NEUROLOGY BOARD REVIEW MANUAL
Metabolic Disorders in
The Hospital Physician Neurology Board Review
Manual is a study guide for residents and
practicing physicians preparing for board
examinations in neurology. Each quarterly Editor: Catherine Gallagher, MD
manual reviews a topic essential to the cur- Assistant Professor of Neurology, University of Wisconsin Movement
rent practice of neurology. Disorders Program, Staff Physician, Middleton VA Hospital,
PUBLISHING STAFF Madison, WI
PRESIDENT, GROUP PUBLISHER Contributors:
Bruce M. White
Gregory M. Rice, MD
EDITORIAL DIRECTOR Fellow in Clinical and Biochemical Genetics, Departments of Medical
Debra Dreger Genetics and Pediatrics, University of Wisconsin, Madison, WI
Rita E. Gould
David Hsu, MD, PhD
Assistant Professor of Neurology, Department of Neurology, University
EXECUTIVE VICE PRESIDENT of Wisconsin, Madison, WI
Barbara T. White
OF OPERATIONS Table of Contents
Jean M. Gaul
PRODUCTION DIRECTOR Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Suzanne S. Banish
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
Lysosomal Storage Disorders . . . . . . . . . . . . . . . . . . . . . 10
SALES & MARKETING MANAGER
Deborah D. Chavis Peroxisomal Biogenesis Disorders . . . . . . . . . . . . . . . . . 11
NOTE FROM THE PUBLISHER:
White Matter Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 12
This publication has been developed without
Gray Matter Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 14
involvement of or review by the American
Board of Psychiatry and Neurology. Other Metabolic Disorders . . . . . . . . . . . . . . . . . . . . . . . 14
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Endorsed by the
Association for Hospital
Medical Education Cover Illustration by Kathryn K. Johnson
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www.turner - white.com 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 DISORDERS CAUSED BY ENERGY FAILURE
This manual reviews metabolic diseases that affect
the nervous system, focusing on the usual presentations GLYCOGEN STORAGE DISORDERS (GSD)
from the perspective of a pediatric neurologist. Many of Glycogen is an important source of stored glucose
these disorders also have milder presentations in later found primarily in liver and muscle. Defects in glycogen
life, which are not discussed here. This review presents mobilization can lead to energy failure during times of
sufficient information to begin a workup and to insti- fasting and exercise.
tute initial interventions. A beginning neurologist will
need to learn more about each disorder as he or she GSD Type II
closes in on the definitive diagnosis. If a diagnosis is not GSD type II (Pompe’s disease) is caused by deficiency of
readily apparent by clinical presentation (Table 1), one the lysosomal enzyme acid maltase (α-1-4-glucosidase).1
must resort to a more systematic approach. The infantile form presents as severe hypotonia and car-
In this review, disorders are generally grouped diomyopathy and is usually fatal before 12 months of age.
according to defects of the various biochemical path- The childhood form affects only skeletal muscle and pre-
ways (Figure 1). Metabolic disorders caused by energy sents as progressive weakness. Creatine kinase (CK) levels
failure can involve defects in the mobilization of glyco- are markedly elevated, and muscle biopsy demonstrates
gen (ie, glycogen storage diseases) or fats (ie, fatty acid oxi- glycogen storage in muscle fibers and absence of acid mal-
dation defects) or defects in the citric acid cycle or respi- tase. Hypoglycemia is not seen in GSD type II.
ratory chain (ie, mitochondrial disorders). These disorders
tend to present as decompensations with stress or in- GSD Type V
creased energy demand. Metabolic disorders caused by GSD type V (McArdle’s disease) is caused by defi-
defects in amino acid metabolism include the organic ciency of myophosphorylase and presents in adolescents
acidemias, aminoacidopathies, and urea cycle defects. These as cramps and muscle fatigue shortly after initiating
disorders tend to present in infancy as increasing lethar- exercise. A “second wind” effect can occur (ie, renewed
gy and vomiting with initiation of feeds. Lysosomal disor- ability to continue exercising if patients rest briefly after
ders result in the accumulation of large carbohydrate– the onset of fatigue). Laboratory studies show elevated
lipid complexes and present as dysmorphism with CK levels, post-exertional myoglobinuria, and a failure
organomegaly, psychiatric symptoms, or white matter of the normal rise in lactate levels with exercise. The
disease. Aside from the glycogen storage disorders, the forearm ischemic test is the classic exercise test but is dif-
disorders of carbohydrate metabolism are rather heteroge- ficult to perform reliably. Muscle biopsy shows glycogen
neous. Finally, some primarily white matter disorders are storage in muscle and absence of myophosphorylase.
suggested by clinical presentation, such as increasing Moderate exercise with careful warmup is advisable.
spasticity and abnormalities in white matter on mag- Dietary treatments have been disappointing.
netic resonance imaging (MRI), whereas primarily gray
matter disorders present as seizures and cognitive decline. FATTY ACID OXIDATION DISORDERS
In the United States, most states screen newborns for Fatty acid oxidation disorders consist of autosomal
phenylketonuria, galactosemia, hypothyroidism, con- recessive defects in either the transport of fatty acids into
genital adrenal hyperplasia, hemoglobinopathies, and mitochondria or in the intramitochondrial β-oxidation
maple syrup urine disease. Some states employ tandem of fatty acids. A prolonged fast or significant stress (eg, ill-
mass spectroscopy, which gives amino acid and acylcar- ness, surgery) may deplete liver stores of glycogen. If fatty
nitine profiles. These tests are useful for diagnosing stores fail to be mobilized for fuel, the result is the classic
many metabolic disorders, as described below. 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, encephalomyelopa- VLCAD deficiency Myoclonic epilepsy with ragged red fibers
thy, and lactic acidosis with stroke-like LCHAD deficiency (MERRF)
episodes (MELAS) Unverricht-Lundborg disease (Baltic
Carnitine transporter deficiency
Infantile CPT2 deficiency
Propionic acidemia Neuronal ceroid lipofuscinosis
GSD II (Pompe’s disease)
Methylmalonic acidemia Lafora’s disease
GSD III (Cori’s disease)
Isovaleric acidemia Sialidosis type 1
Glutaric acidemia type I Psychiatric/behavioral change
Cherry red spots on the macula
Urea cycle disorders Wilson’s disease
Congenital disorders of glycosylation Neuronal ceroid lipofuscinosis
Menkes’ syndrome X-Linked adrenoleukodystrophy
Fabry’s disease Juvenile- and adult-onset metachromatic
Leigh disease leukodystrophy
Electron transport chain defects Late-onset GM2 gangliosidosis
Multiple sulfatase deficiency
Pyruvate dehydrogenase complex deficiency Lesch-Nyhan syndrome
Biotinidase deficiency Porphyria (episodic)
GSD type V (McArdle’s disease)
Reye-like syndrome Urea cycle disorders (episodic)
Adult CPT2 deficiency
Fatty acid oxidation disorders Sanfilippo’s syndrome (mucopolysaccharido-
VLCAD deficiency sis III)
Urea cycle disorders
LCHAD deficiency Hunter’s syndrome (mucopolysaccharidosis II)
Carnitine transporter deficiency
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 Carbohydrates
especially sensitive to fatty acid oxidation defects include Glycogen
the brain (which depends on ketones for fuel in the fast- Galactose Glucose-6-P
ed state), the heart and muscles (due to high metabolic
Fructose Amino acids Fatty acids
demand and because fatty fuels spare proteolysis), and
the liver (which relies on energy derived from fatty acid NH3 Urea
oxidation for gluconeogenesis and ureagenesis). Man- Pyruvate Lactate Urea
agement for all fatty acid oxidation disorders includes cycle
avoiding prolonged fasts and aggressive use of dextrose- Acetyl CoA
containing fluids during decompensations. β-oxidation
Carnitine must bind to long-chain fatty acids for fatty cycle
acid transport across the mitochondrial double mem-
brane. Carnitine enters the cell through a carnitine ATP ADP
transporter. It is bound to the fatty acyl group by carni- Mitochondrion Respiratory chain
tine palmitoyl transferase 1 (CPT1) at the outer mito-
chondrial membrane. Acylcarnitine is then transported Figure 1. Basic pathways of intermediary metabolism. Glucose-
to the inner mitochondrial membrane by acylcarnitine 6-P = glucose-6-phosphate. (Adapted with permission from
translocase. At the inner mitochondrial membrane, acyl- Hoffmann GF, Nyhan WL, Zschocke J. Inherited metabolic dis-
carnitine is disassembled into acyl coenzyme A (CoA) eases. Philadelphia: Lippincott Williams & Wilkins; 2002:6.)
