metabolic disorders in pediatric...

2 Hospital Physician Board Review Manual www.turner -white.com

INTRODUCTION

This manual reviews metabolic diseases that affectthe nervous system, focusing on the usual presentationsfrom the perspective of a pediatric neurologist. Many ofthese disorders will also have milder presentations inlater life; these are not discussed. 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 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 II.

GSD Type V

GSD type V (McArdle disease) is caused by deficien-cy of myophosphorylase and presents in adolescents ascramps and muscle fatigue shortly after initiating exer-cise. A “second wind” effect can occur (ie, renewed abil-ity to continue exercising if patients rest briefly after theonset of fatigue). Laboratory studies show elevated CKlevels, post-exertional myoglobinuria, and a failure ofnormal rise in lactate levels with exercise. The forearmischemic test is the classic exercise test but is difficult toperform reliably. Muscle biopsy shows glycogen storagein muscle and absence of myophosphorylase. Moderateexercise with careful warmup is advisable. Dietary treat-ments 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).Management for all fatty acid oxidation disordersincludes avoiding prolonged fasts and aggressive use ofdextrose-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

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Table 1. Clinical Presentations and Differential Diagnosis of Metabolic Disorders

CPT = carnitine-palmitoyl-transferase; GSD = glycogen storage diseases; LCHAD = long–chain hydroxy acyl CoA dehydrogenase deficiency;VLCAD = very-long-chain acyl CoA dehydrogenase. (Adapted from Nyhan WL, Ozand PT. Atlas of metabolic diseases. New York: Chapman andHall; 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

Homocystinuria

Propionic acidemia

Methylmalonic acidemia

Isovaleric acidemia

Glutaric acidemia type I

Urea cycle disorders

Congenital disorders of glycosylation

Menkes disease

Fabry disease

Leigh syndrome

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 carnitine-palmitoyl-transferase-2deficiency

GSD II (Pompe disease)

GSD III (Cori disease)

Mitochondrial disorders

Cherry red spots on the macula

Tay-Sachs disease

Sandhoff disease

GM1 gangliosidosis

Niemann-Pick disease

Sialidosis

Multiple sulfatase deficiency

Rhabdomyolysis/myoglobinuria

GSD type V (McArdle disease)

Adult CPT-2 deficiency

VLCAD deficiency

LCHAD deficiency

Carnitine transporter deficiency

Mitochondrial disorders

Progressive myoclonic epilepsies

Myoclonic epilepsy with ragged red fibers

Unverricht-Lundborg disease (Balticmyoclonus)

Neuronal ceroid lipofuscinosis

Lafora body 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 disease (mucopolysaccharidosis III)

Hunter disease (mucopolysaccharidosis II)

Carbohydrates

GlycogenGlucose

Galactose Glucose-6-P

Fructose Ammino acids Fatty acids

Pyruvate Lactate

MitrochondrionCytosol

Acetyl CoA

ATP ADP

Ketones

UreaNH3

Respiratory chain

Krebscycle

β-oxidation

Ureacycle

Figure 1. Basic pathways of intermediary metabolism. Glucose-6-P = glucose-6-phosphatase. (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 showsdecreased long-chain acylcarnitines (C16, C18).Chronic treatment with medium-chain fatty acids maybe of benefit.

CPT2 deficiency has an infantile (liver) and adult(muscle) form. The infantile form presents ashepatomegaly, liver failure, cardiomegaly, arrhythmias,and seizures, with hypoketotic hypoglycemia. The adult

form presents in the teens to twenties as episodic rhab-domyolysis and myoglobinuria following prolongedexercise, cold exposure, infection, or fasting, with ele-vated CK levels and myoglobinuria.

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 dehydroge-nase (LCHAD) deficiency are associated with cardiomy-opathy, skeletal myopathy, post-exertional rhabdomyoly-sis, and hypoketotic hypoglycemia with decompensations.Children with VLCAD deficiency can present with a Reye-like syndrome, which can be fatal. Mothers carrying afetus with LCHAD deficiency can present with hemolysis,elevated liver function tests, and low platelet counts(HELLP syndrome). Diagnosis is by acylcarnitine profile,which shows elevated long-chain acylcarnitines andhydroxy-acylcarnitines, respectively, in patients withVLCAD 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 hydroxyacylCoA dehydrogenase; M = skeletal muscle; MCAD = medium-chain acyl CoA dehydrogenase; N = neonate; nl = normal. (Adapted from NyhanWL, Ozand PT. Atlas of metabolic diseases. New York: Chapman and Hall; 1998.)

oxidation and amino acid metabolism. The classicneonatal 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, from 50 to 250). However, 40% of patients have

normal lactate levels at rest. Furthermore, mitochondri-al DNA panels are abnormal in only 10% of patients.11

Thus muscle biopsy remains a key to diagnosis. Musclebiopsy 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

Syndrome 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.

