metabolic disorders in pediatric neurology

Metabolic Disorders inPediatric NeurologyEditor: Catherine Gallagher, MDAssistant Professor of Neurology, University of Wisconsin MovementDisorders Program, Staff Physician, Middleton VA Hospital, Madison, WI

Contributors: Gregory M. Rice, MDFellow in Clinical and Biochemical Genetics, Departments of MedicalGenetics and Pediatrics, University of Wisconsin, Madison, WI

David Hsu, MD, PhD Assistant Professor of Neurology, Department of Neurology, Universityof Wisconsin, Madison, WI

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NEUROLOGY BOARD REVIEW MANUAL

www.turner -white.com Neurology Volume 9, Part 2 1

STATEMENT OF EDITORIAL PURPOSE

The Hospital Physician Neurology Board ReviewManual is a study guide for residents andpracticing physicians preparing for boardexaminations in neurology. Each quarterlymanual reviews a topic essential to the cur-rent practice of neurology.

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NOTE FROM THE PUBLISHER:This publication has been developed withoutinvolvement of or review by the AmericanBoard of Psychiatry and Neurology.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Disorders Caused by Energy Failure. . . . . . . . . . . . . . . . . 2

Disorders of Amino Acid Metabolism. . . . . . . . . . . . . . . . 6

Disorders of Carbohydrate Metablism . . . . . . . . . . . . . . . 9

Lysosomal Storage Disorders . . . . . . . . . . . . . . . . . . . . . 10

Peroxisomal Biogenesis Disorders . . . . . . . . . . . . . . . . . 11

White Matter Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 12

Gray Matter Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Other Metabolic Disorders . . . . . . . . . . . . . . . . . . . . . . . 14

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Table of Contents

Cover Illustration by Kathryn K. Johnson

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INTRODUCTION

This manual reviews metabolic diseases that affectthe nervous system, focusing on the usual presentationsfrom the perspective of a pediatric neurologist. Many ofthese disorders also have milder presentations in laterlife, which are not discussed here. This review presentssufficient information to begin a workup and to insti-tute initial interventions. A beginning neurologist willneed to learn more about each disorder as he or shecloses in on the definitive diagnosis. If a diagnosis is notreadily apparent by clinical presentation (Table 1), onemust resort to a more systematic approach.

In this review, disorders are generally groupedaccording to defects of the various biochemical path-ways (Figure 1). Metabolic disorders caused by energyfailure can involve defects in the mobilization of glyco-gen (ie, glycogen storage diseases) or fats (ie, fatty acid oxi-dation defects) or defects in the citric acid cycle or respi-ratory chain (ie, mitochondrial disorders). These disorderstend to present as decompensations with stress or in-creased energy demand. Metabolic disorders caused bydefects in amino acid metabolism include the organicacidemias, aminoacidopathies, and urea cycle defects. Thesedisorders tend to present in infancy as increasing lethar-gy and vomiting with initiation of feeds. Lysosomal disor-ders result in the accumulation of large carbohydrate–lipid complexes and present as dysmorphism withorganomegaly, psychiatric symptoms, or white matterdisease. Aside from the glycogen storage disorders, thedisorders of carbohydrate metabolism are rather heteroge-neous. Finally, some primarily white matter disorders aresuggested by clinical presentation, such as increasingspasticity and abnormalities in white matter on mag-netic resonance imaging (MRI), whereas primarily graymatter disorders present as seizures and cognitive decline.

In the United States, most states screen newborns forphenylketonuria, galactosemia, hypothyroidism, con-genital adrenal hyperplasia, hemoglobinopathies, andmaple syrup urine disease. Some states employ tandemmass spectroscopy, which gives amino acid and acylcar-nitine profiles. These tests are useful for diagnosingmany metabolic disorders, as described below.

DISORDERS CAUSED BY ENERGY FAILURE

GLYCOGEN STORAGE DISORDERS (GSD)

Glycogen is an important source of stored glucosefound primarily in liver and muscle. Defects in glycogenmobilization can lead to energy failure during times offasting and exercise.

GSD Type II

GSD type II (Pompe’s disease) is caused by deficiency ofthe lysosomal enzyme acid maltase (α-1-4-glucosidase).1

The infantile form presents as severe hypotonia and car-diomyopathy and is usually fatal before 12 months of age.The childhood form affects only skeletal muscle and pre-sents as progressive weakness. Creatine kinase (CK) levelsare markedly elevated, and muscle biopsy demonstratesglycogen storage in muscle fibers and absence of acid mal-tase. Hypoglycemia is not seen in GSD type II.

GSD Type V

GSD type V (McArdle’s disease) is caused by defi-ciency of myophosphorylase and presents in adolescentsas cramps and muscle fatigue shortly after initiatingexercise. A “second wind” effect can occur (ie, renewedability to continue exercising if patients rest briefly afterthe onset of fatigue). Laboratory studies show elevatedCK levels, post-exertional myoglobinuria, and a failureof the normal rise in lactate levels with exercise. Theforearm ischemic test is the classic exercise test but is dif-ficult to perform reliably. Muscle biopsy shows glycogenstorage 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 autosomalrecessive defects in either the transport of fatty acids intomitochondria or in the intramitochondrial β-oxidationof fatty acids. A prolonged fast or significant stress (eg, ill-ness, surgery) may deplete liver stores of glycogen. If fattystores fail to be mobilized for fuel, the result is the classiclaboratory finding of hypoketotic hypoglycemia.2 A mild to

NEUROLOGY BOARD REVIEW MANUAL

Metabolic Disorders in Pediatric NeurologyGregory M. Rice, MD, and David Hsu, MD, PhD

moderate hyperammonemia may also be seen. Organsespecially sensitive to fatty acid oxidation defects includethe brain (which depends on ketones for fuel in the fast-ed state), the heart and muscles (due to high metabolicdemand and because fatty fuels spare proteolysis), andthe liver (which relies on energy derived from fatty acidoxidation for gluconeogenesis and ureagenesis). Man-agement for all fatty acid oxidation disorders includesavoiding prolonged fasts and aggressive use of dextrose-containing fluids during decompensations.

Carnitine must bind to long-chain fatty acids for fattyacid transport across the mitochondrial double mem-brane. Carnitine enters the cell through a carnitinetransporter. It is bound to the fatty acyl group by carni-tine palmitoyl transferase 1 (CPT1) at the outer mito-chondrial membrane. Acylcarnitine is then transportedto the inner mitochondrial membrane by acylcarnitinetranslocase. At the inner mitochondrial membrane, acyl-carnitine is disassembled into acyl coenzyme A (CoA)and free carnitine by carnitine palmitoyl transferase 2(CPT2). Acyl CoA then enters β-oxidation while freecarnitine is recirculated to the cell cytoplasm. The first


M e t a b o l i c D i s o r d e r s i n P e d i a t r i c N e u r o l o g y

Table 1. Clinical Presentations and Differential Diagnosis of Metabolic 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.)