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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Metabolic Disorders in Pediatric Neurology
Table 2. Carnitine-Associated and Fatty Acid Disorders
Acylcarnitine Age of Tissue
Deficiency Total Free (F) Esters (E) E:F Ratio Profile Onset Affected
Transporter ↓↓ ↓ ↓↓ < 0.3 (nl) ↓All esters I/C H/M/L
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 dehydro- form presents in the teens to twenties as episodic rhab-
genases, which are distinct depending on the acyl group domyolysis and myoglobinuria with elevated CK levels
chain length. following prolonged exercise, cold exposure, infection,
Carnitine also acts as a scavenger of potentially toxic or fasting.
acyl CoA metabolites, forming acylcarnitine esters that
are excreted in the urine. A secondary carnitine defi- Disorders of β-Oxidation and Ketogenesis
ciency results when urinary acylcarnitine loss is ex- Medium-chain acyl CoA dehydrogenase (MCAD)
cessive. Blood carnitine levels then show an elevated deficiency is the most common of the fatty acid oxida-
acylcarnitine ester-to-free carnitine ratio (ie, > 0.4).2 Val- tion disorders. MCAD helps metabolize medium-chain
proic acid therapy can cause secondary carnitine defi- fatty acids to ketones, which are used as fuel during
ciency in this way by forming valproyl carnitine ester. times of stress and fasting. Acute presentation consists
Screening laboratory tests include plasma free and of lethargy, vomiting, seizure, and progressive enceph-
total carnitines, plasma acylcarnitine profile, and urine alopathy after fasting or physical stress. An initial attack
acylglycines. Laboratory findings are summarized in may result in sudden infant death. Management in-
Table 2. Interpretation of urine acylglycines is complex cludes moderate dietary fat restriction and carnitine
and is omitted in this review. supplementation.
Very-long-chain acyl CoA dehydrogenase (VLCAD)
Carnitine Disorders deficiency and long-chain 3-hydroxy acyl CoA dehy-
Carnitine transporter deficiency leads to total body drogenase (LCHAD) deficiency are associated with
carnitine depletion secondary to increased renal loss. cardiomyopathy, skeletal myopathy, post-exertional
Symptoms include muscle weakness and cardiomyopa- rhabdomyolysis, and hypoketotic hypoglycemia with de-
thy. Carnitine given in high doses reverses symptoms compensations. Children with VLCAD deficiency can pre-
and can be lifesaving.2 sent with a Reye-like syndrome, which can be fatal.
CPT1 deficiency presents as a Reye-like syndrome, Mothers carrying a fetus with LCHAD deficiency can pre-
with progressive encephalopathy, seizures secondary to sent with hemolysis, elevated liver function tests, and low
hypoglycemia, hepatomegaly, moderate hyperammo- platelet counts (HELLP syndrome). Diagnosis is by acyl-
nemia, and elevated liver enzymes. Skeletal and cardiac carnitine profile, which shows elevated long-chain acyl-
muscle are not involved. Acylcarnitine profile shows de- carnitines and hydroxy-acylcarnitines, respectively, in
creased long-chain acylcarnitines (C16, C18). Chronic patients with VLCAD deficiency and LCHAD deficiency.
treatment with medium-chain fatty acids may be of ben- Medium-chain triglycerides (MCT oil) are supplemented.
efit. Glutaric acidemia type II (multiple acyl CoA
CPT2 deficiency has an infantile (liver) and adult dehydrogenase deficiency) involves defects in the flavin
(muscle) form. The infantile form presents as hep- adenine dinucleotide (FAD)–dependent electron
atomegaly, liver failure, cardiomegaly, arrhythmias, and transfer from dehydrogenase enzymes to the electron
seizures, with hypoketotic hypoglycemia. The adult transport chain. This disorder affects both fatty acid
4 Hospital Physician Board Review Manual www.turner - white.com
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-year-
old 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 imag-
ing features. Radiographics 2002;22:470. Radiological Society of North America.)
Biochemical analysis of muscle can reveal decreases in Treatment involves supplementation with thiamine,
activity of the respiratory chain complexes I to IV. Elec- which is a cofactor for PDHC, and a high fat, low carbo-
tron microscopy shows overabundant, enlarged, and hydrate diet. Acetazolamide may abort attacks.17
bizarrely shaped mitochondria with paracrystalline inclu-
sions. Brain MRI may show lesions of the basal ganglia,
thalamus, midbrain, or cerebral white matter. In the cere- DISORDERS OF AMINO ACID METABOLISM
bral white matter, recurrent stroke-like events may occur,
with transitory migrating lesions that cross vascular terri-
tories (Figure 2). Magnetic resonance (MR) spectros- ORGANIC ACIDEMIAS
copy may show elevated lactate peaks in these lesions.12,13 Organic acidemias are caused by autosomal recessive
Impaired autoregulation of cerebral vasculature has disorders of amino acid metabolism. The usual presenta-
been suggested as the etiology of stroke-like events.14 tion is that of nonspecific poor feeding, lethargy, and vom-
iting in the neonatal period, eventually progressing to
Treatment coma. Symptoms are often initially mistaken for sepsis.