MELAS4

MERRF5

CPEO6

Kearns-Sayre syndrome4

Leigh syndrome, or sub-acute necrotizingencephalomyelopathy7

Leber hereditary opticneuropathy8

Neurogenic muscleweakness, ataxia, andretinitis pigmentosa7

Friedreich 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 deletion; only skeletal mus-cle affected

Multiple mtDNA deletion; all tissues affected;check serial ECGs

Severe neurodegenerative disease; most dieby 3 years of age

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 syndrome)

Endocrine: diabetes, hypoparathyroidism

Adapted with permission from Cohen BH, Gold DR. Mitochondrialcytopathy in adults: What we know so far. Cleveland Clin J Med2001;68:625-641.

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 paracrystallineinclusions. Brain MRI may show lesions of the basal gan-glia, thalamus, midbrain, or cerebral white matter. In thecerebral white matter, recurrent stroke-like events mayoccur, with transitory migrating lesions that cross vascu-lar territories (Figure 2). Magnetic resonance 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 similar 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 car-bohydrate 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 sign 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 hyperam-monemia can be severe, and a single attack can cause per-manent cognitive disability. Seizures, spasticity, behavioralproblems, and ataxia are common. Metabolic stroke withan acute decompensation can occur. Many patients willdevelop renal failure and require renal transplantation.Methylmalonic acid can also be elevated in disorders ofcobalamin (vitamin B12) metabolism, and megaloblasticanemia can seen. Brain MRI may show bilateral globuspallidus infarction. Management of methylmalonic acid-emia consists of vitamin B12 supplementation and dietaryprotein 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 acutedecompensation. 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. Neurotoxicphenylketones then accumulate. Testing shows elevat-ed levels of blood phenylalanine and urine phenylke-tones. Infants are normal at birth but in the first yearof life manifest progressive cognitive delay, micro-cephaly, spasticity, recurrent eczematous rash, and amousy odor. Seizures occur in 25% of untreated PKUpatients.19 Newborn screening and early treatment canprevent these symptoms. Treatment in classic PKU con-sists of dietary restriction of phenylalanine and closemonitoring of blood phenylalanine levels. Women withPKU should have phenylalanine levels under controlbefore attempting to conceive. Fetuses exposed to highlevels of phenylalanine are at risk for congenital heartdisease, intrauterine growth restriction, mental retar-dation, and microcephaly. Approximately 2% of PKUpatients have normal phenylalanine hydroxylase ac-tivity but are deficient in the cofactor tetrahydro-biopterin.20 These patients require biopterin supple-mentation.

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 ofleucine, isoleucine, and valine. The classic form pre-sents in the first week of life with poor feeding, lethargy,and vomiting, quickly progressing to coma, seizures anddeath if untreated. An intermittent form may presentlater in life with attacks of transient ataxia, sometimesaccompanied by cerebral edema.21 These attacks aretriggered by intercurrent illness or stresses. Urine,sweat, and cerumen often smell like maple syrup.Acidosis and hyperammonemia are uncommon.

In the United States, many states screen 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.)

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 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,may be beneficial. Valproic acid, which inhibits metabo-lism of 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 deficiency,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 tachyp-nea) 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 than24 hours27 are correlated with death or profound mentalretardation. Ammonia levels less than 180 µg/dL usuallyresults in normal development or only mild mental retar-dation.26 Milder forms including female carriers ofornithine transcarbamylase deficiency can have a moresubtle presentation.

