Metabolic Disorders in Pediatric Neurology

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NEUROLOGY BOARD REVIEW MANUAL

Gregory M. Rice, MD, and David Hsu, MD, PhD

INTRODUCTION DISORDERS CAUSED BY ENERGY FAILURE

This manual reviews metabolic diseases that affect the nervous system, focusing on the usual presentations GLYCOGEN STORAGE DISORDERS (GSD) from the perspective of a pediatric neurologist. Many of Glycogen is an important source of stored glucose these disorders will also have milder presentations in found primarily in liver and muscle. Defects in glycogen later life; these are not discussed. This review presents mobilization can lead to energy failure during times of sufficient information to begin a workup and to insti- fasting and exercise. tute initial interventions. A beginning neurologist will need to learn more about each disorder as he or she GSD TYPE II closes in on the definitive diagnosis. If a diagnosis is not GSD type II (Pompe disease) is caused by deficiency of readily apparent by clinical presentation (Table 1), one the lysosomal enzyme acid maltase (α-1-4-glucosidase).1 must resort to a more systematic approach. The infantile form presents as severe hypotonia and car- In this review, disorders are generally grouped diomyopathy and is usually fatal before 12 months of age. according to defects of the various biochemical path- The childhood form affects only skeletal muscle and pre- ways (Figure 1). Metabolic disorders caused by energy sents as progressive weakness. Creatine kinase (CK) levels failure can involve defects in the mobilization of glyco- are markedly elevated, and muscle biopsy demonstrates gen (ie, glycogen storage diseases) or fats (ie, fatty acid oxi- glycogen storage in muscle fibers and absence of acid mal- dation defects) or defects in the citric acid cycle or respi- tase. Hypoglycemia is not seen in GSD II. ratory chain (ie, mitochondrial disorders). These disorders tend to present as decompensations with stress or in- GSD Type V creased energy demand. Metabolic disorders caused by GSD type V (McArdle disease) is caused by deficien- defects in amino acid metabolism include the organic cy of myophosphorylase and presents in adolescents as acidemias, aminoacidopathies, and urea cycle defects. These cramps and muscle fatigue shortly after initiating exer- disorders tend to present in infancy as increasing lethar- cise. A “second wind” effect can occur (ie, renewed abil- gy and vomiting with initiation of feeds. Lysosomal disor- ity to continue exercising if patients rest briefly after the ders result in the accumulation of large carbohydrate– onset of fatigue). Laboratory studies show elevated CK lipid complexes and present as dysmorphism with levels, post-exertional myoglobinuria, and a failure of organomegaly, psychiatric symptoms, or white matter normal rise in lactate levels with exercise. The forearm disease. Aside from the glycogen storage disorders, the ischemic test is the classic exercise test but is difficult to disorders of carbohydrate metabolism are rather heteroge- perform reliably. Muscle biopsy shows glycogen storage neous. Finally, some primarily white matter disorders are in muscle and absence of myophosphorylase. Moderate suggested by clinical presentation, such as increasing exercise with careful warmup is advisable. Dietary treat- spasticity and abnormalities in white matter on mag- ments have been disappointing. netic resonance imaging (MRI), whereas primarily gray matter disorders present as seizures and cognitive decline. FATTY ACID OXIDATION DISORDERS In the United States, most states screen newborns for Fatty acid oxidation disorders consist of autosomal phenylketonuria, galactosemia, hypothyroidism, con- recessive defects in either the transport of fatty acids into genital adrenal hyperplasia, hemoglobinopathies, and mitochondria or in the intramitochondrial β-oxidation maple syrup urine disease. Some states employ tandem of fatty acids. A prolonged fast or significant stress (eg, ill- mass spectroscopy, which gives amino acid and acylcar- ness, surgery) may deplete liver stores of glycogen. If fatty nitine profiles. These tests are useful for diagnosing stores fail to be mobilized for fuel, the result is the classic many metabolic disorders, as described below. laboratory finding of hypoketotic hypoglycemia.2 A mild to

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Table 1. Clinical Presentations and Differential Diagnosis of Metabolic Disorders