Treatment is with L-carnitine, B vitamins (riboflavin Laboratory findings include metabolic acidosis with an
and thiamine), and coenzyme Q or idebenone. Biotin, elevated anion gap, sometimes with ketosis and hyper-
antioxidants (vitamins A and C), folate, and lipoic acid ammonemia (Table 5). Diagnosis during the acute illness
are also used.15 Dichloroacetic acid may lower lactate depends on plasma amino acids, plasma acylcarnitine
levels in some patients.16 Response to treatment is vari- profile, urine organic acids, and urine acylglycine profile.
able, with some patients experiencing improvement in The detailed analysis of these profiles is often complex
energy and function but many experiencing no dis- and is not discussed here. Acute treatment involves with-
cernible improvement. holding protein feeds and aggressively pushing dextrose-
containing fluids, to induce an anabolic state. Chronic
PYRUVATE DEHYDROGENASE COMPLEX DEFICIENCY treatment consists of specific dietary protein restriction.
Pyruvate dehydrogenase complex (PDHC) deficien- Carnitine supplementation can be helpful.18
cy blocks entry of pyruvate into the citric acid cycle,
resulting in elevated lactate and pyruvate levels. PDHC Propionic Acidemia
deficiency presents similarly to the mitochondrial disor- Propionic acidemia is caused by a deficiency in propi-
ders. The severe neonatal form is fatal in infancy. Leigh onyl CoA carboxylase. Most children have some cognitive
disease can develop later in infancy. Diagnosis is based disability even with optimal therapy. Cardiomyopathy,
on finding elevated lactate and pyruvate levels with pancreatitis, osteoporosis, and movement disorders are
preservation of the lactate-to-pyruvate ratio (ie, < 20). late complications.
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Metabolic Disorders in Pediatric Neurology
UREA CYCLE DISORDERS
HCO3 + NH4 + 2 ATP Mitochondrion The urea cycle converts ammonia, which is a toxic
byproduct of protein metabolism, into urea (Figure 3).
Cytoplasm All urea cycle disorders are autosomal recessive with the
phosphate e e exception of ornithine transcarbamylase (OTC) defi-
tr ull ull ciency, which is X-linked.
Ornithine Similar to the organic acidemias, urea cycle disorders
ASS 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 pro-
Arginine gresses to coma, seizures, and death if left untreated.
Fumarate Cerebral edema (with a bulging fontanelle and tachy-
Figure 3. The urea cycle and its disorders. ARG = arginase defi- pnea) can occur early and progresses rapidly. Metabolic
ciency; ASL = argininosuccinic acid lyase deficiency; ASS = argin- strokes may also occur. All urea cycle disorders, with the
inosuccinic acid synthetase deficiency; CPSI = carbamyl phosphate exception of argininemia, are accompanied by hyperam-
synthetase I deficiency; OTC = ornithine transcarboxylase defi- monemia. Ammonia levels exceeding 200 µg/dL cause
ciency. (Adapted with permission from Summar ML, Tuchman M. lethargy and vomiting, levels greater than 300 µg/dL
Urea cycle disorders overview. GeneReviews. Available at www. result in coma, and levels exceeding 500 µg/dL cause
geneclinics.org/profiles/ucd-overview. Accessed 8 Apr 2005.) seizures.17 Any catabolic state, including the immediate
postnatal period before initiation of feeding, can provoke
a crisis because of associated proteolysis. Permanent neu-
patients are at risk for seizures, psychiatric disorders, and rologic sequelae can occur after a single crisis. Ammonia
thromboembolic events, including stroke, myocardial in- levels greater than 350 µg/dL26 and coma for longer than
farction, and pulmonary emboli.22 Treatment involves 3 days27 are correlated with death or profound mental
protein restriction; supplementation with vitamin B6, vit- retardation. Ammonia levels less than 180 µg/dL usually
amin B12, and folate; and stroke prophylaxis with aspirin. result in normal development or only mild mental retar-
dation.26 Milder forms, as seen with female carriers of
Nonketotic Hyperglycinemia OTC deficiency, can have a more subtle presentation.
Nonketotic hyperglycinemia (glycine encephalopa-
thy) is caused by a defect in glycine cleavage.23 This Treatment
defect results in elevated glycine levels in the blood, Hyperammonemia in an encephalopathic infant is a
urine, and cerebrospinal fluid (CSF). The neonatal medical emergency. In addition to determining ammo-
form presents as lethargy and poor feeding after the ini- nia levels and acid-base status, laboratory studies
tiation of protein feeds, quickly progressing to persistent should be ordered for electrolytes, calcium, glucose, lac-
seizures, encephalopathy, and coma. Apnea is common tate, liver enzymes, free and total carnitine, quantitative
and persistent hiccups have also been seen. Diagnosis plasma amino acids, and urine organic acids. Acute
depends on simultaneous measurement of CSF and management for all urea cycle disorders consists of
plasma glycine levels. A CSF-to-plasma glycine ratio (1) stopping all protein intake; (2) starting an intra-
greater than 0.06 supports this diagnosis.24 Acute man- venous infusion of 10% glucose plus lipid to promote
agement includes use of sodium benzoate to help nor- the anabolic state; and (3) starting arginine hydrochlo-
malize plasma glycine level. Dextromethorphan, an ride, sodium benzoate, and sodium phenylacetate with
NMDA (N-methyl-D-aspartate) receptor antagonist, may intravenous loading doses, followed by maintenance
be beneficial. Valproic acid, which inhibits metabolism infusions. Peritoneal dialysis or hemodialysis should be
of glycine, is contraindicated. The prognosis for the considered if there is clinical deterioration and ammo-
neonatal form is poor. Survivors often have spastic quad- nia levels are not responding. Chronic management
riplegia, intractable seizures, and severe mental retarda- typically includes protein restriction and oral sodium
tion. Infantile, childhood, and adult-onset forms exist benzoate and sodium phenylacetate supplementa-
but are uncommon; these forms have milder outcomes. tion.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 disor- age, acute episodes of hyperammonemia become less
der but does not reverse accumulated neurologic frequent. Developmental delays are common even with
injury. In the severe forms of the urea cycle disorders good compliance.