Stroke/stroke-like episodes

Mitochondrial myopathy, encephalomyelopa-thy, and lactic acidosis with stroke-likeepisodes (MELAS)

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

Cardiomyopathy

VLCAD deficiency

LCHAD deficiency

Carnitine transporter deficiency

Infantile CPT2 deficiency

GSD II (Pompe’s disease)

GSD III (Cori’s disease)

Mitochondrial disorders

Cherry red spots on the macula

Tay-Sachs disease

Sandhoff’s disease

GM1 gangliosidosis

Niemann-Pick disease

Sialidosis

Multiple sulfatase deficiency

Rhabdomyolysis/myoglobinuria

GSD type V (McArdle’s disease)

Adult CPT2 deficiency

VLCAD deficiency

LCHAD deficiency

Carnitine transporter deficiency

Mitochondrial disorders

Progressive myoclonic epilepsies

Myoclonic epilepsy with ragged red fibers(MERRF)

Unverricht-Lundborg disease (Balticmyoclonus)

Neuronal ceroid lipofuscinosis

Lafora’s disease

Sialidosis type 1

Psychiatric/behavioral change

Wilson’s disease

Neuronal ceroid lipofuscinosis

X-Linked adrenoleukodystrophy

Juvenile- and adult-onset metachromaticleukodystrophy

Late-onset GM2 gangliosidosis

Lesch-Nyhan syndrome

Porphyria (episodic)

Urea cycle disorders (episodic)

Sanfilippo’s syndrome (mucopolysaccharido-sis III)

Hunter’s syndrome (mucopolysaccharidosis II)

Carbohydrates

GlycogenGlucose

Galactose Glucose-6-P

Fructose Amino acids Fatty acids

Pyruvate Lactate

MitochondrionCytosol

Acetyl CoA

ATP ADP

Ketones

UreaNH3

Respiratory chain

Krebscycle

β-oxidation

Ureacycle

Figure 1. Basic pathways of intermediary metabolism. Glucose-6-P = glucose-6-phosphate. (Adapted with permission fromHoffmann GF, Nyhan WL, Zschocke J. Inherited metabolic dis-eases. Philadelphia: Lippincott Williams & Wilkins; 2002:6.)

step in β-oxidation is performed by acyl CoA dehydro-genases, which are distinct depending on the acyl groupchain length.

Carnitine also acts as a scavenger of potentially toxicacyl CoA metabolites, forming acylcarnitine esters thatare excreted in the urine. A secondary carnitine defi-ciency results when urinary acylcarnitine loss is ex-cessive. Blood carnitine levels then show an elevatedacylcarnitine ester-to-free carnitine ratio (ie, > 0.4).2 Val-proic acid therapy can cause secondary carnitine defi-ciency in this way by forming valproyl carnitine ester.

Screening laboratory tests include plasma free andtotal carnitines, plasma acylcarnitine profile, and urineacylglycines. Laboratory findings are summarized inTable 2. Interpretation of urine acylglycines is complexand is omitted in this review.

Carnitine Disorders

Carnitine transporter deficiency leads to total bodycarnitine depletion secondary to increased renal loss.Symptoms include muscle weakness and cardiomyopa-thy. Carnitine given in high doses reverses symptomsand can be lifesaving.2

CPT1 deficiency presents as a Reye-like syndrome,with progressive encephalopathy, seizures secondary tohypoglycemia, hepatomegaly, moderate hyperammo-nemia, and elevated liver enzymes. Skeletal and cardiacmuscle are not involved. Acylcarnitine profile shows de-creased long-chain acylcarnitines (C16, C18). Chronictreatment with medium-chain fatty acids may be of ben-efit.

CPT2 deficiency has an infantile (liver) and adult(muscle) form. The infantile form presents as hep-atomegaly, liver failure, cardiomegaly, arrhythmias, andseizures, with hypoketotic hypoglycemia. The adult

form presents in the teens to twenties as episodic rhab-domyolysis and myoglobinuria with elevated CK levelsfollowing 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 oxida-tion disorders. MCAD helps metabolize medium-chainfatty acids to ketones, which are used as fuel duringtimes of stress and fasting. Acute presentation consistsof lethargy, vomiting, seizure, and progressive enceph-alopathy after fasting or physical stress. An initial attackmay result in sudden infant death. Management in-cludes moderate dietary fat restriction and carnitinesupplementation.

Very-long-chain acyl CoA dehydrogenase (VLCAD)deficiency and long-chain 3-hydroxy acyl CoA dehy-drogenase (LCHAD) deficiency are associated withcardiomyopathy, skeletal myopathy, post-exertionalrhabdomyolysis, and hypoketotic hypoglycemia with de-compensations. Children with VLCAD deficiency can pre-sent with a Reye-like syndrome, which can be fatal.Mothers carrying a fetus with LCHAD deficiency can pre-sent with hemolysis, elevated liver function tests, and lowplatelet counts (HELLP syndrome). Diagnosis is by acyl-carnitine profile, which shows elevated long-chain acyl-carnitines and hydroxy-acylcarnitines, respectively, inpatients 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 flavinadenine dinucleotide (FAD)–dependent electrontransfer from dehydrogenase enzymes to the electrontransport chain. This disorder affects both fatty acid



Table 2. Carnitine-Associated and Fatty Acid Disorders

SerumAcylcarnitine 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 acylcoenzyme A dehydrogenase; M = skeletal muscle; MCAD = medium-chain acyl coenzyme A dehydrogenase; N = neonate; nl = normal. (Adaptedfrom Nyhan WL, Ozand PT. Atlas of metabolic diseases. New York: Chapman and Hall; 1998.)

oxidation and amino acid metabolism. The classic neo-natal form is severe and presents as a Reye-like syn-drome, followed by seizures and progressive neurode-generation. Dysmorphism and cystic kidneys may bepresent. Diagnosis is by recognizing a complex patternin plasma acylcarnitines, urine organic acids, and urineacylglycines, including urine glutaric acid.

MITOCHONDRIAL DISORDERS

Mitochondrial disorders are caused by a geneticdefect in either nuclear or mitochondrial DNA. Manymitochondrial syndromes have been defined, but thereis significant overlap with a complex relationship be-tween identified genetic defects and classic mitochon-drial syndromes3 (Table 3).4–9

Clinical Features

Mitochondrial disorders are highly variable in pre-sentation. Suspicion for a mitochondrial defect increas-es if there is multisystem involvement of high energy sys-tems3,10 (Table 4). Diagnosis of mitochondrial disordersbegins with analysis of serum lactate, pyruvate, and CKlevels. Classically, lactate is elevated even at rest, with alactate-to-pyruvate ratio greater than 25 (more com-monly, 50–250). However, 40% of patients have normal

lactate levels at rest. Furthermore, mitochondrial DNApanels are abnormal in only 10% of patients.11 Thus,muscle biopsy remains a key to diagnosis. Muscle biop-sy may show ragged red fibers on Gomori trichromestain; succinate dehydrogenase stains the same fibersblue, and cytochrome c oxidase stains reveal deficientmitochondrial respiratory chain protein synthesis.



