoglycemia with decompensations. Children with VLCAD deficiency can present with a Reye-like syndrome, which can be fatal.
Mothers carrying a fetus with LCHAD deficiency can present with hemolysis, elevated liver function tests, and low
platelet counts (HELLP syndrome). Diagnosis is by acylcarnitine profile, which shows elevated long-chain acylcarnitines and hydroxy-acylcarnitines, respectively, in
patients with VLCAD deficiency and LCHAD deficiency.
Medium-chain triglycerides (MCT oil) are supplemented.
Glutaric acidemia type II (multiple acyl CoA
dehydrogenase deficiency) involves defects in the flavin
adenine dinucleotide (FAD)–dependent electron
transfer from dehydrogenase enzymes to the electron
transport chain. This disorder affects both fatty acid
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Metabolic Disorders in Pediatric Neurology
Table 3. Mitochondrial Disorders
Disorder
Characteristic Findings
Comments
MELAS4
Recurrent stroke-like events, migrating lesions on MRI, episodic
encephalopathy, migraines, seizures
Leucine tRNA mtDNA mutation in 80%
MERRF5
Myoclonic epilepsy, ataxia, optic atrophy, hearing loss
Lysine tRNA mtDNA mutation in 80%
CPEO6
CPEO, ptosis, variable skeletal muscle weakness
Multiple mtDNA deletions; only skeletal
muscle affected
Kearns-Sayre syndrome4
CPEO, retinitis pigmentosa, and one of following: cerebellar ataxia,
conduction block, CSF protein > 100 mg/dL
Multiple mtDNA deletions; all tissues affected; check serial ECGs
Leigh disease, or subacute necrotizing
encephalomyelopathy7
Ataxia, hypotonia, ophthalmoplegia, dysphagia, dystonia
MRI: lesions of basal ganglia, thalamus, brainstem
Severe neurodegenerative disease; most die
by 3 years of age; multiple mutations
associated
Leber’s hereditary optic
neuropathy8
Acute: optic nerve hyperemia, vascular tortuosity
Chronic: optic atrophy
Uncommon: cardiac conduction abnormalities
Painless; initially asymmetric; progresses over
weeks to months
NARP7
Neuropathy, ataxia, retinitis pigmentosa, proximal weakness, mental retardation
Can go years without exacerbation;
mtATPase affected
Friedreich’s ataxia9
Ataxia, areflexia, loss of vibration and proprioceptive sense, with
onset before age 25 years
Associated: diabetes, cardiomyopathy, scoliosis, optic atrophy,
deafness
Trinucleotide expansion in Frataxin gene;
autosomal recessive (nuclear gene)
Causes intramitochondrial iron accumulation;
most die in mid-30s
Milder variant exists with retained reflexes
CPEO = chronic progressive external ophthalmoplegia; CSF = cerebrospinal fluid; ECG = electrocardiogram; MELAS = mitochondrial myopathy,
encephalopathy, and lactic acidosis with stroke-like episodes; MERRF = myoclonic epilepsy with ragged red fibers; MRI = magnetic resonance imaging; mt = mitochondrial; NARP = neurogenic muscle weakness, ataxia, and retinitis pigmentosa.
oxidation and amino acid metabolism. The classic neonatal form is severe and presents as a Reye-like syndrome, followed by seizures and progressive neurodegeneration. Dysmorphism and cystic kidneys may be
present. Diagnosis is by recognizing a complex pattern
in plasma acylcarnitines, urine organic acids, and urine
acylglycines, including urine glutaric acid.
MITOCHONDRIAL DISORDERS
Mitochondrial disorders are caused by a genetic
defect in either nuclear or mitochondrial DNA. Many
mitochondrial syndromes have been defined, but there
is significant overlap with a complex relationship between identified genetic defects and classic mitochondrial syndromes3 (Table 3).4 – 9
Clinical Features
Mitochondrial disorders are highly variable in presentation. Suspicion for a mitochondrial defect increases if there is multisystem involvement of high energy systems3,10 (Table 4). Diagnosis of mitochondrial disorders
begins with analysis of serum lactate, pyruvate, and CK
levels. Classically, lactate is elevated even at rest, with a
lactate-to-pyruvate ratio greater than 25 (more commonly, 50–250). However, 40% of patients have normal
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Table 4. Clinical Features of Mitochondrial Disorders
Brain: psychiatric disorder, seizures, ataxia, myoclonus, migraine,
stroke-like events
Eyes: optic neuropathy, retinitis pigmentosa, ptosis, external ophthalmoplegia
Ears: sensorineural hearing loss
Nerve: neuropathic pain, areflexia, gastrointestinal pseudoobstruction, dysautonomia
Muscle: hypotonia, weakness, exercise intolerance, cramping
Heart: conduction block, cardiomyopathy, arrhythmia
Liver: hypoglycemia, liver failure
Kidneys: proximal renal tubular dysfunction (Fanconi’s syndrome)
Endocrine system: diabetes, hypoparathyroidism
Adapted from Cohen BH, Gold DR. Mitochondrial cytopathy in
adults: What we know so far. Cleveland Clin J Med 2001;68:625–41
with permission from The Cleveland Clinic Foundation. Copyright ©
2001, all rights reserved.
lactate levels at rest. Furthermore, mitochondrial DNA
panels are abnormal in only 10% of patients.11 Thus,
muscle biopsy remains a key to diagnosis. Muscle biopsy may show ragged red fibers on Gomori trichrome
stain; succinate dehydrogenase stains the same fibers
blue, and cytochrome c oxidase stains reveal deficient
mitochondrial respiratory chain protein synthesis.