Treatment

Hyperammonemia in an encephalopathic infant is amedical emergency. In addition to determining ammo-nia levels and acid-base status, laboratory studies shouldbe ordered for electrolytes, calcium, glucose, lactate,liver enzymes, free and total carnitine, quantitative plas-ma amino acids, and urine organic acids. Acute man-agement for all urea cycle disorders consists of (1) stop-ping all protein intake; (2) starting an intravenousinfusion of 10% glucose plus lipid to promote the ana-bolic state; and (3) starting arginine HCl, sodium ben-zoate, and sodium phenylacetate with intravenous load-ing doses followed by maintenance infusions. Peritonealdialysis or hemodialysis should be considered if there isclinical deterioration and ammonia levels are notresponding. Chronic management typically includesprotein restriction, and oral sodium benzoate and sodi-um phenylacetate supplementation.25 Because the urea



Mitochondrion

Cytoplasm

Asparate

Argininosuccinate

FumarateArginineUrea

Ornithine

Ornithine

Citrull

ine

Citrull

ineCarbamlyphosphate

HCO3 + NH4 + 2 ATP

N-acetylglutamateCPSI

ARG

ASL

ASS

OTC

Figure 3. The urea cycle and its disorders. ARG = arginase defi-ciency; ASL = arginosuccinic acid lyase deficiency; ASS = argino-succinic acid synthetase deficiency; CPS-I = 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.)

cycle takes place in the liver, liver transplantation is cura-tive for the metabolic disorder but does not reverse accu-mulated neurologic injury. In the severe forms of the ureacycle disorders (eg, carbamyl phosphate synthetase I[CPS1] deficiency, ornithine transcarbamylase [OTC]deficiency), liver transplantation before 1 year of age isassociated with better survival into the childhood yearswith mild (rather than profound) mental retardation.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 includesmental retardation, motor deficits, and death.

OTC deficiency is identical to CPS1 deficiency inpresentation except that urine orotic acids are elevated.Plasma amino acids show decreased citrulline and argi-nine. Due to skewed X-inactivation, 15% of females willdevelop 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 maydemonstrate failure to thrive, hepatomegaly, and un-usual hair, including alopecia and trichorrhexisnodosa. Plasma amino acids show elevated citrullinewith decreased arginine. Argininosuccinic acid is ele-vated in plasma and present in urine. Treatment in-volves protein restriction and arginine supplementa-

tion. With age, acute episodes of hyperammonemiabecome less frequent. Developmental delays are com-mon even with good 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 heterogenous group of mostly autosomalrecessive disorders with deficient glycosylation of glyco-proteins.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 BODY DISEASE

Lafora body disease is an autosomal recessivepolyglucosan storage disorder that presents asmyoclonic seizures in the mid-teens, with rapid neu-rocognitive deterioration. Neurons show Lafora bodieswith a core that stains very dark with periodic acidSchiff, with a lighter outer “halo.” Skin, liver, or musclebiopsy can also be diagnostic.32

LYSOSOMAL STORAGE DISORDERS

Lysosomes are involved in the degradation of largemolecules, including mucopolysaccharides, sphin-golipids, 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 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 ofsymptoms is between 3 and 6 months of age. The initialsign is an excessive startle reflex. A macular cherry redspot (see Table 1) almost always is present at this stage,and psychomotor regression then begins. By age 1 year,the child is unresponsive and spastic. Seizures andmacrocephaly soon follow, and most children die by 4 to5 years of age. Late-onset GM2 gangliosidosis, also morecommon in Ashkenazi Jews, presents in childhood andadulthood. Symptoms include weakness, personalitychange, tongue atrophy and fasciculations, tremor, andmixed upper and lower motor neuron signs. Dysarthria,ataxia, and progressive spasticity and dementia follow. Acherry red macula is not present in late-onset disease.Diagnosis of both forms of GM2 gangliosidosis is byassays of hexosaminidase A activity in serum, leukocytes,or cultured fibroblasts. No treatment is available.

SANDHOFF DISEASE

Sandhoff disease is a rare autosomal recessive disor-der 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 IH MR, CF, CC DS, HS α-L-iduronidase

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

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

Hunter II MR, CF DS, HS Iduronate sulfatase

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

Morquio types A IVA, IVB CC, ± MR KS and Distinct for each typeand B CS (type A);

KS (type B)

CF = coarse facial features, CC = corneal clouding, 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

Intermediate between Hurler and Scheie

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 DISEASE

Fabry disease is an X-linked recessive disorder causedby α-galactosidase deficiency. Presentation is usually dur-ing adolescence or early adulthood with painful crises inthe extremities and paresthesias. Angiokeratomas andgastrointestinal complaints are often present. There isan increased risk for stroke, heart disease, renal failure,pulmonary complications, and hearing loss. Intelligenceis normal. Diagnosis is by enzyme assay showing de-creased activity. α-Galactosidase replacement therapy isavailable 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 cases, children have cherry red spots. Opis-thotonus and hyperreflexia are common, whereasseizure is uncommon. Death occurs between ages 2 and4 years. Diagnosis is based on enzyme assay. Foamy cellsare observed in bone marrow and blood.