Table 3. Mitochondrial Disorders

Disorder Characteristic Findings Comments

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 imag-ing; mt = mitochondrial; NARP = neurogenic muscle weakness, ataxia, and retinitis pigmentosa.

MELAS4

MERRF5

CPEO6

Kearns-Sayre syndrome4

Leigh disease, or sub-acute necrotizingencephalomyelopathy7

Leber’s hereditary opticneuropathy8

NARP7

Friedreich’s ataxia9

Recurrent stroke-like events, migrating lesions on MRI, episodicencephalopathy, migraines, seizures

Myoclonic epilepsy, ataxia, optic atrophy, hearing loss

CPEO, ptosis, variable skeletal muscle weakness

CPEO, retinitis pigmentosa, and one of following: cerebellar ataxia,conduction block, CSF protein > 100 mg/dL

Ataxia, hypotonia, ophthalmoplegia, dysphagia, dystoniaMRI: lesions of basal ganglia, thalamus, brainstem

Acute: optic nerve hyperemia, vascular tortuosity Chronic: optic atrophyUncommon: cardiac conduction abnormalities

Neuropathy, ataxia, retinitis pigmentosa, proximal weakness, men-tal retardation

Ataxia, areflexia, loss of vibration and proprioceptive sense, withonset before age 25 years

Associated: diabetes, cardiomyopathy, scoliosis, optic atrophy,deafness

Leucine tRNA mtDNA mutation in 80%

Lysine tRNA mtDNA mutation in 80%

Multiple mtDNA deletions; only skeletal muscle affected

Multiple mtDNA deletions; all tissues affect-ed; check serial ECGs

Severe neurodegenerative disease; most dieby 3 years of age; multiple mutations associated

Painless; initially asymmetric; progresses overweeks to months

Can go years without exacerbation;mtATPase affected

Trinucleotide expansion in Frataxin gene;autosomal recessive (nuclear gene)

Causes intramitochondrial iron accumulation;most die in mid-30s

Milder variant exists with retained reflexes

Table 4. Clinical Features of Mitochondrial Disorders

Brain: psychiatric disorder, seizures, ataxia, myoclonus, migraine,stroke-like events

Eyes: optic neuropathy, retinitis pigmentosa, ptosis, external ophthal-moplegia

Ears: sensorineural hearing loss

Nerve: neuropathic pain, areflexia, gastrointestinal pseudo-obstruction, 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 inadults: What we know so far. Cleveland Clin J Med 2001;68:625–41with permission from The Cleveland Clinic Foundation. Copyright ©2001, all rights reserved.

Biochemical analysis of muscle can reveal decreases inactivity of the respiratory chain complexes I to IV. Elec-tron microscopy shows overabundant, enlarged, andbizarrely shaped mitochondria with paracrystalline inclu-sions. Brain MRI may show lesions of the basal ganglia,thalamus, midbrain, or cerebral white matter. In the cere-bral white matter, recurrent stroke-like events may occur,with transitory migrating lesions that cross vascular terri-tories (Figure 2). Magnetic resonance (MR) spectros-copy may show elevated lactate peaks in these lesions.12,13

Impaired autoregulation of cerebral vasculature hasbeen suggested as the etiology of stroke-like events.14

Treatment

Treatment is with L-carnitine, B vitamins (riboflavinand thiamine), and coenzyme Q or idebenone. Biotin,antioxidants (vitamins A and C), folate, and lipoic acidare also used.15 Dichloroacetic acid may lower lactatelevels in some patients.16 Response to treatment is vari-able, with some patients experiencing improvement inenergy and function but many experiencing no dis-cernible improvement.

PYRUVATE DEHYDROGENASE COMPLEX DEFICIENCY

Pyruvate dehydrogenase complex (PDHC) deficien-cy blocks entry of pyruvate into the citric acid cycle,resulting in elevated lactate and pyruvate levels. PDHCdeficiency presents similarly to the mitochondrial disor-ders. The severe neonatal form is fatal in infancy. Leighdisease can develop later in infancy. Diagnosis is basedon finding elevated lactate and pyruvate levels withpreservation of the lactate-to-pyruvate ratio (ie, < 20).

Treatment involves supplementation with thiamine,which is a cofactor for PDHC, and a high fat, low carbo-hydrate diet. Acetazolamide may abort attacks.17

DISORDERS OF AMINO ACID METABOLISM

ORGANIC ACIDEMIAS

Organic acidemias are caused by autosomal recessivedisorders of amino acid metabolism. The usual presenta-tion is that of nonspecific poor feeding, lethargy, and vom-iting in the neonatal period, eventually progressing tocoma. Symptoms are often initially mistaken for sepsis.Laboratory findings include metabolic acidosis with anelevated anion gap, sometimes with ketosis and hyper-ammonemia (Table 5). Diagnosis during the acute illnessdepends on plasma amino acids, plasma acylcarnitineprofile, urine organic acids, and urine acylglycine profile.The detailed analysis of these profiles is often complexand is not discussed here. Acute treatment involves with-holding protein feeds and aggressively pushing dextrose-containing fluids, to induce an anabolic state. Chronictreatment consists of specific dietary protein restriction.Carnitine supplementation can be helpful.18

Propionic Acidemia

Propionic acidemia is caused by a deficiency in propi-onyl CoA carboxylase. Most children have some cognitivedisability even with optimal therapy. Cardiomyopathy,pancreatitis, osteoporosis, and movement disorders arelate complications.



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 leftoccipital lobe (arrows). Follow-up MRI 15 months later showed resolution of the occipital lesion but with new left temporal lesion (notshown). (B) Photomicrograph (original magnification, ×40; Gomori methenamine silver stain) of the muscle biopsy reveals scatteredragged red fibers (arrows). (C) Electron micrograph reveals an increased number of mitochondria (arrows), which are irregular andenlarged. (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.)

A B C

Methylmalonic Acidemia

Methylmalonic acidemia is caused by a defect inmethylmalonyl CoA mutase. Acidosis and hyperammo-nemia can be severe, and a single attack can cause per-manent cognitive disability. Seizures, spasticity, behav-ioral problems, and ataxia are common. Metabolicstroke with an acute decompensation can occur. Manypatients will develop renal failure and require renaltransplantation. Methylmalonic acid can also be elevat-ed in disorders of cobalamin (vitamin B12) metabolism,and megaloblastic anemia can be seen. Brain MRI mayshow bilateral globus pallidus infarction. Managementof methylmalonic acidemia consists of vitamin B12 sup-plementation and dietary protein restriction.