Neurology Volume 9, Part 2 5
Metabolic Disorders in Pediatric Neurology
A
B
C
Figure 2. Mitochondrial myopathy, encephalomyelopathy, and lactic acidosis with stroke-like episodes (MELAS) syndrome in a 10-yearold boy with migrating infarction. (A) Initial T2-weighted magnetic resonance image (MRI) shows a high signal intensity lesion in the left
occipital lobe (arrows). Follow-up MRI 15 months later showed resolution of the occipital lesion but with new left temporal lesion (not
shown). (B) Photomicrograph (original magnification, ×40; Gomori methenamine silver stain) of the muscle biopsy reveals scattered
ragged red fibers (arrows). (C) Electron micrograph reveals an increased number of mitochondria (arrows), which are irregular and
enlarged. (Adapted with permission from Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in children: a pictorial review of MR imaging features. Radiographics 2002;22:470. Radiological Society of North America.)
Biochemical analysis of muscle can reveal decreases in
activity of the respiratory chain complexes I to IV. Electron microscopy shows overabundant, enlarged, and
bizarrely shaped mitochondria with paracrystalline inclusions. Brain MRI may show lesions of the basal ganglia,
thalamus, midbrain, or cerebral white matter. In the cerebral white matter, recurrent stroke-like events may occur,
with transitory migrating lesions that cross vascular territories (Figure 2). Magnetic resonance (MR) spectroscopy may show elevated lactate peaks in these lesions.12,13
Impaired autoregulation of cerebral vasculature has
been suggested as the etiology of stroke-like events.14
Treatment
Treatment is with L-carnitine, B vitamins (riboflavin
and thiamine), and coenzyme Q or idebenone. Biotin,
antioxidants (vitamins A and C), folate, and lipoic acid
are also used.15 Dichloroacetic acid may lower lactate
levels in some patients.16 Response to treatment is variable, with some patients experiencing improvement in
energy and function but many experiencing no discernible improvement.
PYRUVATE DEHYDROGENASE COMPLEX DEFICIENCY
Pyruvate dehydrogenase complex (PDHC) deficiency blocks entry of pyruvate into the citric acid cycle,
resulting in elevated lactate and pyruvate levels. PDHC
deficiency presents similarly to the mitochondrial disorders. The severe neonatal form is fatal in infancy. Leigh
disease can develop later in infancy. Diagnosis is based
on finding elevated lactate and pyruvate levels with
preservation of the lactate-to-pyruvate ratio (ie, < 20).
6 Hospital Physician Board Review Manual
Treatment involves supplementation with thiamine,
which is a cofactor for PDHC, and a high fat, low carbohydrate diet. Acetazolamide may abort attacks.17
DISORDERS OF AMINO ACID METABOLISM
ORGANIC ACIDEMIAS
Organic acidemias are caused by autosomal recessive
disorders of amino acid metabolism. The usual presentation is that of nonspecific poor feeding, lethargy, and vomiting in the neonatal period, eventually progressing to
coma. Symptoms are often initially mistaken for sepsis.
Laboratory findings include metabolic acidosis with an
elevated anion gap, sometimes with ketosis and hyperammonemia (Table 5). Diagnosis during the acute illness
depends on plasma amino acids, plasma acylcarnitine
profile, urine organic acids, and urine acylglycine profile.
The detailed analysis of these profiles is often complex
and is not discussed here. Acute treatment involves withholding protein feeds and aggressively pushing dextrosecontaining fluids, to induce an anabolic state. Chronic
treatment consists of specific dietary protein restriction.
Carnitine supplementation can be helpful.18
Propionic Acidemia
Propionic acidemia is caused by a deficiency in propionyl CoA carboxylase. Most children have some cognitive
disability even with optimal therapy. Cardiomyopathy,
pancreatitis, osteoporosis, and movement disorders are
late complications.
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Metabolic Disorders in Pediatric Neurology
Methylmalonic Acidemia
Methylmalonic acidemia is caused by a defect in
methylmalonyl CoA mutase. Acidosis and hyperammonemia can be severe, and a single attack can cause permanent cognitive disability. Seizures, spasticity, behavioral problems, and ataxia are common. Metabolic
stroke with an acute decompensation can occur. Many
patients will develop renal failure and require renal
transplantation. Methylmalonic acid can also be elevated in disorders of cobalamin (vitamin B12) metabolism,
and megaloblastic anemia can be seen. Brain MRI may
show bilateral globus pallidus infarction. Management
of methylmalonic acidemia consists of vitamin B12 supplementation and dietary protein restriction.
Glutaric Acidemia Type I
Glutaric acidemia type I is caused by a deficiency in
glutaryl CoA dehydrogenase, which results in dystonia,
ataxia, cognitive disability, and spasticity. Metabolic acidosis is not a prominent feature even with acute decompensation. Diagnostic studies are often normal
when affected individuals are healthy. Neuroimaging
shows frontotemporal atrophy with basal ganglia lesions. Basal ganglia injury can appear even with a first
attack. Macrocephaly is common. Chronic management consists of carnitine supplementation and protein restriction.18
AMINOACIDOPATHIES
Classic Phenylketonuria
Classic phenylketonuria (PKU) is caused by a deficiency in the enzyme phenylalanine hydroxylase,
which converts phenylalanine to tyrosine. As a result,
neurotoxic phenylketones accumulate. Testing shows
elevated levels of blood phenylalanine and urine
phenylketones. Infants are normal at birth, but in the
first year of life manifest progressive cognitive delay,
microcephaly, spasticity, recurrent eczematous rash,
and a mousy odor. Seizures occur in 25% of untreated
PKU patients.19 Newborn screening and early treatment can prevent these symptoms. Treatment in classic
PKU consists of dietary restriction of phenylalanine
and close monitoring of blood phenylalanine levels.
Women with PKU should have phenylalanine levels
under control before attempting to conceive. Fetuses
exposed to high levels of phenylalanine are at risk for
congenital heart disease, intrauterine growth restriction, mental retardation, and microcephaly. Approximately 2% of PKU patients have normal phenylalanine hydroxylase activity but are deficient in the
cofactor tetrahydrobiopterin.20 These patients require
biopterin supplementation.