(eg, carbamyl phosphate synthetase 1 [CPS1] deficien- Argininemia is caused by a defect in arginase.
cy, OTC deficiency), liver transplantation before 1 year Argininemia is unique among the urea cycle disorders
of age is associated with better survival into the child- in that it rarely causes acute hyperammonemic crisis.
hood years, with mild (rather than profound) mental Ammonias may chronically be mildly elevated. Spastic-
retardation.28 ity and developmental regression develop early in
childhood, often with cyclic vomiting, seizures, and fail-
Specific Disorders ure to thrive. Children are often misdiagnosed as hav-
CPS1 deficiency blocks formation of carbamyl phos- ing cerebral palsy. Diagnosis is based on elevated argi-
phate and has the classic presentation described above. nine in plasma, although levels can be normal in the
Orotic acid is a metabolite of carbamyl phosphate. immediate newborn period. Treatment involves an
Thus, CPS1 deficiency is the only urea cycle disorder arginine-restricted diet. The prognosis includes mental
without elevated urine orotic acid. Plasma amino acids retardation, seizures, and spastic diparesis.
show decreased citrulline and arginine. Chronic man-
agement is as described above plus arginine supple-
mentation. Prognosis is poor with neonatal presenta- DISORDERS OF CARBOHYDRATE METABOLISM
tions. Recurrent exacerbations occur even with optimal
therapy. Survivors are generally profoundly mentally
retarded. Initial presentation is usually in the neonatal GALACTOSEMIA
period but can be delayed into childhood. The out- Galactosemia results from a deficiency in galactose-
come in later-onset cases can be milder but still in- 1-phosphate uridyltransferase.30 Neonates present with
cludes mental retardation, motor deficits, and death. vomiting, poor feeding, and lethargy following the ini-
OTC deficiency is identical to CPS1 deficiency in tiation of breast or bottle feeding. Jaundice and hepato-
presentation, except that urine orotic acids are elevat- megaly are seen, and simultaneous Escherichia coli sepsis
ed. Plasma amino acids show decreased citrulline and is associated. Untreated infants develop profound men-
arginine. Due to skewed X-inactivation, 15% of females tal retardation and, often, renal failure. Lenticular cata-
will develop hyperammonemia;29 many of these females racts develop after only 1 month if untreated. Those
learn to avoid meat. A protein load can induce symp- with suboptimal control are at risk for behavioral and
toms. The catabolic postpartum state can also provoke learning problems. Even with good dietary control,
a crisis. Chronic management involves protein restric- patients may have subtle cognitive delays or learning
tion and oral sodium benzoate, phenylacetate, and cit- disabilities. Action tremor may become a prominent
rulline supplementation. Prognosis is the same as for complaint, refractory to medical therapy. Females are at
CPS1 deficiency. risk for premature ovarian failure, even if treated. The
Citrullinemia is caused by a defect in argininosuc- diagnosis is suggested by finding reducing substances in
cinic acid synthetase. The presentation is similar to that urine and confirmed by elevations in serum galactose-
of CPS1 deficiency, but prognosis for survivors of the 1-phosphate. Treatment is based on dietary restriction
initial episode is somewhat better, with future exacerba- of galactose.
tions becoming easier to manage with age. A milder,
late-onset form of citrullinemia exists. Plasma amino CONGENITAL DISORDERS OF GLYCOSYLATION
acids show elevated citrulline and reduced arginine. Congenital disorders of glycosylation (CDG, former-
Chronic management is the same as for CPS1 deficien- ly called carbohydrate-deficient glycoprotein syn-
cy, but arginine supplementation is essential. drome) are a heterogeneous group of mostly autoso-
Argininosuccinic aciduria is caused by deficiency of mal recessive disorders with deficient glycosylation of
argininosuccinic acid lyase. Affected children may dem- glycoproteins.31 CDG Ia is the most common type and
onstrate failure to thrive, hepatomegaly, and unusual involves deficiency of phosphomannomutase. CDG Ib
hair, including alopecia and trichorrhexis nodosa. is unique in presenting as hypoglycemia and protein-
Plasma amino acids show elevated citrulline with de- losing enteropathy, without neurologic features. CDG
creased arginine. Argininosuccinic acid is elevated in as a group is suggested in an infant or a child with some
plasma and present in urine. Treatment involves pro- combination of failure to thrive, stroke-like episodes, a
tein restriction and arginine supplementation. With clotting or bleeding tendency, hypotonia, psychomotor
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Metabolic Disorders in Pediatric Neurology
Table 6. Mucopolysaccharidoses (MPS)
Syndrome MPS Type Features Compound Defect Comments
Hurler’s IH MR, CF, CC DS, HS α-L-iduronidase Cardiac disease; motor weakness;
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
Sanfilippo’s types A–D IIIA–D MR HS Distinct for each type Severe behavior problems; speech delay
Morquio’s types A IVA, IVB CC, ± MR KS and Distinct for each type Odontoid hypoplasia; bony abnormalities
and B CS (type A);
KS (type 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, hypogo- forms of MPS are autosomal recessive except MPS type II
nadism, ataxia, and cerebellar hypoplasia. There may (Hunter’s syndrome), which is X-linked recessive. Neo-
be inverted nipples and unusual fat deposits in the nates appear normal. Onset of disease is insidious. Other
suprapubic and supragluteal regions. Peripheral neu- features are listed in Table 6. Urinary testing for MPS sug-
ropathy may occur. Severity of symptoms is highly vari- gests the diagnosis, which is confirmed by enzyme assays
able. Most adults are wheelchair bound. Diagnosis and from leukocytes or fibroblasts.
separation into subtypes is by transferrin electrophore-
sis. Coagulation studies may show deficiencies of factor SPHINGOLIPIDOSES
XI, proteins C and S, and antithrombin. Oral mannose The sphingolipidoses involve abnormal metabolism
is effective in CDG Ib, but no treatment exists for the and accumulation of sphingolipids. Deficiency of hex-
other types of CDG.31 osaminidase A alone results in GM2 gangliosidosis, the
classic form of which is Tay-Sachs disease. Tay-Sachs dis-
LAFORA’S DISEASE ease is more common in Ashkenazi Jews than in the gen-
Lafora’s disease is an autosomal recessive poly- eral population and is autosomal recessive. Onset of symp-
glucosan storage disorder that presents as myoclonic toms is between 3 and 6 months of age. The initial sign is
seizures in the mid-teens, with rapid neurocognitive an excessive startle reflex. A macular cherry red spot
deterioration. Neurons show Lafora bodies with a core (Table 1) almost always is present at this stage, and psy-
that stains very dark with periodic acid Schiff, with a chomotor regression then begins. By age 1 year, the child
lighter outer halo. Skin, liver, or muscle biopsy can also is unresponsive and spastic. Seizures and macrocephaly
be diagnostic.32 soon follow, and most children die between 4 and 5 years
of age. Late-onset GM2 gangliosidosis, also more com-
mon in Ashkenazi Jews, presents in childhood and adult-
LYSOSOMAL STORAGE DISORDERS hood. Symptoms include weakness, personality change,
tongue atrophy and fasciculations, tremor, and mixed
Lysosomes are involved in the degradation of large upper and lower motor neuron signs. Dysarthria, ataxia,
molecules, including mucopolysaccharides, sphingo- and progressive spasticity and dementia follow. A cherry
lipids, sphingomyelin, and several others. Progressive red macula is not present in late-onset disease. Diagnosis
organomegaly, dysmorphism, and neurodegeneration of both forms of GM2 gangliosidosis is by assays of hex-
are typical. osaminidase A activity in serum, leukocytes, or cultured
fibroblasts. No treatment is available.