Niemann-Pick Type C

Niemann-Pick type C is an autosomal recessive dis-order that may present in neonates as severe liver orlung disease or in children as upgaze palsy or apraxia,ataxia, seizures, dementia, dysarthria, dysphagia, anddystonia. Adults present with psychiatric symptoms.Diagnosis is suggested by finding impaired cholesterolesterification and is confirmed by genetic testing for theNPC1 and NPC2 genes. Foamy cells are observed inliver, spleen, and marrow. Sea-blue histocytes are seenin marrow 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 disorderis Zellweger syndrome (cerebrohepatorenal syndrome),an autosomal recessive disorder caused by deficiency ofmultiple proteins responsible for peroxisomal assembly.

Zellweger syndrome presents at birth as severe hypoto-nia, high forehead, wide-open fontanelles, hepato-megaly, and hyporeflexia. Intractable seizures, liver dys-function, renal cysts, cardiac defects, retinal dystrophy,and sensorineural hearing loss are common. Brain MRIdemonstrates severe hypomyelination of the hemi-spheres, with neuronal migrational defects (eg, polymi-crogyria, pachygyria, periventricular heterotopias).Plasma very-long-chain fatty acids (C26:0 and C26:1) areelevated. After the neonatal period, phytanic acid also iselevated. Specific genetic testing is available for 6 knownmutations, the most common affecting the PEX1 gene.The majority of affected infants die in the first year.Severe psychomotor retardation develops in survivors.35

Milder presentations of peroxisomal biogenesis



Figure 4. Alexander disease in a 5-year-old boy with macro-cephaly. (A) T2-weighted magnetic resonance image (MRI) showssymmetric demyelination in the frontal lobe white matter includ-ing the subcortical U fibers. (B) Photomicrograph (original magni-fication, ×100; hematoxylin and eosin stain) of the pathologic spec-imen 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. Hypotoniais characteristic in the neonatal period, whereas psychi-atric disturbance is typical in children and adults. Dis-cussed below are vanishing white matter disorder,Alexander disease, metachromatic leukodystrophy,Pelizaeus-Merzbacher disease, X-linked adrenoleukodys-trophy, Canavan disease, and Krabbe 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 aged 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 leading 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 DISEASE

Alexander disease classically presents at approximate-ly 6 months of age as megalencephaly, progressive spas-ticity, seizures, and developmental regression. Death iscommon 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 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 by 5 to 7 years of age. The spasticity may affect thelegs preferentially. The nystagmus can sometimesresolve. Milder cases present later, and children whopresent 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 (see Figure 5). The etiology is duplicationor mutation of the proteolipid protein gene (PLP1) 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 at 5 to 8 years of age as a subacute onset of behavioral prob-lems, visual loss, hyperpigmented skin, and adrenalinsufficiency, leading to progressive spasticity, optic atro-phy, late seizures, and eventual vegetative state. Death istypical by 3 years after diagnosis. Brain MRI showsdemyelination, which begins in the splenium of the cor-pus callosum and spreads in a posterior to anterior pat-tern. The leading edge of demyelination enhances withcontrast (Figure 6). The defect is in the ABCD1 gene,which codes for a peroxisomal membrane ATP-bindingcassette protein transporter. As a result, very-long-chainfatty acids are not degraded and, thus, accumulate.Diagnosis is suggested by MRI findings and by elevatedvery-long-chain fatty acids in blood, especially C26:0but not C26:1 (elevated C26:0 plus C26:1 suggestsZellweger syndrome).