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Table 5. Metabolic Causes of Lethargy and Vomiting in the
Infant and Child
Acid-Base Status
Elevated
Ammonia
Normal
Ammonia
Acidemia with elevated
anion gap
Organic acidemia
(neonate)
Organic acidemia
(older child)
No acidemia
Urea cycle disorder
Galactosemia,
MSUD
MSUD = maple syrup urine disease. (Adapted with permission from
Silverstein S. Laughing your way to passing the pediatric boards. 2nd
ed. Stamford [CT]: Medhumor Medical Publications; 2000:286).
Copyright © 2000.
Maple Syrup Urine Disease
Maple syrup urine disease (MSUD) is caused by a
deficiency in branched-chain α-ketoacid dehydrogenase, which is responsible for the metabolism of leucine, isoleucine, and valine. The classic form presents in
the first week of life as poor feeding, lethargy, and vomiting, quickly progressing to coma, seizures, and death
if untreated. An intermittent form may present later in
life as attacks of transient ataxia, sometimes accompanied by cerebral edema.21 These attacks are triggered by
intercurrent illness or stresses. Urine, sweat, and cerumen often smell like maple syrup. Acidosis and hyperammonemia are uncommon.
In the United States, many states screen newborns
for MSUD. Testing during an attack shows elevated
leucine, isoleucine, and valine in blood as well as
branched-chain metabolites in urine, but these levels
may be normal in the immediate neonatal period
before branched-chain amino acids have accumulated
and in the intermittent form between attacks. Acute
management includes aggressive high calorie intravenous or nasogastric feeds, sometimes with intravenous insulin to help induce an anabolic state. Special
MSUD total parenteral nutrition is available with the
proper mixture of amino acids. Chronic management
relies on dietary restriction of branched-chain amino
acids. With early diagnosis and tight metabolic control,
the prognosis is for normal development.
Classic Homocystinuria
Classic homocystinuria is an autosomal recessive disorder caused by a defect in the enzyme cystathionine
β-synthetase, resulting in elevations of homocystine and
methionine. Infants are usually asymptomatic, but mental retardation can develop in untreated patients. Adults
are often tall and thin, and most have significant myopia.
Lens dislocation (ectopia lentis) may develop later in life,
but the lens is usually dislocated inferiorly, which is the
opposite of what is seen in Marfan syndrome. Untreated
Neurology Volume 9, Part 2 7
Metabolic Disorders in Pediatric Neurology
HCO3 + NH4 + 2 ATP
CPSI
Mitochondrion
N-acetylglutamate
Carbamyl
phosphate
Cytoplasm
e
in
ull
tr
Ci
OTC
e
Asparate
in
ull
tr
Ci
Ornithine
ASS
Ornithine
Argininosuccinate
ASL
Urea
ARG
Arginine
Fumarate
Figure 3. The urea cycle and its disorders. ARG = arginase deficiency; ASL = argininosuccinic acid lyase deficiency; ASS = argininosuccinic acid synthetase deficiency; CPSI = carbamyl phosphate
synthetase I deficiency; OTC = ornithine transcarboxylase deficiency. (Adapted with permission from Summar ML, Tuchman M.
Urea cycle disorders overview. GeneReviews. Available at www.
geneclinics.org/profiles/ucd-overview. Accessed 8 Apr 2005.)
patients are at risk for seizures, psychiatric disorders, and
thromboembolic events, including stroke, myocardial infarction, and pulmonary emboli.22 Treatment involves
protein restriction; supplementation with vitamin B6, vitamin B12, and folate; and stroke prophylaxis with aspirin.
Nonketotic Hyperglycinemia
Nonketotic hyperglycinemia (glycine encephalopathy) is caused by a defect in glycine cleavage.23 This
defect results in elevated glycine levels in the blood,
urine, and cerebrospinal fluid (CSF). The neonatal
form presents as lethargy and poor feeding after the initiation of protein feeds, quickly progressing to persistent
seizures, encephalopathy, and coma. Apnea is common
and persistent hiccups have also been seen. Diagnosis
depends on simultaneous measurement of CSF and
plasma glycine levels. A CSF-to-plasma glycine ratio
greater than 0.06 supports this diagnosis.24 Acute management includes use of sodium benzoate to help normalize plasma glycine level. Dextromethorphan, an
NMDA (N-methyl-D-aspartate) receptor antagonist, may
be beneficial. Valproic acid, which inhibits metabolism
of glycine, is contraindicated. The prognosis for the
neonatal form is poor. Survivors often have spastic quadriplegia, intractable seizures, and severe mental retardation. Infantile, childhood, and adult-onset forms exist
but are uncommon; these forms have milder outcomes.
8 Hospital Physician Board Review Manual
UREA CYCLE DISORDERS
The urea cycle converts ammonia, which is a toxic
byproduct of protein metabolism, into urea (Figure 3).
All urea cycle disorders are autosomal recessive with the
exception of ornithine transcarbamylase (OTC) deficiency, which is X-linked.
Clinical Features
Similar to the organic acidemias, urea cycle disorders
classically present in neonates as lethargy, poor feeding,
and vomiting soon after initiating protein feeds.25 What
distinguishes the urea cycle disorders from the organic
acidemias, however, is hyperammonemia without acidosis
(Table 5). In an acute crisis, encephalopathy quickly progresses to coma, seizures, and death if left untreated.
Cerebral edema (with a bulging fontanelle and tachypnea) can occur early and progresses rapidly. Metabolic
strokes may also occur. All urea cycle disorders, with the
exception of argininemia, are accompanied by hyperammonemia. Ammonia levels exceeding 200 µg/dL cause
lethargy and vomiting, levels greater than 300 µg/dL
result in coma, and levels exceeding 500 µg/dL cause
seizures.17 Any catabolic state, including the immediate
postnatal period before initiation of feeding, can provoke
a crisis because of associated proteolysis. Permanent neurologic sequelae can occur after a single crisis. Ammonia
levels greater than 350 µg/dL26 and coma for longer than
3 days27 are correlated with death or profound mental
retardation. Ammonia levels less than 180 µg/dL usually
result in normal development or only mild mental retardation.26 Milder forms, as seen with female carriers of
OTC deficiency, can have a more subtle presentation.