Glutaric Acidemia Type I

Glutaric acidemia type I is caused by a deficiency inglutaryl CoA dehydrogenase, which results in dystonia,ataxia, cognitive disability, and spasticity. Metabolic aci-dosis is not a prominent feature even with acute de-compensation. Diagnostic studies are often normalwhen affected individuals are healthy. Neuroimagingshows frontotemporal atrophy with basal ganglia le-sions. Basal ganglia injury can appear even with a firstattack. Macrocephaly is common. Chronic manage-ment consists of carnitine supplementation and pro-tein restriction.18

AMINOACIDOPATHIESClassic Phenylketonuria

Classic phenylketonuria (PKU) is caused by a defi-ciency in the enzyme phenylalanine hydroxylase,which converts phenylalanine to tyrosine. As a result,neurotoxic phenylketones accumulate. Testing showselevated levels of blood phenylalanine and urinephenylketones. Infants are normal at birth, but in thefirst year of life manifest progressive cognitive delay,microcephaly, spasticity, recurrent eczematous rash,and a mousy odor. Seizures occur in 25% of untreatedPKU patients.19 Newborn screening and early treat-ment can prevent these symptoms. Treatment in classicPKU consists of dietary restriction of phenylalanineand close monitoring of blood phenylalanine levels.Women with PKU should have phenylalanine levelsunder control before attempting to conceive. Fetusesexposed to high levels of phenylalanine are at risk forcongenital heart disease, intrauterine growth restric-tion, mental retardation, and microcephaly. Approx-imately 2% of PKU patients have normal phenylala-nine hydroxylase activity but are deficient in thecofactor tetrahydrobiopterin.20 These patients requirebiopterin supplementation.

Maple Syrup Urine Disease

Maple syrup urine disease (MSUD) is caused by adeficiency in branched-chain α-ketoacid dehydroge-nase, which is responsible for the metabolism of leu-cine, isoleucine, and valine. The classic form presents inthe first week of life as poor feeding, lethargy, and vom-iting, quickly progressing to coma, seizures, and deathif untreated. An intermittent form may present later inlife as attacks of transient ataxia, sometimes accompa-nied by cerebral edema.21 These attacks are triggered byintercurrent illness or stresses. Urine, sweat, and ceru-men often smell like maple syrup. Acidosis and hyper-ammonemia are uncommon.

In the United States, many states screen newbornsfor MSUD. Testing during an attack shows elevatedleucine, isoleucine, and valine in blood as well asbranched-chain metabolites in urine, but these levelsmay be normal in the immediate neonatal periodbefore branched-chain amino acids have accumulatedand in the intermittent form between attacks. Acutemanagement includes aggressive high calorie intra-venous or nasogastric feeds, sometimes with intra-venous insulin to help induce an anabolic state. SpecialMSUD total parenteral nutrition is available with theproper mixture of amino acids. Chronic managementrelies on dietary restriction of branched-chain aminoacids. With early diagnosis and tight metabolic control,the prognosis is for normal development.

Classic Homocystinuria

Classic homocystinuria is an autosomal recessive dis-order caused by a defect in the enzyme cystathionine β-synthetase, resulting in elevations of homocystine andmethionine. Infants are usually asymptomatic, but men-tal retardation can develop in untreated patients. Adultsare 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 theopposite of what is seen in Marfan syndrome. Untreated



Table 5. Metabolic Causes of Lethargy and Vomiting in theInfant and Child

Elevated NormalAcid-Base Status Ammonia Ammonia

Acidemia with elevated Organic acidemia Organic acidemiaanion gap (neonate) (older child)

No acidemia Urea cycle disorder Galactosemia, MSUD

MSUD = maple syrup urine disease. (Adapted with permission fromSilverstein S. Laughing your way to passing the pediatric boards. 2nded. Stamford [CT]: Medhumor Medical Publications; 2000:286).Copyright © 2000.

http://www.passtheboards.com/

patients are at risk for seizures, psychiatric disorders, andthromboembolic events, including stroke, myocardial in-farction, and pulmonary emboli.22 Treatment involvesprotein restriction; supplementation with vitamin B6, vit-amin B12, and folate; and stroke prophylaxis with aspirin.

Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia (glycine encephalopa-thy) is caused by a defect in glycine cleavage.23 Thisdefect results in elevated glycine levels in the blood,urine, and cerebrospinal fluid (CSF). The neonatalform presents as lethargy and poor feeding after the ini-tiation of protein feeds, quickly progressing to persistentseizures, encephalopathy, and coma. Apnea is commonand persistent hiccups have also been seen. Diagnosisdepends on simultaneous measurement of CSF andplasma glycine levels. A CSF-to-plasma glycine ratiogreater than 0.06 supports this diagnosis.24 Acute man-agement includes use of sodium benzoate to help nor-malize plasma glycine level. Dextromethorphan, anNMDA (N-methyl-D-aspartate) receptor antagonist, maybe beneficial. Valproic acid, which inhibits metabolismof glycine, is contraindicated. The prognosis for theneonatal form is poor. Survivors often have spastic quad-riplegia, intractable seizures, and severe mental retarda-tion. Infantile, childhood, and adult-onset forms existbut are uncommon; these forms have milder outcomes.

UREA CYCLE DISORDERS

The urea cycle converts ammonia, which is a toxicbyproduct of protein metabolism, into urea (Figure 3).All urea cycle disorders are autosomal recessive with theexception of ornithine transcarbamylase (OTC) defi-ciency, which is X-linked.

Clinical Features

Similar to the organic acidemias, urea cycle disordersclassically present in neonates as lethargy, poor feeding,and vomiting soon after initiating protein feeds.25 Whatdistinguishes the urea cycle disorders from the organicacidemias, however, is hyperammonemia without acidosis(Table 5). In an acute crisis, encephalopathy quickly pro-gresses to coma, seizures, and death if left untreated.Cerebral edema (with a bulging fontanelle and tachy-pnea) can occur early and progresses rapidly. Metabolicstrokes may also occur. All urea cycle disorders, with theexception of argininemia, are accompanied by hyperam-monemia. Ammonia levels exceeding 200 µg/dL causelethargy and vomiting, levels greater than 300 µg/dLresult in coma, and levels exceeding 500 µg/dL causeseizures.17 Any catabolic state, including the immediatepostnatal period before initiation of feeding, can provokea crisis because of associated proteolysis. Permanent neu-rologic sequelae can occur after a single crisis. Ammonialevels greater than 350 µg/dL26 and coma for longer than3 days27 are correlated with death or profound mentalretardation. Ammonia levels less than 180 µg/dL usuallyresult in normal development or only mild mental retar-dation.26 Milder forms, as seen with female carriers ofOTC deficiency, can have a more subtle presentation.