In the mucopolysaccharidoses (MPS), impaired degra- SANDHOFF’S DISEASE
dation of various mucopolysaccharides (also known as gly- Sandhoff’s disease is a rare autosomal recessive dis-
cosaminoglycans) cause variable combinations of coarse order caused by deficiencies in both hexosaminidase A
facies, short stature, bony defects, stiff joints, mental retar- and B. It is not more prevalent in Ashkenazi Jews.
dation, hepatosplenomegaly, and corneal clouding. All Clinical features are identical to those of Tay-Sachs
10 Hospital Physician Board Review Manual www.turner - white.com
Metabolic Disorders in Pediatric Neurology
disease, with additional findings of hepatosplenomeg-
aly 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 is an X-linked recessive disorder
caused by α-galactosidase deficiency. Presentation is usu-
ally during adolescence or early adulthood, with painful
crises in the extremities and paresthesias. Angiokera-
tomas and gastrointestinal complaints are often present.
There is an increased risk for stroke, heart disease, renal
failure, pulmonary complications, and hearing loss. In- A
telligence is normal. Diagnosis is by enzyme assay show-
ing decreased activity. α-Galactosidase replacement ther-
apy is available and appears promising.33
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 psycho-
motor regression in the first several months of life. In
half of the cases, children have macular cherry red
spots. Opisthotonus and hyperreflexia are common, B
whereas seizure is uncommon. Death occurs between Figure 4. Alexander’s disease in a 5-year-old boy with macro-
ages 2 and 4 years. Diagnosis is based on enzyme assay. cephaly. (A) T2-weighted magnetic resonance image shows sym-
Foamy cells are observed in bone marrow and blood. metric demyelination in the frontal lobe white matter, including
the subcortical U fibers. (B) Photomicrograph (original magnifica-
Niemann-Pick Type C
tion, ×100; hematoxylin and eosin stain) of the pathologic speci-
Niemann-Pick type C is an autosomal recessive disor- men shows deposition of Rosenthal fibers (arrows). (Adapted with
der that may present in neonates as severe liver or lung permission from Cheon JE, Kim IO, Hwang YS, et al. Leukodys-
disease or in children as upgaze palsy or apraxia, ataxia, trophy in children: a pictorial review of MR imaging features. Ra-
seizures, dementia, dysarthria, dysphagia, and dystonia. diographics 2002;22:473. Radiological Society of North America.)
Adults present with psychiatric symptoms. Diagnosis is
suggested by finding impaired cholesterol esterification
and is confirmed by genetic testing for the NPC1 and Zellweger’s syndrome presents at birth as severe hypoto-
NPC2 genes. Foamy cells are observed in the liver, nia, high forehead, wide-open fontanelles, hepatomegaly,
spleen, and marrow. Sea-blue histocytes are seen in the and hyporeflexia. Intractable seizures, liver dysfunction,
marrow in advanced disease. Cholesterol-lowering renal cysts, cardiac defects, retinal dystrophy, and sen-
drugs reduce cholesterol levels, but no treatment sorineural hearing loss are common. Brain MRI demon-
improves neurologic symptoms.34 strates severe hypomyelination of the hemispheres, with
neuronal migrational defects (eg, polymicrogyria, pachy-
gyria, periventricular heterotopias). Plasma very-long-
PEROXISOMAL BIOGENESIS DISORDERS chain fatty acids (C26:0 and C26:1) are elevated. After the
neonatal period, phytanic acid also is elevated. Specific
Peroxisomes degrade very-long-chain fatty acids (C24, genetic testing is available for 6 known mutations, the
C26). The classic peroxisomal biogenesis disorder is most common affecting the PEX1 gene. The majority of
Zellweger’s syndrome (cerebrohepatorenal syndrome), affected infants die in the first year. Severe psychomotor
an autosomal recessive disorder caused by deficiency of retardation develops in survivors.35
multiple proteins responsible for peroxisomal assembly. Milder presentations of peroxisomal biogenesis
www.turner - white.com Neurology Volume 9, Part 2 11
Metabolic Disorders in Pediatric Neurology
disorders include neonatal adrenoleukodystrophy (not tified in association with Alexander’s disease. GFAP is a
related to X-linked adrenoleukodystrophy, which is dis- major component of Rosenthal fibers. Juvenile- and
cussed below) and Refsum disease. Both conditions adult-onset forms of Alexander disease have a milder
can present in infancy or childhood as hypotonia, devel- course, with no macrocephaly or cognitive decline but
opmental delay, vitamin K–responsive bleeding tenden- with a higher incidence of bulbar signs, ataxia, and posi-
cy (due to liver dysfunction), sensorineural hearing tive family history. Demyelination in late-onset disease is
loss, retinitis pigmentosa, neuropathy, and ataxia. The seen posteriorly rather than anteriorly.40,41
spectrum is continuous with no simple phenotype-
genotype correlations, and diagnosis can be delayed METACHROMATIC LEUKODYSTROPHY
into late adulthood.35 Metachromatic leukodystrophy (sulfatide lipidosis) is
an autosomal recessive disorder usually caused by defi-
ciency of arylsulfatase A and, less commonly, by deficien-
WHITE MATTER DISORDERS cy of the sphingolipid activator protein, saposin B.
Sulfatides then accumulate, leading to myelin destabi-
White matter disorders classically present as progres- lization. The late infantile form is most common, with
sive spasticity and neurocognitive regression. Hypotonia is onset after 1 year of age. This form is characterized by
characteristic in the neonatal period, whereas psychiatric ataxia, hypotonia, and peripheral neuropathy, followed
disturbance is typical in children and adults. Discussed later by progressive spasticity and cognitive decline. In
below are vanishing white matter disorder, Alexander’s the juvenile and adult forms, central nervous system
disease, metachromatic leukodystrophy, Pelizaeus- (CNS) symptoms are more prominent, with behavioral
Merzbacher disease, X-linked adrenoleukodystrophy, disturbances, spasticity, and cognitive decline. Brain MRI
Canavan’s disease, and Krabbe’s disease.36,37 A useful shows demyelination of periventricular white matter sym-
mnemonic for recalling these disorders is VAMPACK. metrically, with involvement of the corpus callosum, early
sparing of the subcortical U fibers, and late atrophy.