Treatment
Hyperammonemia in an encephalopathic infant is a
medical emergency. In addition to determining ammonia levels and acid-base status, laboratory studies
should be ordered for electrolytes, calcium, glucose, lactate, liver enzymes, free and total carnitine, quantitative
plasma amino acids, and urine organic acids. Acute
management for all urea cycle disorders consists of
(1) stopping all protein intake; (2) starting an intravenous infusion of 10% glucose plus lipid to promote
the anabolic state; and (3) starting arginine hydrochloride, sodium benzoate, and sodium phenylacetate with
intravenous loading doses, followed by maintenance
infusions. Peritoneal dialysis or hemodialysis should be
considered if there is clinical deterioration and ammonia levels are not responding. Chronic management
typically includes protein restriction and oral sodium
benzoate and sodium phenylacetate supplementation.25 Because the urea cycle takes place in the liver,
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Metabolic Disorders in Pediatric Neurology
liver transplantation is curative for the metabolic disorder but does not reverse accumulated neurologic
injury. In the severe forms of the urea cycle disorders
(eg, carbamyl phosphate synthetase 1 [CPS1] deficiency, OTC deficiency), liver transplantation before 1 year
of age is associated with better survival into the childhood years, with mild (rather than profound) mental
retardation.28
Specific Disorders
CPS1 deficiency blocks formation of carbamyl phosphate and has the classic presentation described above.
Orotic acid is a metabolite of carbamyl phosphate.
Thus, CPS1 deficiency is the only urea cycle disorder
without elevated urine orotic acid. Plasma amino acids
show decreased citrulline and arginine. Chronic management is as described above plus arginine supplementation. Prognosis is poor with neonatal presentations. Recurrent exacerbations occur even with optimal
therapy. Survivors are generally profoundly mentally
retarded. Initial presentation is usually in the neonatal
period but can be delayed into childhood. The outcome in later-onset cases can be milder but still includes mental retardation, motor deficits, and death.
OTC deficiency is identical to CPS1 deficiency in
presentation, except that urine orotic acids are elevated. Plasma amino acids show decreased citrulline and
arginine. Due to skewed X-inactivation, 15% of females
will develop hyperammonemia;29 many of these females
learn to avoid meat. A protein load can induce symptoms. The catabolic postpartum state can also provoke
a crisis. Chronic management involves protein restriction and oral sodium benzoate, phenylacetate, and citrulline supplementation. Prognosis is the same as for
CPS1 deficiency.
Citrullinemia is caused by a defect in argininosuccinic acid synthetase. The presentation is similar to that
of CPS1 deficiency, but prognosis for survivors of the
initial episode is somewhat better, with future exacerbations becoming easier to manage with age. A milder,
late-onset form of citrullinemia exists. Plasma amino
acids show elevated citrulline and reduced arginine.
Chronic management is the same as for CPS1 deficiency, but arginine supplementation is essential.
Argininosuccinic aciduria is caused by deficiency of
argininosuccinic acid lyase. Affected children may demonstrate failure to thrive, hepatomegaly, and unusual
hair, including alopecia and trichorrhexis nodosa.
Plasma amino acids show elevated citrulline with decreased arginine. Argininosuccinic acid is elevated in
plasma and present in urine. Treatment involves protein restriction and arginine supplementation. With
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age, acute episodes of hyperammonemia become less
frequent. Developmental delays are common even with
good compliance.
Argininemia is caused by a defect in arginase.
Argininemia is unique among the urea cycle disorders
in that it rarely causes acute hyperammonemic crisis.
Ammonias may chronically be mildly elevated. Spasticity and developmental regression develop early in
childhood, often with cyclic vomiting, seizures, and failure to thrive. Children are often misdiagnosed as having cerebral palsy. Diagnosis is based on elevated arginine in plasma, although levels can be normal in the
immediate newborn period. Treatment involves an
arginine-restricted diet. The prognosis includes mental
retardation, seizures, and spastic diparesis.
DISORDERS OF CARBOHYDRATE METABOLISM
GALACTOSEMIA
Galactosemia results from a deficiency in galactose1-phosphate uridyltransferase.30 Neonates present with
vomiting, poor feeding, and lethargy following the initiation of breast or bottle feeding. Jaundice and hepatomegaly are seen, and simultaneous Escherichia coli sepsis
is associated. Untreated infants develop profound mental retardation and, often, renal failure. Lenticular cataracts develop after only 1 month if untreated. Those
with suboptimal control are at risk for behavioral and
learning problems. Even with good dietary control,
patients may have subtle cognitive delays or learning
disabilities. Action tremor may become a prominent
complaint, refractory to medical therapy. Females are at
risk for premature ovarian failure, even if treated. The
diagnosis is suggested by finding reducing substances in
urine and confirmed by elevations in serum galactose1-phosphate. Treatment is based on dietary restriction
of galactose.