Treatment

Hyperammonemia in an encephalopathic infant is amedical emergency. In addition to determining ammo-nia levels and acid-base status, laboratory studiesshould be ordered for electrolytes, calcium, glucose, lac-tate, liver enzymes, free and total carnitine, quantitativeplasma amino acids, and urine organic acids. Acutemanagement for all urea cycle disorders consists of (1) stopping all protein intake; (2) starting an intra-venous infusion of 10% glucose plus lipid to promotethe anabolic state; and (3) starting arginine hydrochlo-ride, sodium benzoate, and sodium phenylacetate withintravenous loading doses, followed by maintenanceinfusions. Peritoneal dialysis or hemodialysis should beconsidered if there is clinical deterioration and ammo-nia levels are not responding. Chronic managementtypically includes protein restriction and oral sodiumbenzoate and sodium phenylacetate supplementa-tion.25 Because the urea cycle takes place in the liver,



Mitochondrion

Cytoplasm

Asparate

Argininosuccinate

FumarateArginineUrea

Ornithine

Ornithine

Citrull

ine

Citrull

ineCarbamylphosphate

HCO3 + NH4 + 2 ATP

N-acetylglutamateCPSI

ARG

ASL

ASS

OTC

Figure 3. The urea cycle and its disorders. ARG = arginase defi-ciency; ASL = argininosuccinic acid lyase deficiency; ASS = argin-inosuccinic acid synthetase deficiency; CPSI = carbamyl phosphatesynthetase I deficiency; OTC = ornithine transcarboxylase defi-ciency. (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.)

liver transplantation is curative for the metabolic disor-der but does not reverse accumulated neurologicinjury. In the severe forms of the urea cycle disorders(eg, carbamyl phosphate synthetase 1 [CPS1] deficien-cy, OTC deficiency), liver transplantation before 1 yearof age is associated with better survival into the child-hood years, with mild (rather than profound) mentalretardation.28

Specific Disorders

CPS1 deficiency blocks formation of carbamyl phos-phate and has the classic presentation described above.Orotic acid is a metabolite of carbamyl phosphate.Thus, CPS1 deficiency is the only urea cycle disorderwithout elevated urine orotic acid. Plasma amino acidsshow decreased citrulline and arginine. Chronic man-agement is as described above plus arginine supple-mentation. Prognosis is poor with neonatal presenta-tions. Recurrent exacerbations occur even with optimaltherapy. Survivors are generally profoundly mentallyretarded. Initial presentation is usually in the neonatalperiod but can be delayed into childhood. The out-come in later-onset cases can be milder but still in-cludes mental retardation, motor deficits, and death.

OTC deficiency is identical to CPS1 deficiency inpresentation, except that urine orotic acids are elevat-ed. Plasma amino acids show decreased citrulline andarginine. Due to skewed X-inactivation, 15% of femaleswill develop hyperammonemia;29 many of these femaleslearn to avoid meat. A protein load can induce symp-toms. The catabolic postpartum state can also provokea crisis. Chronic management involves protein restric-tion and oral sodium benzoate, phenylacetate, and cit-rulline supplementation. Prognosis is the same as forCPS1 deficiency.

Citrullinemia is caused by a defect in argininosuc-cinic acid synthetase. The presentation is similar to thatof CPS1 deficiency, but prognosis for survivors of theinitial episode is somewhat better, with future exacerba-tions becoming easier to manage with age. A milder,late-onset form of citrullinemia exists. Plasma aminoacids show elevated citrulline and reduced arginine.Chronic management is the same as for CPS1 deficien-cy, but arginine supplementation is essential.

Argininosuccinic aciduria is caused by deficiency ofargininosuccinic acid lyase. Affected children may dem-onstrate failure to thrive, hepatomegaly, and unusualhair, including alopecia and trichorrhexis nodosa.Plasma amino acids show elevated citrulline with de-creased arginine. Argininosuccinic acid is elevated inplasma and present in urine. Treatment involves pro-tein restriction and arginine supplementation. With

age, acute episodes of hyperammonemia become lessfrequent. Developmental delays are common even withgood compliance.

Argininemia is caused by a defect in arginase.Argininemia is unique among the urea cycle disordersin that it rarely causes acute hyperammonemic crisis.Ammonias may chronically be mildly elevated. Spastic-ity and developmental regression develop early inchildhood, often with cyclic vomiting, seizures, and fail-ure to thrive. Children are often misdiagnosed as hav-ing cerebral palsy. Diagnosis is based on elevated argi-nine in plasma, although levels can be normal in theimmediate newborn period. Treatment involves an arginine-restricted diet. The prognosis includes mentalretardation, seizures, and spastic diparesis.

DISORDERS OF CARBOHYDRATE METABOLISM

GALACTOSEMIA

Galactosemia results from a deficiency in galactose-1-phosphate uridyltransferase.30 Neonates present withvomiting, poor feeding, and lethargy following the ini-tiation of breast or bottle feeding. Jaundice and hepato-megaly are seen, and simultaneous Escherichia coli sepsisis associated. Untreated infants develop profound men-tal retardation and, often, renal failure. Lenticular cata-racts develop after only 1 month if untreated. Thosewith suboptimal control are at risk for behavioral andlearning problems. Even with good dietary control,patients may have subtle cognitive delays or learningdisabilities. Action tremor may become a prominentcomplaint, refractory to medical therapy. Females are atrisk for premature ovarian failure, even if treated. Thediagnosis is suggested by finding reducing substances inurine and confirmed by elevations in serum galactose-1-phosphate. Treatment is based on dietary restrictionof galactose.

CONGENITAL DISORDERS OF GLYCOSYLATION

Congenital disorders of glycosylation (CDG, former-ly called carbohydrate-deficient glycoprotein syn-drome) are a heterogeneous group of mostly autoso-mal recessive disorders with deficient glycosylation ofglycoproteins.31 CDG Ia is the most common type andinvolves deficiency of phosphomannomutase. CDG Ibis unique in presenting as hypoglycemia and protein-losing enteropathy, without neurologic features. CDGas a group is suggested in an infant or a child with somecombination of failure to thrive, stroke-like episodes, aclotting or bleeding tendency, hypotonia, psychomotor



retardation, strabismus, retinitis pigmentosa, hypogo-nadism, ataxia, and cerebellar hypoplasia. There maybe inverted nipples and unusual fat deposits in thesuprapubic and supragluteal regions. Peripheral neu-ropathy may occur. Severity of symptoms is highly vari-able. Most adults are wheelchair bound. Diagnosis andseparation into subtypes is by transferrin electrophore-sis. Coagulation studies may show deficiencies of factorXI, proteins C and S, and antithrombin. Oral mannoseis effective in CDG Ib, but no treatment exists for theother types of CDG.31

LAFORA’S DISEASE

Lafora’s disease is an autosomal recessive poly-glucosan storage disorder that presents as myoclonicseizures in the mid-teens, with rapid neurocognitivedeterioration. Neurons show Lafora bodies with a corethat stains very dark with periodic acid Schiff, with alighter outer halo. Skin, liver, or muscle biopsy can alsobe diagnostic.32

LYSOSOMAL STORAGE DISORDERS

Lysosomes are involved in the degradation of largemolecules, including mucopolysaccharides, sphingo-lipids, sphingomyelin, and several others. Progressiveorganomegaly, dysmorphism, and neurodegenerationare typical.