CANAVAN DISEASE

Canavan 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 DISEASE

Krabbe 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. (A) T2-weightedmagnetic resonance image (MRI) shows numerous tubular struc-tures with low signal intensity in a radiating (“tigroid”) patternwithin the demyelinated deep white matter. Note sparing of sub-cortical U fibers. (Adapted with permission from Cheon JE, KimIO, Hwang YS, et al. Leukodystrophy in children: a pictorial re-view of MR imaging features. Radiographics 2002;22:464. Radio-logical Society of North America.)

Figure 6. X-Linked adrenoleukodystrophy (ALD) in a 5-year-old boy. (A) T2-weighted magnetic resonance image (MRI)shows symmetric confluent demyelination in the peritrigonalwhite matter and the splenium of the corpus callosum. (B) Gadolinium-enhanced T1-weighted MRI reveals enhance-ment of the leading edge of active demyelination and inflamma-tion (arrows). (Adapted with permission from Cheon JE, Kim IO,Hwang YS, et al. Leukodystrophy in children: a pictorial reviewof MR imaging features. Radiographics 2002;22:467. RadiologicalSociety of 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 diseases classically present as seizuresand loss of function of affected cortex. Prototypical graymatter diseases 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 Theinfantile, late infantile, and juvenile forms are morelikely to be accompanied by retinal blindness. The adultform is usually not associated with visual loss. Thoseaffected by the infantile form are normal at birth. Onsetof seizures and visual loss occurs within 2 years anddeath is typical by age 10 years. In the late infantileform, initial symptoms are seizures between ages 2 and

4 years, followed by developmental regression, demen-tia, pyramidal and extrapyramidal signs, and visual loss;death occurs between ages 6 and 30 years. The juvenileform presents between ages 4 and 10 years as rapidlyprogressive visual loss leading to total blindness within 2to 4 years; seizures begin between ages 5 and 18 yearsand death occurs in the teens to thirties. The adult-onset form presents in the thirties, resulting in deathwithin 10 years later. All of the NCLs are autosomalrecessive except the adult form, which is autosomaldominant. The genes involved are PPT1 (at locusCLN1), CLN2 through CLN6, and CLN 8. PPT1 de-fects can present at any age, whereas CLN3 and CLN4present in children and adults. Electron microscopy ofwhite blood cells, skin, conjunctiva, or anal mucosashows fingerprint, curvilinear, or granular osmiophilicdeposits. More specific enzyme assays and genetic test-ing are available. Treatment is supportive. Seizures maybe worsened by phenytoin and carbamazepine.Lamotrigine may be the most efficacious and best-tolerated anticonvulsant. Trihexyphenidyl improvesdystonia 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, antev-erted 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 disease in a 6-month-old boy with macro-cephaly. T2-weighted magnetic resonance image (MRI) showsextensive high-signal intensity areas throughout the white matter.Note involvement of the subcortical U fibers. (Adapted with per-mission from Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophyin children: a pictorial review of MR imaging features. Radio-graphics 2002;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 DISEASE

Menkes (kinky hair) disease is an X-linked recessivedisorder of copper transport resulting in low serum cop-per levels, decreased intestinal copper absorption, andreduced activity of copper-dependent enzymes. Affectedmales develop normally during the first months of life,but development then slows and regression occurs. Myo-clonic seizures in response to stimulation are an early andalmost constant feature. Dysautonomia occurs. The hairtakes on a brittle, steel wool appearance. Other findingson 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 asrefractory seizures, acquired microcephaly, ataxia, andlow CSF glucose between 1 and 4 months of age. Symp-toms are due to defective transport of glucose across theblood-brain barrier. Seizures respond to the ketogenicdiet.52,53

ACKNOWLEDGEMENT

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

REFERENCES

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 defectsin infantile epilepsy. J Child Neurol 2002;17 Suppl 3:3S57–83.

3. DiMauro S, Andreu AL, Musumeci O, Bonilla E. Diseases of oxi-dative phosphorylation due to mtDNA mutations. Semin Neurol2001;21:251–60.

4. DiMauro S. MELAS. GeneReviews. Available at www.geneclinics.org/profiles/melas. Accessed 22 Apr 2005.

5. DiMauro S, Hirano M. MERRF. GeneReviews. Available atwww.geneclinics.org/profiles/merrf. Accessed 22 Apr 2005.

6. DiMauro S, Hirano M. Mitochondrial DNA deletion syndromes.GeneReviews. Available at www.geneclinics.org/profiles/kss.Accessed 22 Apr 2005.