CONGENITAL DISORDERS OF GLYCOSYLATION
Congenital disorders of glycosylation (CDG, formerly called carbohydrate-deficient glycoprotein syndrome) are a heterogeneous group of mostly autosomal recessive disorders with deficient glycosylation of
glycoproteins.31 CDG Ia is the most common type and
involves deficiency of phosphomannomutase. CDG Ib
is unique in presenting as hypoglycemia and proteinlosing enteropathy, without neurologic features. CDG
as a group is suggested in an infant or a child with some
combination of failure to thrive, stroke-like episodes, a
clotting or bleeding tendency, hypotonia, psychomotor
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Metabolic Disorders in Pediatric Neurology
Table 6. Mucopolysaccharidoses (MPS)
Syndrome
Hurler’s
MPS Type
Features
Affected
Compound
IH
MR, CF, CC
Defect
Comments
DS, HS
α-L-iduronidase
Cardiac disease; motor weakness;
dysostosis multiplex
Scheie’s
IS
CF, CC
DS, HS
α-L-iduronidase
Dysostosis multiplex; milder than Hurler’s
Hurler-Scheie
IHS
CF, CC, ± MR
DS, HS
α-L-iduronidase
Intermediate between Hurler’s and Scheie’s
Hunter’s
II
MR, CF
DS, HS
Iduronate sulfatase
Motor weakness; aggressive
IIIA–D
MR
HS
Distinct for each type
Severe behavior problems; speech delay
IVA, IVB
CC, ± MR
KS and
CS (type A);
KS (type B)
Distinct for each type
Odontoid hypoplasia; bony abnormalities
Sanfilippo’s types A–D
Morquio’s types A
and B
CC = corneal clouding; CF = coarse facial features; CS = chondroitin sulfate; DS = dermatan sulfate; HS = heparan sulfate; KS keratan sulfate; MR =
mental retardation. (Adapted with permission from Nyhan WL, Ozand PT. Atlas of metabolic diseases. New York: Chapman and Hall; 1998:441.)
retardation, strabismus, retinitis pigmentosa, hypogonadism, ataxia, and cerebellar hypoplasia. There may
be inverted nipples and unusual fat deposits in the
suprapubic and supragluteal regions. Peripheral neuropathy may occur. Severity of symptoms is highly variable. Most adults are wheelchair bound. Diagnosis and
separation into subtypes is by transferrin electrophoresis. Coagulation studies may show deficiencies of factor
XI, proteins C and S, and antithrombin. Oral mannose
is effective in CDG Ib, but no treatment exists for the
other types of CDG.31
LAFORA’S DISEASE
Lafora’s disease is an autosomal recessive polyglucosan storage disorder that presents as myoclonic
seizures in the mid-teens, with rapid neurocognitive
deterioration. Neurons show Lafora bodies with a core
that stains very dark with periodic acid Schiff, with a
lighter outer halo. Skin, liver, or muscle biopsy can also
be diagnostic.32
LYSOSOMAL STORAGE DISORDERS
Lysosomes are involved in the degradation of large
molecules, including mucopolysaccharides, sphingolipids, sphingomyelin, and several others. Progressive
organomegaly, dysmorphism, and neurodegeneration
are typical.
MUCOPOLYSACCHARIDOSES
In the mucopolysaccharidoses (MPS), impaired degradation of various mucopolysaccharides (also known as glycosaminoglycans) cause variable combinations of coarse
facies, short stature, bony defects, stiff joints, mental retardation, hepatosplenomegaly, and corneal clouding. All
10 Hospital Physician Board Review Manual
forms of MPS are autosomal recessive except MPS type II
(Hunter’s syndrome), which is X-linked recessive. Neonates appear normal. Onset of disease is insidious. Other
features are listed in Table 6. Urinary testing for MPS suggests the diagnosis, which is confirmed by enzyme assays
from leukocytes or fibroblasts.
SPHINGOLIPIDOSES
The sphingolipidoses involve abnormal metabolism
and accumulation of sphingolipids. Deficiency of hexosaminidase A alone results in GM2 gangliosidosis, the
classic form of which is Tay-Sachs disease. Tay-Sachs disease is more common in Ashkenazi Jews than in the general population and is autosomal recessive. Onset of symptoms is between 3 and 6 months of age. The initial sign is
an excessive startle reflex. A macular cherry red spot
(Table 1) almost always is present at this stage, and psychomotor regression then begins. By age 1 year, the child
is unresponsive and spastic. Seizures and macrocephaly
soon follow, and most children die between 4 and 5 years
of age. Late-onset GM2 gangliosidosis, also more common in Ashkenazi Jews, presents in childhood and adulthood. Symptoms include weakness, personality change,
tongue atrophy and fasciculations, tremor, and mixed
upper and lower motor neuron signs. Dysarthria, ataxia,
and progressive spasticity and dementia follow. A cherry
red macula is not present in late-onset disease. Diagnosis
of both forms of GM2 gangliosidosis is by assays of hexosaminidase A activity in serum, leukocytes, or cultured
fibroblasts. No treatment is available.
SANDHOFF’S DISEASE
Sandhoff’s disease is a rare autosomal recessive disorder caused by deficiencies in both hexosaminidase A
and B. It is not more prevalent in Ashkenazi Jews.
Clinical features are identical to those of Tay-Sachs
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Metabolic Disorders in Pediatric Neurology
disease, with additional findings of hepatosplenomegaly and bony deformities. Diagnosis is by enzyme assays
of hexosaminidase. Foamy histiocytes are sometimes
seen in bone marrow. No treatment is available.
FABRY’S DISEASE
Fabry’s disease is an X-linked recessive disorder
caused by α-galactosidase deficiency. Presentation is usually during adolescence or early adulthood, with painful
crises in the extremities and paresthesias. Angiokeratomas and gastrointestinal complaints are often present.
There is an increased risk for stroke, heart disease, renal
failure, pulmonary complications, and hearing loss. Intelligence is normal. Diagnosis is by enzyme assay showing decreased activity. α-Galactosidase replacement therapy is available and appears promising.33
NIEMANN-PICK DISEASE
Niemann-Pick Type A
Niemann-Pick type A is caused by sphingomyelinase
deficiency, which results in accumulation of lipids,
mainly sphingomyelin. Infants are normal at birth but
develop feeding problems, hepatomegaly, and psychomotor regression in the first several months of life. In
half of the cases, children have macular cherry red
spots. Opisthotonus and hyperreflexia are common,
whereas seizure is uncommon. Death occurs between
ages 2 and 4 years. Diagnosis is based on enzyme assay.