Stroke/stroke-like episodes Cardiomyopathy Progressive myoclonic epilepsies Mitochondrial myopathy, encephalomyelopa- VLCAD deficiency Myoclonic epilepsy with ragged red fibers thy, and lactic acidosis with stroke-like LCHAD deficiency Unverricht-Lundborg disease (Baltic episodes Carnitine transporter deficiency myoclonus) Homocystinuria Infantile carnitine-palmitoyl-transferase-2 Neuronal ceroid lipofuscinosis Propionic acidemia deficiency Lafora body disease Methylmalonic acidemia GSD II (Pompe disease) Sialidosis type 1 Isovaleric acidemia GSD III (Cori disease) Psychiatric/behavioral change Glutaric acidemia type I Mitochondrial disorders Wilson’s disease Urea cycle disorders Cherry red spots on the macula Neuronal ceroid lipofuscinosis Congenital disorders of glycosylation Tay-Sachs disease X-Linked adrenoleukodystrophy Menkes disease Sandhoff disease Juvenile- and adult-onset metachromatic Fabry disease leukodystrophy GM1 gangliosidosis Leigh syndrome Niemann-Pick disease Late-onset GM2 gangliosidosis Electron transport chain defects Sialidosis Lesch-Nyhan syndrome Pyruvate dehydrogenase complex deficiency Multiple sulfatase deficiency Porphyria (episodic) Biotinidase deficiency Rhabdomyolysis/myoglobinuria Urea cycle disorders (episodic) Reye-like syndrome GSD type V (McArdle disease) Sanfilippo disease (mucopolysaccharidosis III) Fatty acid oxidation disorders Adult CPT-2 deficiency Hunter disease (mucopolysaccharidosis II) Urea cycle disorders VLCAD deficiency Organic acidemias LCHAD deficiency Carnitine transporter deficiency Mitochondrial 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 and Hall; 1998; and Clarke JT. A clinical guide to inherited metabolic diseases. 2nd ed. New York: Cambridge University Press; 2002.)

Carbohydrates moderate hyperammonemia may also be seen. Organs Glucose especially sensitive to fatty acid oxidation defects include Glycogen the brain (which depends on ketones for fuel in the fast- Galactose Glucose-6-P ed state), the heart and muscles (due to high metabolic Ammino acids Fatty acids demand and because fatty fuels spare proteolysis), and Fructose the liver (which relies on energy derived from fatty acid NH3 Urea oxidation for gluconeogenesis and ureagenesis). Pyruvate Lactate Urea Management for all fatty acid oxidation disorders cycle includes avoiding prolonged fasts and aggressive use of Acetyl CoA dextrose-containing fluids during decompensations. β-oxidation Krebs Ketones Carnitine must bind to long-chain fatty acids for fatty cycle acid transport across the mitochondrial double membrane. Carnitine enters the cell through a carnitine ATP ADP transporter. It is bound to the fatty acyl group by carni- Mitrochondrion Respiratory chain Cytosol tine palmitoyl transferase 1 (CPT1) at the outer mitochondrial membrane. Acylcarnitine is then transported Figure 1. Basic pathways of intermediary metabolism. Glucose- to the inner mitochondrial membrane by acylcarnitine 6-P = glucose-6-phosphatase. (Adapted with permission from translocase. At the inner mitochondrial membrane, acyl- Hoffmann GF, Nyhan WL, Zschocke J. Inherited metabolic dis- carnitine is disassembled into acyl coenzyme A (CoA) eases. Philadelphia: Lippincott Williams & Wilkins; 2002:6.) and free carnitine by carnitine palmitoyl transferase 2 (CPT2). Acyl CoA then enters β-oxidation while free carnitine is recirculated to the cell cytoplasm. The first www.turner-white.com Neurology Volume 9, Part 2 3

Table 2. Carnitine-Associated and Fatty Acid Disorders Serum Acylcarnitine Age of Tissue Deficiency Total Free (F) Esters (E) E:F Ratio Profile Onset Affected Transporter ↓↓ ↓ ↓↓ < 0.3 (nl) ↓All esters I/C H/M/L CPT1 ↑↑ ↓↓ < 0.2 ↓C16, C18 I/C L Translocase ↓↓ ↑ > 0.4 ↑C16, C18 N H/L CPT2 (liver) ↓↓ ↑ > 0.4 ↑C16, C18 N/I H/L CPT2 (muscle) ↓↓ ↑ > 0.4 ↑C16, C18 C/A H/M MCAD ↓↓ ↑ > 0.4 ↑C6, C8, C10:1 I/C L LCHAD ↓↓ ↑ > 0.4 ↑C16-OH, C18-OH I/C H/M/L