MUCOPOLYSACCHARIDOSES

In the mucopolysaccharidoses (MPS), impaired degra-dation of various mucopolysaccharides (also known as gly-cosaminoglycans) cause variable combinations of coarsefacies, short stature, bony defects, stiff joints, mental retar-dation, hepatosplenomegaly, and corneal clouding. All

forms of MPS are autosomal recessive except MPS type II(Hunter’s syndrome), which is X-linked recessive. Neo-nates appear normal. Onset of disease is insidious. Otherfeatures are listed in Table 6. Urinary testing for MPS sug-gests the diagnosis, which is confirmed by enzyme assaysfrom leukocytes or fibroblasts.

SPHINGOLIPIDOSES

The sphingolipidoses involve abnormal metabolismand accumulation of sphingolipids. Deficiency of hex-osaminidase A alone results in GM2 gangliosidosis, theclassic form of which is Tay-Sachs disease. Tay-Sachs dis-ease is more common in Ashkenazi Jews than in the gen-eral population and is autosomal recessive. Onset of symp-toms is between 3 and 6 months of age. The initial sign isan excessive startle reflex. A macular cherry red spot(Table 1) almost always is present at this stage, and psy-chomotor regression then begins. By age 1 year, the childis unresponsive and spastic. Seizures and macrocephalysoon follow, and most children die between 4 and 5 yearsof age. Late-onset GM2 gangliosidosis, also more com-mon in Ashkenazi Jews, presents in childhood and adult-hood. Symptoms include weakness, personality change,tongue atrophy and fasciculations, tremor, and mixedupper and lower motor neuron signs. Dysarthria, ataxia,and progressive spasticity and dementia follow. A cherryred macula is not present in late-onset disease. Diagnosisof both forms of GM2 gangliosidosis is by assays of hex-osaminidase A activity in serum, leukocytes, or culturedfibroblasts. No treatment is available.

SANDHOFF’S DISEASE

Sandhoff’s disease is a rare autosomal recessive dis-order caused by deficiencies in both hexosaminidase Aand B. It is not more prevalent in Ashkenazi Jews.Clinical features are identical to those of Tay-Sachs



Table 6. Mucopolysaccharidoses (MPS)

Affected Syndrome MPS Type Features Compound Defect Comments

Hurler’s IH MR, CF, CC DS, HS α-L-iduronidase

Scheie’s IS CF, CC DS, HS α-L-iduronidase

Hurler-Scheie IHS CF, CC, ± MR DS, HS α-L-iduronidase

Hunter’s II MR, CF DS, HS Iduronate sulfatase

Sanfilippo’s types A–D IIIA–D MR HS Distinct for each type

Morquio’s types A IVA, IVB CC, ± MR KS and Distinct for each typeand 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.)

Cardiac disease; motor weakness; dysostosis multiplex

Dysostosis multiplex; milder than Hurler’s

Intermediate between Hurler’s and Scheie’s

Motor weakness; aggressive

Severe behavior problems; speech delay

Odontoid hypoplasia; bony abnormalities

disease, with additional findings of hepatosplenomeg-aly and bony deformities. Diagnosis is by enzyme assaysof hexosaminidase. Foamy histiocytes are sometimesseen in bone marrow. No treatment is available.

FABRY’S DISEASE

Fabry’s disease is an X-linked recessive disordercaused by α-galactosidase deficiency. Presentation is usu-ally during adolescence or early adulthood, with painfulcrises in the extremities and paresthesias. Angiokera-tomas and gastrointestinal complaints are often present.There is an increased risk for stroke, heart disease, renalfailure, pulmonary complications, and hearing loss. In-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 DISEASENiemann-Pick Type A

Niemann-Pick type A is caused by sphingomyelinasedeficiency, which results in accumulation of lipids,mainly sphingomyelin. Infants are normal at birth butdevelop feeding problems, hepatomegaly, and psycho-motor regression in the first several months of life. Inhalf of the cases, children have macular cherry redspots. Opisthotonus and hyperreflexia are common,whereas seizure is uncommon. Death occurs betweenages 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 disor-der that may present in neonates as severe liver or lungdisease or in children as upgaze palsy or apraxia, ataxia,seizures, dementia, dysarthria, dysphagia, and dystonia.Adults present with psychiatric symptoms. Diagnosis issuggested by finding impaired cholesterol esterificationand is confirmed by genetic testing for the NPC1 andNPC2 genes. Foamy cells are observed in the liver,spleen, and marrow. Sea-blue histocytes are seen in themarrow in advanced disease. Cholesterol-loweringdrugs reduce cholesterol levels, but no treatmentimproves neurologic symptoms.34

PEROXISOMAL BIOGENESIS DISORDERS

Peroxisomes degrade very-long-chain fatty acids (C24,C26). The classic peroxisomal biogenesis disorder isZellweger’s syndrome (cerebrohepatorenal syndrome),an autosomal recessive disorder caused by deficiency ofmultiple proteins responsible for peroxisomal assembly.

Zellweger’s syndrome presents at birth as severe hypoto-nia, high forehead, wide-open fontanelles, hepatomegaly,and hyporeflexia. Intractable seizures, liver dysfunction,renal cysts, cardiac defects, retinal dystrophy, and sen-sorineural hearing loss are common. Brain MRI demon-strates severe hypomyelination of the hemispheres, withneuronal migrational defects (eg, polymicrogyria, pachy-gyria, periventricular heterotopias). Plasma very-long-chain fatty acids (C26:0 and C26:1) are elevated. After theneonatal period, phytanic acid also is elevated. Specificgenetic testing is available for 6 known mutations, themost common affecting the PEX1 gene. The majority ofaffected infants die in the first year. Severe psychomotorretardation develops in survivors.35

Milder presentations of peroxisomal biogenesis



Figure 4. Alexander’s disease in a 5-year-old boy with macro-cephaly. (A) T2-weighted magnetic resonance image shows sym-metric demyelination in the frontal lobe white matter, includingthe subcortical U fibers. (B) Photomicrograph (original magnifica-tion, ×100; hematoxylin and eosin stain) of the pathologic speci-men shows deposition of Rosenthal fibers (arrows). (Adapted withpermission from Cheon JE, Kim IO, Hwang YS, et al. Leukodys-trophy in children: a pictorial review of MR imaging features. Ra-diographics 2002;22:473. Radiological Society of North America.)