Foamy cells are observed in bone marrow and blood.
Niemann-Pick Type C
Niemann-Pick type C is an autosomal recessive disorder that may present in neonates as severe liver or lung
disease or in children as upgaze palsy or apraxia, ataxia,
seizures, dementia, dysarthria, dysphagia, and dystonia.
Adults present with psychiatric symptoms. Diagnosis is
suggested by finding impaired cholesterol esterification
and is confirmed by genetic testing for the NPC1 and
NPC2 genes. Foamy cells are observed in the liver,
spleen, and marrow. Sea-blue histocytes are seen in the
marrow in advanced disease. Cholesterol-lowering
drugs reduce cholesterol levels, but no treatment
improves neurologic symptoms.34
PEROXISOMAL BIOGENESIS DISORDERS
Peroxisomes degrade very-long-chain fatty acids (C24,
C26). The classic peroxisomal biogenesis disorder is
Zellweger’s syndrome (cerebrohepatorenal syndrome),
an autosomal recessive disorder caused by deficiency of
multiple proteins responsible for peroxisomal assembly.
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A
B
Figure 4. Alexander’s disease in a 5-year-old boy with macrocephaly. (A) T2-weighted magnetic resonance image shows symmetric demyelination in the frontal lobe white matter, including
the subcortical U fibers. (B) Photomicrograph (original magnification, ×100; hematoxylin and eosin stain) of the pathologic specimen shows deposition of Rosenthal fibers (arrows). (Adapted with
permission from Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in children: a pictorial review of MR imaging features. Radiographics 2002;22:473. Radiological Society of North America.)
Zellweger’s syndrome presents at birth as severe hypotonia, high forehead, wide-open fontanelles, hepatomegaly,
and hyporeflexia. Intractable seizures, liver dysfunction,
renal cysts, cardiac defects, retinal dystrophy, and sensorineural hearing loss are common. Brain MRI demonstrates severe hypomyelination of the hemispheres, with
neuronal migrational defects (eg, polymicrogyria, pachygyria, periventricular heterotopias). Plasma very-longchain fatty acids (C26:0 and C26:1) are elevated. After the
neonatal period, phytanic acid also is elevated. Specific
genetic testing is available for 6 known mutations, the
most common affecting the PEX1 gene. The majority of
affected infants die in the first year. Severe psychomotor
retardation develops in survivors.35
Milder presentations of peroxisomal biogenesis
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Metabolic Disorders in Pediatric Neurology
disorders include neonatal adrenoleukodystrophy (not
related to X-linked adrenoleukodystrophy, which is discussed below) and Refsum disease. Both conditions
can present in infancy or childhood as hypotonia, developmental delay, vitamin K–responsive bleeding tendency (due to liver dysfunction), sensorineural hearing
loss, retinitis pigmentosa, neuropathy, and ataxia. The
spectrum is continuous with no simple phenotypegenotype correlations, and diagnosis can be delayed
into late adulthood.35
WHITE MATTER DISORDERS
White matter disorders classically present as progressive spasticity and neurocognitive regression. Hypotonia is
characteristic in the neonatal period, whereas psychiatric
disturbance is typical in children and adults. Discussed
below are vanishing white matter disorder, Alexander’s
disease, metachromatic leukodystrophy, PelizaeusMerzbacher disease, X-linked adrenoleukodystrophy,
Canavan’s disease, and Krabbe’s disease.36,37 A useful
mnemonic for recalling these disorders is VAMPACK.
VANISHING WHITE MATTER DISEASE
Vanishing white matter disease (childhood ataxia with
central hypomyelination) is an autosomal recessive disorder that usually presents in children age 2 to 6 years as
slowly progressive cerebellar ataxia, spasticity, variable
optic atrophy, and relatively preserved cognitive abilities.38
Infections and minor head trauma may lead to altered
level of consciousness, developing into coma. Brain MRI
shows progressive loss of white matter diffusely with cystic
degeneration. CSF may show elevated glycine. Lateronset (including adult-onset) disease has been described
and is associated with a milder clinical course. Mutations
have been found in genes that encode eukaryotic initiation factor 2B (eIF2B) subunits, which in turn may affect
the regulation of protein synthesis during cellular stress.39
ALEXANDER’S DISEASE
Alexander’s disease classically presents at approximately 6 months of age as megalencephaly, progressive
spasticity, seizures, and developmental regression. Death
is common in infancy and usually occurs before age
10 years. Brain MRI shows frontally dominant demyelination involving the subcortical U fibers and contrast
enhancement in the deep frontal white matter, basal ganglia, and periventricular rim. Pathology shows astrocytic
intracytoplasmic inclusion bodies called Rosenthal fibers
(Figure 4). More than 30 mutations of genes encoding
the glial fibrillary acidic protein (GFAP) have been iden-
12 Hospital Physician Board Review Manual
tified in association with Alexander’s disease. GFAP is a
major component of Rosenthal fibers. Juvenile- and
adult-onset forms of Alexander disease have a milder
course, with no macrocephaly or cognitive decline but
with a higher incidence of bulbar signs, ataxia, and positive family history. Demyelination in late-onset disease is
seen posteriorly rather than anteriorly.40,41
METACHROMATIC LEUKODYSTROPHY
Metachromatic leukodystrophy (sulfatide lipidosis) is
an autosomal recessive disorder usually caused by deficiency of arylsulfatase A and, less commonly, by deficiency of the sphingolipid activator protein, saposin B.
Sulfatides then accumulate, leading to myelin destabilization. The late infantile form is most common, with
onset after 1 year of age. This form is characterized by
ataxia, hypotonia, and peripheral neuropathy, followed
later by progressive spasticity and cognitive decline. In
the juvenile and adult forms, central nervous system
(CNS) symptoms are more prominent, with behavioral
disturbances, spasticity, and cognitive decline. Brain MRI
shows demyelination of periventricular white matter symmetrically, with involvement of the corpus callosum, early
sparing of the subcortical U fibers, and late atrophy.