7. Thorburn DR, Rahman S. Mitochondrial DNA-associated Leighsyndrome and NARP. GeneReviews. Available at www.geneclinics.org/profiles/narp. Accessed 8 Apr 2005.

8. Biousse V, Newman NJ. Neuro-ophthalmology of mitochondri-al diseases. Semin Neurol 2001;21:275–91.

9. Bidichandani SI, Ashizawa T. Friedreich ataxia. GeneReviews.Available at www.geneclinics.org/profiles/friedreich. Accessed 8 Apr 2005.

10. Cohen BH, Gold DR. Mitochondrial cytopathy in adults: whatwe know so far [published erratum in Cleve Clin J Med 2001;68:746]. Cleve Clin J Med 2001;68:625–6, 629–42.

11. Scaglia F, Towbin JA, Craigen WJ, et al. Clinical spectrum, mor-bidity, and mortality in 113 pediatric patients with mitochondr-ial disease. Pediatrics 2004;114:925–31.

12. Lin DD, Crawford TO, Barker PB. Proton MR spectroscopy inthe diagnostic evaluation of suspected mitochondrial disease.AJNR Am J Neuroradiol 2003;24:33–41.

13. Moller HE, Kurlemann G, Putzler M, et al. Magnetic resonancespectroscopy in patients with MELAS. J Neurol Sci 2005;229–230C:131–9.

14. Clark JM, Marks MP, Adalsteinsson E, et al. MELAS: Clinical and



pathologic correlations with MRI, xenon/CT and MR spectros-copy. Neurology 1996;46:223–7.

15. Gillis L, Kaye E. Diagnosis and management of mitochondrialdiseases. Pediatr Clin North Am 2002;49:203–19.

16. De Vivo DC, Jackson A, Wade C, et al. Dichloroacetate treatmentof MELAS-associated lactic acidosis [abstract]. Ann Neurol 1990;28:437.

17. Fenichel GM. Clinical pediatric neurology: a signs and symp-toms approach. 4th ed. Philadelphia: W.B. Saunders; 2001.

18. Seashore MR. The organic acidemias: an overview. GeneReviews.Available at www.geneclinics.org/query?dz=oa-overview. Accessed22 Apr 2005.

19. Pitt DB, Danks DM. The natural history of untreated phenylke-tonuria over 20 years. J Paediatr Child Health 1991;27:189–90.

20. Dhondt JL. Tetrahydrobiopterin deficiencies: preliminary analy-sis from an international survey. J Pediatr 1984;104:501–8.

21. Morton DH, Strauss KA, Robinson DL, et al. Diagnosis andtreatment of maple syrup disease: a study of 36 patients. Pedi-atrics 2002;109:999–1008.

22. Mudd SH, Skovby F, Levy HL, et al. The natural history of homo-cystinuria due to cystathionine beta-synthase deficiency. Am JHum Genet 1985;37:1–31.

23. Applegarth DA, Toone JR. Glycine encephalopathy (nonketotichyperglycinaemia): review and update. J Inherit Metab Dis 2004;27:417–22.

24. Zschocke J, Hoffman GF. Manual of metabolic paediatrics. 2nded. Stuttgart, Germany: Schattauer Publishers; 2004.

25. Leonard JV, Morris AA. Urea cycle disorders. Semin Neonatol2002;7:27–35.

26. Uchino T, Endo F, Matsuda I. Neurodevelopmental outcome oflong-term therapy of urea cycle disorders in Japan. J InheritMetab Dis 1998;21 Suppl 1:151–9.

27. Msall M, Batshaw ML, Suss R, et al. Neurologic outcome in chil-dren with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med 1984;310:1500–5.

28. McBride KL, Miller G, Carter S, et al. Developmental outcomeswith early orthotopic liver transplantation for infants withneonatal-onset urea cycle defects and a female patient with late-onset ornithine transcarbamylase deficiency. Pediatrics 2004;114:e523–6.

29. Pelet A, Rotig A, Bonaiti-Pellie C, et al. Carrier detection in apartially dominant X-linked disease: ornithine transcarbamylasedeficiency. Hum Genet 1990;84:167–71.

30. Elsas LJ. Galactosemia. GeneReviews. Available at www.geneclinics.org/profiles/galactosemia/?Lng=GB. Accessed 22 Apr 2005.