A = adult; C = child; CPT = carnitine palmitoyl transferase; H = heart; I = infant; L = liver/Reye syndrome; LCHAD = long-chain hydroxyacyl CoA dehydrogenase; M = skeletal muscle; MCAD = medium-chain acyl CoA dehydrogenase; N = neonate; nl = normal. (Adapted from Nyhan WL, Ozand PT. Atlas of metabolic diseases. New York: Chapman and Hall; 1998.)

step in β-oxidation is performed by acyl CoA dehydro- form presents in the teens to twenties as episodic rhab- genases, which are distinct depending on the acyl-group domyolysis and myoglobinuria following prolonged chain length. exercise, cold exposure, infection, or fasting, with ele- Carnitine also acts as a scavenger of potentially toxic vated CK levels and myoglobinuria. acyl CoA metabolites, forming acylcarnitine esters that β are excreted in the urine. A secondary carnitine defi- Disorders of -Oxidation and Ketogenesis ciency results when urinary acylcarnitine loss is ex- Medium-chain acyl CoA dehydrogenase (MCAD) cessive. Blood carnitine levels then show an elevated deficiency is the most common of the fatty acid oxida- acylcarnitine ester-to-free carnitine ratio (ie, > 0.4).2 Val- tion disorders. MCAD helps metabolize medium-chain proic acid therapy can cause secondary carnitine defi- fatty acids to ketones, which are used as fuel during ciency in this way by forming valproyl carnitine ester. times of stress and fasting. Acute presentation consists Screening laboratory tests include plasma free and of lethargy, vomiting, seizure, and progressive enceph- total carnitines, plasma acylcarnitine profile, and urine alopathy after fasting or physical stress. An initial attack acylglycines. Laboratory findings are summarized in may result in sudden infant death. Management in- Table 2. Interpretation of urine acylglycines is complex cludes moderate dietary fat restriction and carnitine and is omitted in this review. supplementation. Very-long-chain acyl CoA dehydrogenase (VLCAD) Carnitine Disorders deficiency and long-chain 3-hydroxy acyl CoA dehydroge- Carnitine transporter deficiency leads to total body nase (LCHAD) deficiency are associated with cardiomy- carnitine depletion secondary to increased renal loss. opathy, skeletal myopathy, post-exertional rhabdomyoly- Symptoms include muscle weakness and cardiomyopa- sis, and hypoketotic hypoglycemia with decompensations. thy. Carnitine given in high doses reverses symptoms Children with VLCAD deficiency can present with a Reye- and can be lifesaving.2 like syndrome, which can be fatal. Mothers carrying a CPT1 deficiency presents as a Reye-like syndrome, fetus with LCHAD deficiency can present with hemolysis, with progressive encephalopathy, seizures secondary to elevated liver function tests, and low platelet counts hypoglycemia, hepatomegaly, moderate hyperammo- (HELLP syndrome). Diagnosis is by acylcarnitine profile, nemia, and elevated liver enzymes. Skeletal and cardiac which shows elevated long-chain acylcarnitines and muscle are not involved. Acylcarnitine profile shows hydroxy-acylcarnitines, respectively, in patients with decreased long-chain acylcarnitines (C16, C18). VLCAD deficiency and LCHAD deficiency. Medium- Chronic treatment with medium-chain fatty acids may chain triglycerides (MCT oil) are supplemented. be of benefit. Glutaric acidemia type II (multiple acyl CoA- CPT2 deficiency has an infantile (liver) and adult dehydrogenase deficiency) involves defects in the flavin (muscle) form. The infantile form presents as adenine dinucleotide (FAD)–dependent electron hepatomegaly, liver failure, cardiomegaly, arrhythmias, transfer from dehydrogenase enzymes to the electron and seizures, with hypoketotic hypoglycemia. The adult transport chain. This disorder affects both fatty acid

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Table 3. Mitochondrial Disorders Syndrome Characteristic Findings Comments