There is no enhancement with contrast. A tigroid pattern
with patchy white matter sparing (formerly thought
pathognomic for Pelizaeus-Merzbacher disease) and a
leopard skin pattern have been described. In this case,
the islands of normal-appearing white matter may enhance with contrast, but the demyelinated patches do
not (Figure 5). Diagnosis is by testing for arylsulfatase A
activity. Bone marrow transplantation may be beneficial
in mildly affected patients with late-onset disease.
PELIZAEUS-MERZBACHER DISEASE
Pelizaeus-Merzbacher disease classically presents as
neonatal nystagmus, choreoathetosis, progressive ataxia, spasticity, and developmental regression, with death
often between 5 and 7 years of age. The spasticity may
affect the legs preferentially. The nystagmus can sometimes resolve. Milder cases present later, and children
who present after 1 year of age may live into adulthood.
Brain MRI shows diffusely deficient myelination of the
cerebral hemispheres, with a thin corpus callosum and
atrophy of white matter. Histopathology of early disease
shows patches or stripes of perivascular white matter
sparing, resulting in a tigroid pattern, sometimes also
visible on MRI (Figure 5). The etiology is duplication or
mutation of the proteolipid protein 1 (PLP1) gene on
the X chromosome, resulting in over- or underproduction of proteolipid protein. Diagnosis is by detecting
duplication or mutation of the PLP1 gene.
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Metabolic Disorders in Pediatric Neurology
Figure 5. Metachromatic leukodystrophy. T2-weighted magnetic resonance image shows numerous tubular structures with
low-signal intensity in a radiating (“tigroid”) pattern within the
demyelinated deep white matter. Note sparing of subcortical
U fibers. (Adapted with permission from Cheon JE, Kim IO,
Hwang YS, et al. Leukodystrophy in children: a pictorial review
of MR imaging features. Radiographics 2002;22:464. Radiological
Society of North America.)
X-LINKED ADRENOLEUKODYSTROPHY
X-Linked adrenoleukodystrophy presents between 5
and 8 years of age as a subacute onset of behavioral
problems, visual loss, hyperpigmented skin, and adrenal insufficiency, leading to progressive spasticity, optic
atrophy, late seizures, and eventual vegetative state.
Death is typical by 3 years after diagnosis. Brain MRI
shows demyelination, which begins in the splenium of
the corpus callosum and spreads in a posterior to anterior pattern. The leading edge of demyelination enhances with contrast (Figure 6). The defect is in the
ABCD1 gene, which codes for a peroxisomal membrane ATP-binding cassette protein transporter. As a
result, very-long-chain fatty acids are not degraded
and, thus, accumulate. Diagnosis is suggested by MRI
findings and by elevated very-long-chain fatty acids in
blood, especially C26:0 but not C26:1 (elevated C26:0
plus C26:1 suggests Zellweger’s syndrome).
CANAVAN’S DISEASE
Canavan’s disease (spongiform leukodystrophy) is an
autosomal recessive disorder that presents at 2 to
4 months of age as megalencephaly and hypotonia, leading to developmental regression, progressive spasticity,
and seizures. Brain MRI shows diffuse demyelination that
begins in subcortical and cerebellar white matter, later
involving central white matter (Figure 7). The globus pal-
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A
B
Figure 6. X-Linked adrenoleukodystrophy in a 5-year-old boy.
(A) T2-weighted magnetic resonance image (MRI) shows symmetric confluent demyelination in the peritrigonal white matter
and the splenium of the corpus callosum. (B) Gadoliniumenhanced T1-weighted MRI reveals enhancement of the leading edge of active demyelination and inflammation (arrows).
(Adapted with permission from Cheon JE, Kim IO, Hwang YS,
et al. Leukodystrophy in children: a pictorial review of MR imaging features. Radiographics 2002;22:467. Radiological Society
of North America.)
lidi and thalami are involved, but the caudate is spared.
MR spectroscopy shows a large N-acetylaspartic acid
(NAA) peak. The deficiency is in aspartoacylase. Diagnosis is by finding large quantities of NAA in urine.
KRABBE’S DISEASE
Krabbe’s disease (globoid cell leukodystrophy) is an
autosomal recessive disorder that presents at 1 to
7 months of age as irritability and hyperreactive startle.
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Metabolic Disorders in Pediatric Neurology
Figure 7. Canavan’s disease in a 6-month-old boy with macrocephaly. T2-weighted magnetic resonance image shows extensive
high-signal intensity areas throughout the white matter. Note
involvement of the subcortical U fibers. (Adapted with permission
from Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in children: a pictorial review of MR imaging features. Radiographics
2002;22:472. Radiological Society of North America.)
Developmental regression, spasticity, areflexia, startle
myoclonus, seizures, and blindness follow. Most affected
infants die by 1 year of age. Brain MRI shows diffuse
demyelination beginning in deep white matter, later involving subcortical white matter. Computed tomography
shows calcification in basal ganglia, thalami, and corona
radiata. CSF shows elevated proteins. Motor nerve conduction velocities are prolonged. Diagnosis is by demonstrating deficient galactocerebroside β-galactosidase activity in leukocytes or cultured fibroblasts.
GRAY MATTER DISORDERS
Gray matter disorders classically present as seizures
and loss of function of affected cortex. Prototypical gray
matter disorders include Tay-Sachs disease (discussed
previously) and the neuronal ceroid lipofuscinoses.
The neuronal ceroid lipofuscinoses (NCLs) are a
heterogeneous group of inherited neurodegenerative
lysosomal storage disorders presenting as some combination of visual loss, behavioral change, movement disorder, and seizures, especially myoclonic seizures.42
The infantile, late infantile, and juvenile forms are
more likely to be accompanied by retinal blindness.
The adult form is usually not associated with visual loss.