31. Jaeken J. Komrower Lecture. Congenital disorders of glycosyla-tion (CDG): it’s all in it! J Inherit Metab Dis 2003;26:99–118.

32. Minassian BA. Lafora’s disease: towards a clinical, pathologic,and molecular synthesis. Pediatr Neurol 2001;25:21–9.

33. Wilcox WR, Banikazemi M, Guffon N, et al. Long-term safetyand efficacy of enzyme replacement therapy for Fabry disease.Am J Hum Genet 2004–75:65-74.

34. Patterson MC, Di Bisceglie AM, Higgins JJ, et al. The effect ofcholesterol-lowering agents on hepatic and plasma cholesterolin Niemann-Pick disease type C. Neurology 1993;43:61–4.

35. Steinberg SJ, Raymond GV, Braverman NE, et al. Peroxisome bio-

genesis disorders, Zellweger Syndrome spectrum. GeneReviews.Available at www.genetests.org/query?dz=pbd. Accessed 22 Apr2005.

36. Di Rocco M, Biancheri R, Rossi A, et al. Genetic disorders affect-ing white matter in the pediatric age. Am J Med Genet BNeuropsychiatr Genet 2004;129B:85–93.

37. Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in children:a pictorial review of MR imaging features. Radiographics 2002;22:461–76.

38. van der Knaap MS, Barth PG, Gabreels FJ, et al. A new leukoen-cephalopathy with vanishing white matter. Neurology 1997;48:845–55.

39. Leegwater PA, Pronk JC, van der Knaap MS. Leukoenceph-alopathy with vanishing white matter: from magnetic resonanceimaging pattern to five genes. J Child Neurol 2003;18:639–45.

40. Li R, Johnson AB, Salomons G, et al. Glial fibrillary acidic pro-tein mutations in infantile, juvenile and adult forms of Alex-ander disease. Ann Neurol 2005;57:310–26.

41. van der Knaap MS, Salomons GS, Li R, et al. Unusual variants ofAlexander’s disease. Ann Neurol 2005;57:327–38.

42. Wisniewski KE, Zhong N, Philippart M. Pheno/genotypic cor-relations of neuronal ceroid lipofuscinoses. Neurology 2001;57:576–81.

43. Nyhan WL, Ozand PT. Atlas of metabolic diseases. New York:Chapman and Hall; 1998.

44. Kaler SG. ATP7A-related copper transport disorders. Gene-Reviews. Available at www.geneclinics.org/profiles/menkes.Accessed 22 Apr 2005.

45. Wilson DC, Phillips MJ, Cox DW, Roberts EA. Severe hepaticWilson’s disease in preschool-aged children. J Pediatr 2000;137:719–22.

46. Starosta-Rubinstein S, Young AB, Kluin K, et al. Clinical assess-ment of 31 patients with Wilson’s disease. Correlations with struc-tural changes on magnetic resonance imaging. Arch Neurol1987;44:365–70.

47. Aisen AM, Martel W, Gabrielsen TO, et al. Wilson disease of thebrain: MR imaging. Radiology 1985;157:137–41.

48. Askari FK, Greenson J, Dick RD, et al. Treatment of Wilson’s dis-ease with zinc. XVIII. Initial treatment of the hepatic decom-pensation presentation with trientine and zinc. J Lab Clin Med2003;142:385–90.

49. Brewer GJ, Hedera P, Kluin KJ, et al. Treatment of Wilson dis-ease with ammonium tetrathiomolybdate: III. Initial therapy ina total of 55 neurologically affected patients and follow-up withzinc therapy. Arch Neurol 2003;60:379–85.

50. Gospe SM. Pyridoxine-dependent seizures: findings from recentstudies pose new questions. Pediatr Neurol 2002;26:181–5.

51. Wolf B. Biotinidase deficiency: new directions and practical con-cerns. Curr Treat Options Neurol 2003;5:321–8.

52. De Vivo DC, Trifiletti RR, Jacobson RI, et al. Defective glucosetransport across the blood-brain barrier as a cause of persistenthypoglycorrhachia, seizures, and developmental delay. N Engl JMed 1991;325:703–9.

53. Wang D, Pascual JM, Yang H, et al. Glut-1 deficiency syndrome:clinical, genetic, and therapeutic aspects. Ann Neurol 2005;57:111–8.



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