VANISHING WHITE MATTER DISEASE There is no enhancement with contrast. A tigroid pattern
Vanishing white matter disease (childhood ataxia with with patchy white matter sparing (formerly thought
central hypomyelination) is an autosomal recessive disor- pathognomic for Pelizaeus-Merzbacher disease) and a
der that usually presents in children age 2 to 6 years as leopard skin pattern have been described. In this case,
slowly progressive cerebellar ataxia, spasticity, variable the islands of normal-appearing white matter may en-
optic atrophy, and relatively preserved cognitive abilities.38 hance with contrast, but the demyelinated patches do
Infections and minor head trauma may lead to altered not (Figure 5). Diagnosis is by testing for arylsulfatase A
level of consciousness, developing into coma. Brain MRI activity. Bone marrow transplantation may be beneficial
shows progressive loss of white matter diffusely with cystic in mildly affected patients with late-onset disease.
degeneration. CSF may show elevated glycine. Later-
onset (including adult-onset) disease has been described PELIZAEUS-MERZBACHER DISEASE
and is associated with a milder clinical course. Mutations Pelizaeus-Merzbacher disease classically presents as
have been found in genes that encode eukaryotic initia- neonatal nystagmus, choreoathetosis, progressive atax-
tion factor 2B (eIF2B) subunits, which in turn may affect ia, spasticity, and developmental regression, with death
the regulation of protein synthesis during cellular stress.39 often between 5 and 7 years of age. The spasticity may
affect the legs preferentially. The nystagmus can some-
ALEXANDER’S DISEASE times resolve. Milder cases present later, and children
Alexander’s disease classically presents at approxi- who present after 1 year of age may live into adulthood.
mately 6 months of age as megalencephaly, progressive Brain MRI shows diffusely deficient myelination of the
spasticity, seizures, and developmental regression. Death cerebral hemispheres, with a thin corpus callosum and
is common in infancy and usually occurs before age atrophy of white matter. Histopathology of early disease
10 years. Brain MRI shows frontally dominant demyeli- shows patches or stripes of perivascular white matter
nation involving the subcortical U fibers and contrast sparing, resulting in a tigroid pattern, sometimes also
enhancement in the deep frontal white matter, basal gan- visible on MRI (Figure 5). The etiology is duplication or
glia, and periventricular rim. Pathology shows astrocytic mutation of the proteolipid protein 1 (PLP1) gene on
intracytoplasmic inclusion bodies called Rosenthal fibers the X chromosome, resulting in over- or underproduc-
(Figure 4). More than 30 mutations of genes encoding tion of proteolipid protein. Diagnosis is by detecting
the glial fibrillary acidic protein (GFAP) have been iden- duplication or mutation of the PLP1 gene.
12 Hospital Physician Board Review Manual www.turner - white.com
Metabolic Disorders in Pediatric Neurology
Figure 5. Metachromatic leukodystrophy. T2-weighted mag- A
netic 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 presents between 5
and 8 years of age as a subacute onset of behavioral
problems, visual loss, hyperpigmented skin, and adren-
al insufficiency, leading to progressive spasticity, optic
atrophy, late seizures, and eventual vegetative state. B
Death is typical by 3 years after diagnosis. Brain MRI Figure 6. X-Linked adrenoleukodystrophy in a 5-year-old boy.
shows demyelination, which begins in the splenium of (A) T2-weighted magnetic resonance image (MRI) shows sym-
the corpus callosum and spreads in a posterior to ante- metric confluent demyelination in the peritrigonal white matter
rior pattern. The leading edge of demyelination en- and the splenium of the corpus callosum. (B) Gadolinium-
hances with contrast (Figure 6). The defect is in the enhanced T1-weighted MRI reveals enhancement of the lead-
ABCD1 gene, which codes for a peroxisomal mem- ing edge of active demyelination and inflammation (arrows).
brane ATP-binding cassette protein transporter. As a (Adapted with permission from Cheon JE, Kim IO, Hwang YS,
result, very-long-chain fatty acids are not degraded et al. Leukodystrophy in children: a pictorial review of MR im-
and, thus, accumulate. Diagnosis is suggested by MRI aging features. Radiographics 2002;22:467. Radiological Society
findings and by elevated very-long-chain fatty acids in of North America.)
blood, especially C26:0 but not C26:1 (elevated C26:0
plus C26:1 suggests Zellweger’s syndrome).
lidi and thalami are involved, but the caudate is spared.
CANAVAN’S DISEASE MR spectroscopy shows a large N-acetylaspartic acid
Canavan’s disease (spongiform leukodystrophy) is an (NAA) peak. The deficiency is in aspartoacylase. Diag-
autosomal recessive disorder that presents at 2 to nosis is by finding large quantities of NAA in urine.
4 months of age as megalencephaly and hypotonia, lead-
ing to developmental regression, progressive spasticity, KRABBE’S DISEASE
and seizures. Brain MRI shows diffuse demyelination that Krabbe’s disease (globoid cell leukodystrophy) is an
begins in subcortical and cerebellar white matter, later autosomal recessive disorder that presents at 1 to
involving central white matter (Figure 7). The globus pal- 7 months of age as irritability and hyperreactive startle.
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Metabolic Disorders in Pediatric Neurology
ages 2 and 4 years, followed by developmental regres-
sion, 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
Figure 7. Canavan’s disease in a 6-month-old boy with macro- CLN3 and CLN4 present in children and adults.
cephaly. T2-weighted magnetic resonance image shows extensive Electron microscopy of lymphocytes, skin, conjunctiva,
high-signal intensity areas throughout the white matter. Note or anal mucosa shows fingerprint, curvilinear, or gran-
involvement of the subcortical U fibers. (Adapted with permission ular osmiophilic deposits. More specific enzyme assays
from Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in chil- and genetic testing are available. Treatment is support-
dren: a pictorial review of MR imaging features. Radiographics ive. Seizures may be worsened by phenytoin and car-
2002;22:472. Radiological Society of North America.) bamazepine. Lamotrigine may be the most efficacious
and best-tolerated anticonvulsant. Trihexyphenidyl im-
proves dystonia and sialorrhea.42
Developmental regression, spasticity, areflexia, startle
myoclonus, seizures, and blindness follow. Most affected
infants die by 1 year of age. Brain MRI shows diffuse OTHER METABOLIC DISORDERS
demyelination beginning in deep white matter, later in-
volving subcortical white matter. Computed tomography
shows calcification in basal ganglia, thalami, and corona SMITH-LEMLI-OPITZ SYNDROME
radiata. CSF shows elevated proteins. Motor nerve con- Smith-Lemli-Opitz syndrome is caused by deficiency
duction velocities are prolonged. Diagnosis is by demon- of 7-dehydrocholesterol reductase, which leads to im-
strating deficient galactocerebroside β-galactosidase activ- paired cholesterol synthesis. Patients have ptosis, ante-
ity in leukocytes or cultured fibroblasts. verted nares, micrognathia, microcephaly, hypospadias,
and cardiac defects. Syndactyly of the second and third
toes is almost always present. Presentation is that of
GRAY MATTER DISORDERS poor growth and developmental delay. Diagnosis is
based on elevations of 7-dehydrocholesterol and de-
Gray matter disorders classically present as seizures creased serum cholesterol. Management is with choles-
and loss of function of affected cortex. Prototypical gray terol supplementation.