A

B

disorders include neonatal adrenoleukodystrophy (notrelated to X-linked adrenoleukodystrophy, which is dis-cussed below) and Refsum disease. Both conditionscan present in infancy or childhood as hypotonia, devel-opmental delay, vitamin K–responsive bleeding tenden-cy (due to liver dysfunction), sensorineural hearingloss, retinitis pigmentosa, neuropathy, and ataxia. Thespectrum is continuous with no simple phenotype-genotype correlations, and diagnosis can be delayedinto late adulthood.35

WHITE MATTER DISORDERS

White matter disorders classically present as progres-sive spasticity and neurocognitive regression. Hypotonia ischaracteristic in the neonatal period, whereas psychiatricdisturbance is typical in children and adults. Discussedbelow are vanishing white matter disorder, Alexander’sdisease, metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, X-linked adrenoleukodystrophy,Canavan’s disease, and Krabbe’s disease.36,37 A usefulmnemonic for recalling these disorders is VAMPACK.

VANISHING WHITE MATTER DISEASE

Vanishing white matter disease (childhood ataxia withcentral hypomyelination) is an autosomal recessive disor-der that usually presents in children age 2 to 6 years asslowly progressive cerebellar ataxia, spasticity, variableoptic atrophy, and relatively preserved cognitive abilities.38

Infections and minor head trauma may lead to alteredlevel of consciousness, developing into coma. Brain MRIshows progressive loss of white matter diffusely with cysticdegeneration. CSF may show elevated glycine. Later-onset (including adult-onset) disease has been describedand is associated with a milder clinical course. Mutationshave been found in genes that encode eukaryotic initia-tion factor 2B (eIF2B) subunits, which in turn may affectthe regulation of protein synthesis during cellular stress.39

ALEXANDER’S DISEASE

Alexander’s disease classically presents at approxi-mately 6 months of age as megalencephaly, progressivespasticity, seizures, and developmental regression. Deathis common in infancy and usually occurs before age 10 years. Brain MRI shows frontally dominant demyeli-nation involving the subcortical U fibers and contrastenhancement in the deep frontal white matter, basal gan-glia, and periventricular rim. Pathology shows astrocyticintracytoplasmic inclusion bodies called Rosenthal fibers(Figure 4). More than 30 mutations of genes encodingthe glial fibrillary acidic protein (GFAP) have been iden-

tified in association with Alexander’s disease. GFAP is amajor component of Rosenthal fibers. Juvenile- andadult-onset forms of Alexander disease have a mildercourse, with no macrocephaly or cognitive decline butwith a higher incidence of bulbar signs, ataxia, and posi-tive family history. Demyelination in late-onset disease isseen posteriorly rather than anteriorly.40,41

METACHROMATIC LEUKODYSTROPHY

Metachromatic leukodystrophy (sulfatide lipidosis) isan autosomal recessive disorder usually caused by defi-ciency of arylsulfatase A and, less commonly, by deficien-cy of the sphingolipid activator protein, saposin B.Sulfatides then accumulate, leading to myelin destabi-lization. The late infantile form is most common, withonset after 1 year of age. This form is characterized byataxia, hypotonia, and peripheral neuropathy, followedlater by progressive spasticity and cognitive decline. Inthe juvenile and adult forms, central nervous system(CNS) symptoms are more prominent, with behavioraldisturbances, spasticity, and cognitive decline. Brain MRIshows demyelination of periventricular white matter sym-metrically, with involvement of the corpus callosum, earlysparing of the subcortical U fibers, and late atrophy.There is no enhancement with contrast. A tigroid patternwith patchy white matter sparing (formerly thoughtpathognomic for Pelizaeus-Merzbacher disease) and aleopard skin pattern have been described. In this case,the islands of normal-appearing white matter may en-hance with contrast, but the demyelinated patches donot (Figure 5). Diagnosis is by testing for arylsulfatase Aactivity. Bone marrow transplantation may be beneficialin mildly affected patients with late-onset disease.

PELIZAEUS-MERZBACHER DISEASE

Pelizaeus-Merzbacher disease classically presents asneonatal nystagmus, choreoathetosis, progressive atax-ia, spasticity, and developmental regression, with deathoften between 5 and 7 years of age. The spasticity mayaffect the legs preferentially. The nystagmus can some-times resolve. Milder cases present later, and childrenwho present after 1 year of age may live into adulthood.Brain MRI shows diffusely deficient myelination of thecerebral hemispheres, with a thin corpus callosum andatrophy of white matter. Histopathology of early diseaseshows patches or stripes of perivascular white mattersparing, resulting in a tigroid pattern, sometimes alsovisible on MRI (Figure 5). The etiology is duplication ormutation of the proteolipid protein 1 (PLP1) gene onthe X chromosome, resulting in over- or underproduc-tion of proteolipid protein. Diagnosis is by detectingduplication or mutation of the PLP1 gene.



X-LINKED ADRENOLEUKODYSTROPHY

X-Linked adrenoleukodystrophy presents between 5and 8 years of age as a subacute onset of behavioralproblems, visual loss, hyperpigmented skin, and adren-al insufficiency, leading to progressive spasticity, opticatrophy, late seizures, and eventual vegetative state.Death is typical by 3 years after diagnosis. Brain MRIshows demyelination, which begins in the splenium ofthe corpus callosum and spreads in a posterior to ante-rior pattern. The leading edge of demyelination en-hances with contrast (Figure 6). The defect is in theABCD1 gene, which codes for a peroxisomal mem-brane ATP-binding cassette protein transporter. As aresult, very-long-chain fatty acids are not degradedand, thus, accumulate. Diagnosis is suggested by MRIfindings and by elevated very-long-chain fatty acids inblood, especially C26:0 but not C26:1 (elevated C26:0plus C26:1 suggests Zellweger’s syndrome).

CANAVAN’S DISEASE

Canavan’s disease (spongiform leukodystrophy) is anautosomal recessive disorder that presents at 2 to 4 months of age as megalencephaly and hypotonia, lead-ing to developmental regression, progressive spasticity,and seizures. Brain MRI shows diffuse demyelination thatbegins in subcortical and cerebellar white matter, laterinvolving central white matter (Figure 7). The globus pal-

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. Diag-nosis is by finding large quantities of NAA in urine.

KRABBE’S DISEASE

Krabbe’s disease (globoid cell leukodystrophy) is anautosomal recessive disorder that presents at 1 to 7 months of age as irritability and hyperreactive startle.



Figure 5. Metachromatic leukodystrophy. T2-weighted mag-netic resonance image shows numerous tubular structures withlow-signal intensity in a radiating (“tigroid”) pattern within thedemyelinated 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 reviewof MR imaging features. Radiographics 2002;22:464. RadiologicalSociety of North America.)

Figure 6. X-Linked adrenoleukodystrophy in a 5-year-old boy.(A) T2-weighted magnetic resonance image (MRI) shows sym-metric confluent demyelination in the peritrigonal white matterand the splenium of the corpus callosum. (B) Gadolinium-enhanced T1-weighted MRI reveals enhancement of the lead-ing 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 im-aging features. Radiographics 2002;22:467. Radiological Societyof North America.)