MELAS4 Recurrent stroke-like events, migrating lesions on MRI, episodic Leucine tRNA mtDNA mutation in 80% encephalopathy, migraines, seizures MERRF5 Myoclonic epilepsy, ataxia, optic atrophy, hearing loss Lysine tRNA mtDNA mutation in 80% CPEO6 CPEO, ptosis, variable skeletal muscle weakness Multiple mtDNA deletion; only skeletal muscle affected Kearns-Sayre syndrome CPEO, retinitis pigmentosa, and one of following: cerebellar ataxia, Multiple mtDNA deletion; all tissues affected; 4 conduction block, CSF protein > 100 mg/dL check serial ECGs Leigh syndrome, or sub- Ataxia, hypotonia, ophthalmoplegia, dysphagia, dystonia Severe neurodegenerative disease; most die acute necrotizing MRI: lesions of basal ganglia, thalamus, brainstem by 3 years of age encephalomyelopathy7 Leber hereditary optic Acute: optic nerve hyperemia, vascular tortuosity Painless; initially asymmetric; progresses over neuropathy8 Chronic: optic atrophy weeks to months Uncommon: cardiac conduction abnormalities Neurogenic muscle Neuropathy, ataxia, retinitis pigmentosa, proximal weakness, men- Can go years without exacerbation; weakness, ataxia, and tal retardation mtATPase affected retinitis pigmentosa7 Friedreich ataxia9 Ataxia, areflexia, loss of vibration and proprioceptive sense, with Trinucleotide expansion in Frataxin gene; onset before age 25 years autosomal recessive (nuclear gene) Associated: diabetes, cardiomyopathy, scoliosis, optic atrophy, Causes intramitochondrial iron accumulation; deafness most die in mid-30s, Milder variant exists with retained reflexes CPEO = chronic progressive external ophthalmoplegia; CSF = cerebrospinal fluid; ECG = electrocardiogram; MELAS = mitochondrial myopathy, encephalopathy, and lactic acidosis with stroke-like episodes; MERRF = myoclonic epilepsy with ragged red fibers; MRI = magnetic resonance imaging.; mt = mitochondrial.

oxidation and amino acid metabolism. The classic Table 4. Clinical Features of Mitochondrial Disorders neonatal form is severe and presents as a Reye-like syn- Brain: psychiatric disorder, seizures, ataxia, myoclonus, migraine, drome, followed by seizures and progressive neurode- stroke-like events generation. Dysmorphism and cystic kidneys may be Eyes: optic neuropathy, retinitis pigmentosa, ptosis, external ophthal- present. Diagnosis is by recognizing a complex pattern moplegia in plasma acylcarnitines, urine organic acids, and urine Ears: sensorineural hearing loss acylglycines, including urine glutaric acid. Nerve: neuropathic pain, areflexia, gastrointestinal pseudo- obstruction, dysautonomia MITOCHONDRIAL DISORDERS Muscle: hypotonia, weakness, exercise intolerance, cramping Mitochondrial disorders are caused by a genetic Heart: conduction block, cardiomyopathy, arrhythmia defect in either nuclear or mitochondrial DNA. Many Liver: hypoglycemia, liver failure mitochondrial syndromes have been defined, but there Kidneys: proximal renal tubular dysfunction (Fanconi syndrome) is significant overlap with a complex relationship between identified genetic defects and classic mitochon- Endocrine: diabetes, hypoparathyroidism drial syndromes3 (Table 3).4–9 Adapted with permission from Cohen BH, Gold DR. Mitochondrial cytopathy in adults: What we know so far. Cleveland Clin J Med Clinical Features 2001;68:625-641. Mitochondrial disorders are highly variable in presentation. Suspicion for a mitochondrial defect increas- normal lactate levels at rest. Furthermore, mitochondri- es if there is multisystem involvement of high energy sys- al DNA panels are abnormal in only 10% of patients.11 tems3,10 (Table 4). Diagnosis of mitochondrial disorders Thus muscle biopsy remains a key to diagnosis. Muscle begins with analysis of serum lactate, pyruvate, and CK biopsy may show ragged red fibers on Gomori trichrome levels. Classically, lactate is elevated even at rest, with a stain, succinate dehydrogenase stains the same fibers lactate-to-pyruvate ratio greater than 25 (more com- blue, and cytochrome c oxidase stains reveal deficient monly, from 50 to 250). However, 40% of patients have mitochondrial respiratory chain protein synthesis. www.turner-white.com Neurology Volume 9, Part 2 5

A B C Figure 2. Mitochondrial myopathy, encephalomyelopathy, and lactic acidosis with stroke-like episodes (MELAS) syndrome in a 10-year- old boy with migrating infarction. (A) Initial T2-weighted magnetic resonance image (MRI) shows a high sign intensity lesion in the left occipital lobe (arrows). Follow-up MRI 15 months later showed resolution of the occipital lesion but with new left temporal lesion (not shown). (B) Photomicrograph (original magnification, ×40; Gomori methenamine silver stain) of the muscle biopsy reveals scattered ragged red fibers (arrows). (C) Electron micrograph reveals an increased number of mitochondria (arrows), which are irregular and enlarged. (Adapted with permission from Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in children: a pictorial review of MR imaging features. Radiographics 2002;22:470. Radiological Society of North America.)