matter disorders include Tay-Sachs disease (discussed
previously) and the neuronal ceroid lipofuscinoses. LESCH-NYHAN SYNDROME
The neuronal ceroid lipofuscinoses (NCLs) are a Lesch-Nyhan syndrome is an X-linked recessive dis-
heterogeneous group of inherited neurodegenerative order caused by deficiency of hypoxanthine-guanine
lysosomal storage disorders presenting as some combi- phosphoribosyl transferase (HPRT), an enzyme in-
nation of visual loss, behavioral change, movement dis- volved in the metabolism of purines. This defect leads
order, and seizures, especially myoclonic seizures.42 to hyperuricemia and increased urinary excretion of
The infantile, late infantile, and juvenile forms are uric acid. Most neonates are normal until 3 months of
more likely to be accompanied by retinal blindness. age, when they demonstrate hypotonia and global
The adult form is usually not associated with visual loss. developmental delay. By age 1 to 2 years, choreoatheto-
Those affected by the infantile form are normal at sis and dystonia are apparent, and by age 2 to 3 years,
birth. Onset of seizures and visual loss occurs within the characteristic severe self-mutilating behavior is
2 years and death is typical by age 10 years. In the late apparent. Most children never learn to walk. Renal fail-
infantile form, initial symptoms are seizures between ure due to urate deposition and gouty arthritis occur
14 Hospital Physician Board Review Manual www.turner - white.com
Metabolic Disorders in Pediatric Neurology
later in life. Diagnosis is suggested by an elevated uric copper in blood, works faster than zinc and is also better
acid-to-creatinine ratio. Confirmation is by HPRT activ- tolerated than penicillamine.49
ity. Treatment with allopurinol does not improve the
neurologic outcome.43 OTHER
Pyridoxine-dependent epilepsy presents as neonatal
MENKES’ SYNDROME seizures that respond only to pyridoxine.50 Biotinidase
Menkes’ (kinky hair) syndrome is an X-linked reces- deficiency presents as seizures later in infancy to early
sive disorder of copper transport resulting in low serum childhood, which respond to biotin.51 Glucose trans-
copper levels, decreased intestinal copper absorption, porter 1 (GLUT-1) deficiency syndrome presents be-
and reduced activity of copper-dependent enzymes. tween 1 and 4 months of age as refractory seizures,
Affected males develop normally during the first months acquired microcephaly, ataxia, and low CSF glucose.
of life, but development then slows and regression occurs. Symptoms are due to defective transport of glucose
Myoclonic seizures in response to stimulation are an early across the blood-brain barrier. Seizures respond to a
and almost constant feature. Dysautonomia occurs. The ketogenic diet.52,53
hair takes on a brittle, steel wool appearance. Other find-
ings on examination include skin laxity, sagging jowls, and ACKNOWLEDGEMENT
hypotonia. Cerebral vessels are often tortuous and nar- We thank Justin Stahl, MD, for the white matter mnemon-
rowed. Ischemic infarcts and subdural hematomas can ic VAMPACK. We thank Gregg Nelson, MD, for helpful com-
occur. Death usually occurs before age 3 years. Laboratory ments and for Table 2.
evaluation shows low serum copper and ceruloplasmin.
CSF and plasma catecholamines are abnormal. Molecular
testing is available. Treatment involves subcutaneous or REFERENCES
intravenous copper administration. Results are variable,
possibly because of poor CNS penetration.44 1. Kishnani PS, Howell RR. Pompe disease in infants and children.
J Pediatr 2004;144(5 Suppl):S35–43.
2. Tein I. Role of carnitine and fatty acid oxidation and its defects
WILSON’S DISEASE in infantile epilepsy. J Child Neurol 2002;17 Suppl 3:3S57–83.
Wilson’s disease is an autosomal recessive disorder 3. DiMauro S, Andreu AL, Musumeci O, Bonilla E. Diseases of oxi-
with defective copper transporting ATPase that results in dative phosphorylation due to mtDNA mutations. Semin Neurol
impaired binding of copper to ceruloplasmin and im-
4. DiMauro S. MELAS. GeneReviews. Available at www.geneclinics.
paired excretion of copper into bile. Copper accumu- org/profiles/melas. Accessed 22 Apr 2005.
lates in the liver, and patients present with liver or CNS 5. DiMauro S, Hirano M. MERRF. GeneReviews. Available at
disease. CNS symptoms include tremor, chorea, dystonia, www.geneclinics.org/profiles/merrf. Accessed 22 Apr 2005.
dysarthria, psychiatric disturbance, and cognitive impair- 6. DiMauro S, Hirano M. Mitochondrial DNA deletion syndromes.
GeneReviews. Available at www.geneclinics.org/profiles/kss.
ment. Liver disease is more common in children, with
Accessed 22 Apr 2005.
fulminant liver failure described in preschool-age chil- 7. Thorburn DR, Rahman S. Mitochondrial DNA-associated Leigh
dren.45 CNS disease with mild liver disease more typically syndrome and NARP. GeneReviews. Available at www.geneclinics.
is seen in teens and adults. Laboratory studies show low org/profiles/narp. Accessed 8 Apr 2005.
serum copper and ceruloplasmin and elevated urinary 8. Biousse V, Newman NJ. Neuro-ophthalmology of mitochondri-
al diseases. Semin Neurol 2001;21:275–91.
copper. Copper deposition in Descemet’s membrane is
9. Bidichandani SI, Ashizawa T. Friedreich ataxia. GeneReviews.
seen on slit-lamp examination (Kayser-Fleischer rings). Available at www.geneclinics.org/profiles/friedreich. Accessed
Kayser-Fleischer rings and low serum ceruloplasmin are 8 Apr 2005.
found in more than 90% of those presenting with CNS 10. Cohen BH, Gold DR. Mitochondrial cytopathy in adults: what
disease but may be absent in those with liver disease. MRI we know so far [published erratum in Cleve Clin J Med 2001;
68:746]. Cleve Clin J Med 2001;68:625–6, 629–42.
shows symmetric lesions in basal ganglia, thalamus, and
11. Scaglia F, Towbin JA, Craigen WJ, et al. Clinical spectrum, mor-
brainstem that are bright on T2-weighted sequences. bidity, and mortality in 113 pediatric patients with mitochon-
Asymmetric lesions may be seen in white matter.46,47 drial disease. Pediatrics 2004;114:925–31.
Genetic testing is available. Traditional treatment is with 12. Lin DD, Crawford TO, Barker PB. Proton MR spectroscopy in
a copper chelator (ie, penicillamine or trientine). Trien- the diagnostic evaluation of suspected mitochondrial disease.
AJNR Am J Neuroradiol 2003;24:33–41.
tine plus zinc, which impairs copper absorption from the
13. Moller HE, Kurlemann G, Putzler M, et al. Magnetic resonance
gut, may work as well as penicillamine and is better tol- spectroscopy in patients with MELAS. J Neurol Sci 2005;
erated.48 Tetrathiomolybdate, a promising investigational 229–230C:131–9.
drug that impairs copper absorption in the gut and binds 14. Clark JM, Marks MP, Adalsteinsson E, et al. MELAS: clinical and
www.turner - white.com Neurology Volume 9, Part 2 15
Metabolic Disorders in Pediatric Neurology
pathologic correlations with MRI, xenon/CT and MR spectros- genesis disorders, Zellweger syndrome spectrum. GeneReviews.
copy. Neurology 1996;46:223–7. Available at www.genetests.org/query?dz=pbd. Accessed 22 Apr
15. Gillis L, Kaye E. Diagnosis and management of mitochondrial 2005.
diseases. Pediatr Clin North Am 2002;49:203–19. 36. Di Rocco M, Biancheri R, Rossi A, et al. Genetic disorders affect-
16. De Vivo DC, Jackson A, Wade C, et al. Dichloroacetate treatment ing white matter in the pediatric age. Am J Med Genet B
of MELAS-associated lactic acidosis [abstract]. Ann Neurol 1990; Neuropsychiatr Genet 2004;129:85–93.