Those affected by the infantile form are normal at
birth. Onset of seizures and visual loss occurs within
2 years and death is typical by age 10 years. In the late
infantile form, initial symptoms are seizures between
14 Hospital Physician Board Review Manual
ages 2 and 4 years, followed by developmental regression, dementia, pyramidal and extrapyramidal signs,
and visual loss; death occurs between ages 6 and
30 years. The juvenile form presents between ages 4
and 10 years as rapidly progressive visual loss leading to
total blindness within 2 to 4 years; seizures begin
between ages 5 and 18 years and death occurs in the
teens to thirties. The adult-onset form presents in the
thirties, resulting in death within 10 years. All of the
NCLs are autosomal recessive except the adult form,
which is autosomal dominant. The genes involved are
PPT1 (at locus CLN1), CLN2 through CLN6, and
CLN8. PPT1 defects can present at any age, whereas
CLN3 and CLN4 present in children and adults.
Electron microscopy of lymphocytes, skin, conjunctiva,
or anal mucosa shows fingerprint, curvilinear, or granular osmiophilic deposits. More specific enzyme assays
and genetic testing are available. Treatment is supportive. Seizures may be worsened by phenytoin and carbamazepine. Lamotrigine may be the most efficacious
and best-tolerated anticonvulsant. Trihexyphenidyl improves dystonia and sialorrhea.42
OTHER METABOLIC DISORDERS
SMITH-LEMLI-OPITZ SYNDROME
Smith-Lemli-Opitz syndrome is caused by deficiency
of 7-dehydrocholesterol reductase, which leads to impaired cholesterol synthesis. Patients have ptosis, anteverted nares, micrognathia, microcephaly, hypospadias,
and cardiac defects. Syndactyly of the second and third
toes is almost always present. Presentation is that of
poor growth and developmental delay. Diagnosis is
based on elevations of 7-dehydrocholesterol and decreased serum cholesterol. Management is with cholesterol supplementation.
LESCH-NYHAN SYNDROME
Lesch-Nyhan syndrome is an X-linked recessive disorder caused by deficiency of hypoxanthine-guanine
phosphoribosyl transferase (HPRT), an enzyme involved in the metabolism of purines. This defect leads
to hyperuricemia and increased urinary excretion of
uric acid. Most neonates are normal until 3 months of
age, when they demonstrate hypotonia and global
developmental delay. By age 1 to 2 years, choreoathetosis and dystonia are apparent, and by age 2 to 3 years,
the characteristic severe self-mutilating behavior is
apparent. Most children never learn to walk. Renal failure due to urate deposition and gouty arthritis occur
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Metabolic Disorders in Pediatric Neurology
later in life. Diagnosis is suggested by an elevated uric
acid-to-creatinine ratio. Confirmation is by HPRT activity. Treatment with allopurinol does not improve the
neurologic outcome.43
MENKES’ SYNDROME
Menkes’ (kinky hair) syndrome is an X-linked recessive disorder of copper transport resulting in low serum
copper levels, decreased intestinal copper absorption,
and reduced activity of copper-dependent enzymes.
Affected males develop normally during the first months
of life, but development then slows and regression occurs.
Myoclonic seizures in response to stimulation are an early
and almost constant feature. Dysautonomia occurs. The
hair takes on a brittle, steel wool appearance. Other findings on examination include skin laxity, sagging jowls, and
hypotonia. Cerebral vessels are often tortuous and narrowed. Ischemic infarcts and subdural hematomas can
occur. Death usually occurs before age 3 years. Laboratory
evaluation shows low serum copper and ceruloplasmin.
CSF and plasma catecholamines are abnormal. Molecular
testing is available. Treatment involves subcutaneous or
intravenous copper administration. Results are variable,
possibly because of poor CNS penetration.44
WILSON’S DISEASE
Wilson’s disease is an autosomal recessive disorder
with defective copper transporting ATPase that results in
impaired binding of copper to ceruloplasmin and impaired excretion of copper into bile. Copper accumulates in the liver, and patients present with liver or CNS
disease. CNS symptoms include tremor, chorea, dystonia,
dysarthria, psychiatric disturbance, and cognitive impairment. Liver disease is more common in children, with
fulminant liver failure described in preschool-age children.45 CNS disease with mild liver disease more typically
is seen in teens and adults. Laboratory studies show low
serum copper and ceruloplasmin and elevated urinary
copper. Copper deposition in Descemet’s membrane is
seen on slit-lamp examination (Kayser-Fleischer rings).
Kayser-Fleischer rings and low serum ceruloplasmin are
found in more than 90% of those presenting with CNS
disease but may be absent in those with liver disease. MRI
shows symmetric lesions in basal ganglia, thalamus, and
brainstem that are bright on T2-weighted sequences.
Asymmetric lesions may be seen in white matter.46,47
Genetic testing is available. Traditional treatment is with
a copper chelator (ie, penicillamine or trientine). Trientine plus zinc, which impairs copper absorption from the
gut, may work as well as penicillamine and is better tolerated.48 Tetrathiomolybdate, a promising investigational
drug that impairs copper absorption in the gut and binds
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copper in blood, works faster than zinc and is also better
tolerated than penicillamine.49
OTHER
Pyridoxine-dependent epilepsy presents as neonatal
seizures that respond only to pyridoxine.50 Biotinidase
deficiency presents as seizures later in infancy to early
childhood, which respond to biotin.51 Glucose transporter 1 (GLUT-1) deficiency syndrome presents between 1 and 4 months of age as refractory seizures,
acquired microcephaly, ataxia, and low CSF glucose.
Symptoms are due to defective transport of glucose
across the blood-brain barrier. Seizures respond to a
ketogenic diet.52,53
ACKNOWLEDGEMENT
We thank Justin Stahl, MD, for the white matter mnemonic VAMPACK. We thank Gregg Nelson, MD, for helpful comments and for Table 2.
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16 Hospital Physician Board Review Manual
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