A

B

Developmental regression, spasticity, areflexia, startlemyoclonus, seizures, and blindness follow. Most affectedinfants die by 1 year of age. Brain MRI shows diffusedemyelination beginning in deep white matter, later in-volving subcortical white matter. Computed tomographyshows calcification in basal ganglia, thalami, and coronaradiata. CSF shows elevated proteins. Motor nerve con-duction velocities are prolonged. Diagnosis is by demon-strating deficient galactocerebroside β-galactosidase activ-ity in leukocytes or cultured fibroblasts.

GRAY MATTER DISORDERS

Gray matter disorders classically present as seizuresand loss of function of affected cortex. Prototypical graymatter disorders include Tay-Sachs disease (discussedpreviously) and the neuronal ceroid lipofuscinoses.

The neuronal ceroid lipofuscinoses (NCLs) are aheterogeneous group of inherited neurodegenerativelysosomal storage disorders presenting as some combi-nation of visual loss, behavioral change, movement dis-order, and seizures, especially myoclonic seizures.42

The infantile, late infantile, and juvenile forms aremore 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 atbirth. Onset of seizures and visual loss occurs within 2 years and death is typical by age 10 years. In the lateinfantile form, initial symptoms are seizures between

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 4and 10 years as rapidly progressive visual loss leading tototal blindness within 2 to 4 years; seizures beginbetween ages 5 and 18 years and death occurs in theteens to thirties. The adult-onset form presents in thethirties, resulting in death within 10 years. All of theNCLs are autosomal recessive except the adult form,which is autosomal dominant. The genes involved arePPT1 (at locus CLN1), CLN2 through CLN6, andCLN8. PPT1 defects can present at any age, whereasCLN3 and CLN4 present in children and adults.Electron microscopy of lymphocytes, skin, conjunctiva,or anal mucosa shows fingerprint, curvilinear, or gran-ular osmiophilic deposits. More specific enzyme assaysand genetic testing are available. Treatment is support-ive. Seizures may be worsened by phenytoin and car-bamazepine. Lamotrigine may be the most efficaciousand best-tolerated anticonvulsant. Trihexyphenidyl im-proves dystonia and sialorrhea.42

OTHER METABOLIC DISORDERS

SMITH-LEMLI-OPITZ SYNDROME

Smith-Lemli-Opitz syndrome is caused by deficiencyof 7-dehydrocholesterol reductase, which leads to im-paired cholesterol synthesis. Patients have ptosis, ante-verted nares, micrognathia, microcephaly, hypospadias,and cardiac defects. Syndactyly of the second and thirdtoes is almost always present. Presentation is that ofpoor growth and developmental delay. Diagnosis isbased on elevations of 7-dehydrocholesterol and de-creased serum cholesterol. Management is with choles-terol supplementation.

LESCH-NYHAN SYNDROME

Lesch-Nyhan syndrome is an X-linked recessive dis-order caused by deficiency of hypoxanthine-guaninephosphoribosyl transferase (HPRT), an enzyme in-volved in the metabolism of purines. This defect leadsto hyperuricemia and increased urinary excretion ofuric acid. Most neonates are normal until 3 months ofage, when they demonstrate hypotonia and globaldevelopmental delay. By age 1 to 2 years, choreoatheto-sis and dystonia are apparent, and by age 2 to 3 years,the characteristic severe self-mutilating behavior isapparent. Most children never learn to walk. Renal fail-ure due to urate deposition and gouty arthritis occur



Figure 7. Canavan’s disease in a 6-month-old boy with macro-cephaly. T2-weighted magnetic resonance image shows extensivehigh-signal intensity areas throughout the white matter. Noteinvolvement of the subcortical U fibers. (Adapted with permissionfrom Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in chil-dren: a pictorial review of MR imaging features. Radiographics2002;22:472. Radiological Society of North America.)

later in life. Diagnosis is suggested by an elevated uricacid-to-creatinine ratio. Confirmation is by HPRT activ-ity. Treatment with allopurinol does not improve theneurologic outcome.43

MENKES’ SYNDROME

Menkes’ (kinky hair) syndrome is an X-linked reces-sive disorder of copper transport resulting in low serumcopper levels, decreased intestinal copper absorption,and reduced activity of copper-dependent enzymes.Affected males develop normally during the first monthsof life, but development then slows and regression occurs.Myoclonic seizures in response to stimulation are an earlyand almost constant feature. Dysautonomia occurs. Thehair takes on a brittle, steel wool appearance. Other find-ings on examination include skin laxity, sagging jowls, andhypotonia. Cerebral vessels are often tortuous and nar-rowed. Ischemic infarcts and subdural hematomas canoccur. Death usually occurs before age 3 years. Laboratoryevaluation shows low serum copper and ceruloplasmin.CSF and plasma catecholamines are abnormal. Moleculartesting is available. Treatment involves subcutaneous orintravenous copper administration. Results are variable,possibly because of poor CNS penetration.44

WILSON’S DISEASE

Wilson’s disease is an autosomal recessive disorderwith defective copper transporting ATPase that results inimpaired binding of copper to ceruloplasmin and im-paired excretion of copper into bile. Copper accumu-lates in the liver, and patients present with liver or CNSdisease. CNS symptoms include tremor, chorea, dystonia,dysarthria, psychiatric disturbance, and cognitive impair-ment. Liver disease is more common in children, withfulminant liver failure described in preschool-age chil-dren.45 CNS disease with mild liver disease more typicallyis seen in teens and adults. Laboratory studies show lowserum copper and ceruloplasmin and elevated urinarycopper. Copper deposition in Descemet’s membrane isseen on slit-lamp examination (Kayser-Fleischer rings).Kayser-Fleischer rings and low serum ceruloplasmin arefound in more than 90% of those presenting with CNSdisease but may be absent in those with liver disease. MRIshows symmetric lesions in basal ganglia, thalamus, andbrainstem that are bright on T2-weighted sequences.Asymmetric lesions may be seen in white matter.46,47

Genetic testing is available. Traditional treatment is witha copper chelator (ie, penicillamine or trientine). Trien-tine plus zinc, which impairs copper absorption from thegut, may work as well as penicillamine and is better tol-erated.48 Tetrathiomolybdate, a promising investigationaldrug that impairs copper absorption in the gut and binds

copper in blood, works faster than zinc and is also bettertolerated than penicillamine.49

OTHER

Pyridoxine-dependent epilepsy presents as neonatalseizures that respond only to pyridoxine.50 Biotinidasedeficiency presents as seizures later in infancy to earlychildhood, which respond to biotin.51 Glucose trans-porter 1 (GLUT-1) deficiency syndrome presents be-tween 1 and 4 months of age as refractory seizures,acquired microcephaly, ataxia, and low CSF glucose.Symptoms are due to defective transport of glucoseacross the blood-brain barrier. Seizures respond to aketogenic diet.52,53

ACKNOWLEDGEMENT

We thank Justin Stahl, MD, for the white matter mnemon-ic VAMPACK. We thank Gregg Nelson, MD, for helpful com-ments and for Table 2.

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