28:437. 37. Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in children:
17. Fenichel GM. Clinical pediatric neurology: a signs and symp- a pictorial review of MR imaging features. Radiographics 2002;
toms approach. 4th ed. Philadelphia: W.B. Saunders; 2001. 22:461–76.
18. Seashore MR. The organic acidemias: an overview. GeneReviews. 38. van der Knaap MS, Barth PG, Gabreels FJ, et al. A new leukoen-
Available at www.geneclinics.org/query?dz=oa-overview. Accessed cephalopathy with vanishing white matter. Neurology 1997;48:
22 Apr 2005. 845–55.
19. Pitt DB, Danks DM. The natural history of untreated phenylke- 39. Leegwater PA, Pronk JC, van der Knaap MS. Leukoenceph-
tonuria over 20 years. J Paediatr Child Health 1991;27:189–90. alopathy with vanishing white matter: from magnetic resonance
20. Dhondt JL. Tetrahydrobiopterin deficiencies: preliminary analy- imaging pattern to five genes. J Child Neurol 2003;18:639–45.
sis from an international survey. J Pediatr 1984;104:501–8. 40. Li R, Johnson AB, Salomons G, et al. Glial fibrillary acidic pro-
21. Morton DH, Strauss KA, Robinson DL, et al. Diagnosis and tein mutations in infantile, juvenile and adult forms of Alex-
treatment of maple syrup disease: a study of 36 patients. Pedi- ander disease. Ann Neurol 2005;57:310–26.
atrics 2002;109:999–1008. 41. van der Knaap MS, Salomons GS, Li R, et al. Unusual variants of
22. Mudd SH, Skovby F, Levy HL, et al. The natural history of homo- Alexander’s disease. Ann Neurol 2005;57:327–38.
cystinuria due to cystathionine beta-synthase deficiency. Am J 42. Wisniewski KE, Zhong N, Philippart M. Pheno/genotypic cor-
Hum Genet 1985;37:1–31. relations of neuronal ceroid lipofuscinoses. Neurology 2001;57:
23. Applegarth DA, Toone JR. Glycine encephalopathy (nonketotic 576–81.
hyperglycinaemia): review and update. J Inherit Metab Dis 2004; 43. Nyhan WL, Ozand PT. Atlas of metabolic diseases. New York:
27:417–22. Chapman and Hall; 1998.
24. Zschocke J, Hoffman GF. Manual of metabolic paediatrics. 2nd 44. Kaler SG. ATP7A-related copper transport disorders. Gene-
ed. Stuttgart (DE): Schattauer Publishers; 2004. Reviews. Available at www.geneclinics.org/profiles/menkes.
25. Leonard JV, Morris AA. Urea cycle disorders. Semin Neonatol Accessed 22 Apr 2005.
2002;7:27–35. 45. Wilson DC, Phillips MJ, Cox DW, Roberts EA. Severe hepatic
26. Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome of Wilson’s disease in preschool-aged children. J Pediatr 2000;
long-term therapy of urea cycle disorders in Japan. J Inherit 137:719–22.
Metab Dis 1998;21 Suppl 1:151–9. 46. Starosta-Rubinstein S, Young AB, Kluin K, et al. Clinical assess-
27. Msall M, Batshaw ML, Suss R, et al. Neurologic outcome in chil- ment of 31 patients with Wilson’s disease. Correlations with struc-
dren with inborn errors of urea synthesis. Outcome of urea- tural changes on magnetic resonance imaging. Arch Neurol
cycle enzymopathies. N Engl J Med 1984;310:1500–5. 1987;44:365–70.
28. McBride KL, Miller G, Carter S, et al. Developmental outcomes 47. Aisen AM, Martel W, Gabrielsen TO, et al. Wilson disease of the
with early orthotopic liver transplantation for infants with brain: MR imaging. Radiology 1985;157:137–41.
neonatal-onset urea cycle defects and a female patient with late- 48. Askari FK, Greenson J, Dick RD, et al. Treatment of Wilson’s dis-
onset ornithine transcarbamylase deficiency. Pediatrics 2004; ease with zinc. XVIII. Initial treatment of the hepatic decom-
114:e523–6. pensation presentation with trientine and zinc. J Lab Clin Med
29. Pelet A, Rotig A, Bonaiti-Pellie C, et al. Carrier detection in a 2003;142:385–90.
partially dominant X-linked disease: ornithine transcarbamylase 49. Brewer GJ, Hedera P, Kluin KJ, et al. Treatment of Wilson dis-
deficiency. Hum Genet 1990;84:167–71. ease with ammonium tetrathiomolybdate: III. Initial therapy in
30. Elsas LJ. Galactosemia. GeneReviews. Available at www.geneclinics. a total of 55 neurologically affected patients and follow-up with
org/profiles/galactosemia/?Lng=GB. Accessed 22 Apr 2005. zinc therapy. Arch Neurol 2003;60:379–85.
31. Jaeken J. Komrower Lecture. Congenital disorders of glycosyla- 50. Gospe SM. Pyridoxine-dependent seizures: findings from recent
tion (CDG): it’s all in it! J Inherit Metab Dis 2003;26:99–118. studies pose new questions. Pediatr Neurol 2002;26:181–5.
32. Minassian BA. Lafora’s disease: towards a clinical, pathologic, 51. Wolf B. Biotinidase deficiency: new directions and practical con-
and molecular synthesis. Pediatr Neurol 2001;25:21–9. cerns. Curr Treat Options Neurol 2003;5:321–8.
33. Wilcox WR, Banikazemi M, Guffon N, et al. Long-term safety 52. De Vivo DC, Trifiletti RR, Jacobson RI, et al. Defective glucose
and efficacy of enzyme replacement therapy for Fabry disease. transport across the blood-brain barrier as a cause of persistent
Am J Hum Genet 2004–75:65-74. hypoglycorrhachia, seizures, and developmental delay. N Engl J
34. Patterson MC, Di Bisceglie AM, Higgins JJ, et al. The effect of Med 1991;325:703–9.
cholesterol-lowering agents on hepatic and plasma cholesterol 53. Wang D, Pascual JM, Yang H, et al. Glut-1 deficiency syndrome:
in Niemann-Pick disease type C. Neurology 1993;43:61–4. clinical, genetic, and therapeutic aspects. Ann Neurol 2005;57:
35. Steinberg SJ, Raymond GV, Braverman NE, et al. Peroxisome bio- 111–8.
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