Biochemical analysis of muscle can reveal decreases in Treatment involves supplementation with thiamine, activity of the respiratory chain complexes I to IV. Elec- which is a cofactor for PDHC, and a high fat, low car- tron microscopy shows overabundant, enlarged, and bohydrate diet. Acetazolamide may abort attacks.17 bizarrely shaped mitochondria with paracrystalline inclusions. Brain MRI may show lesions of the basal ganglia, thalamus, midbrain, or cerebral white matter. In the DISORDERS OF AMINO ACID METABOLISM cerebral white matter, recurrent stroke-like events may occur, with transitory migrating lesions that cross vascular territories (Figure 2). Magnetic resonance spectros- ORGANIC ACIDEMIAS copy may show elevated lactate peaks in these lesions.12,13 Organic acidemias are caused by autosomal recessive Impaired autoregulation of cerebral vasculature has disorders of amino acid metabolism. The usual presenta- been suggested as the etiology of stroke-like events.14 tion is that of nonspecific poor feeding, lethargy, and vomiting in the neonatal period, eventually progressing to Treatment coma. Symptoms are often initially mistaken for sepsis. Treatment is with L-carnitine, B vitamins (riboflavin Laboratory findings include metabolic acidosis with an and thiamine), and coenzyme Q or idebenone. Biotin, elevated anion gap, sometimes with ketosis and hyper- antioxidants (vitamins A and C), folate, and lipoic acid ammonemia (Table 5). Diagnosis during the acute illness are also used.15 Dichloroacetic acid may lower lactate depends on plasma amino acids, plasma acylcarnitine levels in some patients.16 Response to treatment is vari- profile, urine organic acids, and urine acylglycine profile. able, with some patients experiencing improvement in The detailed analysis of these profiles is often complex energy and function but many experiencing no dis- and is not discussed here. Acute treatment involves with- cernible improvement. holding protein feeds and aggressively pushing dextrose- containing fluids, to induce an anabolic state. Chronic PYRUVATE DEHYDROGENASE COMPLEX DEFICIENCY treatment consists of specific dietary protein restriction. Pyruvate dehydrogenase complex (PDHC) deficien- Carnitine supplementation can be helpful.18 cy blocks entry of pyruvate into the citric acid cycle, resulting in elevated lactate and pyruvate levels. PDHC Propionic Acidemia deficiency presents similar to the mitochondrial disor- Propionic acidemia is caused by a deficiency in propi- ders. The severe neonatal form is fatal in infancy. Leigh onyl CoA carboxylase. Most children have some cognitive disease can develop later in infancy. Diagnosis is based disability even with optimal therapy. Cardiomyopathy, on finding elevated lactate and pyruvate levels with pancreatitis, osteoporosis, and movement disorders are preservation of the lactate-to-pyruvate ratio (ie, < 20). late complications.

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Methylmalonic Acidemia Table 5. Metabolic Causes of Lethargy and Vomiting in the Methylmalonic acidemia is caused by a defect in Infant and Child methylmalonyl CoA mutase. Acidosis and hyperam- Elevated Normal monemia can be severe, and a single attack can cause per- Acid-Base Status Ammonia Ammonia manent cognitive disability. Seizures, spasticity, behavioral Acidemia with elevated Organic acidemia Organic acidemia problems, and ataxia are common. Metabolic stroke with anion gap (neonate) (older child) an acute decompensation can occur. Many patients will No acidemia Urea cycle disorder Galactosemia, develop renal failure and require renal transplantation. MSUD Methylmalonic acid can also be elevated in disorders of MSUD = maple syrup urine disease. (Adapted with permission from cobalamin (vitamin B12) metabolism, and megaloblastic Silverstein S. Laughing your way to passing the pediatric boards. 2nd anemia can seen. Brain MRI may show bilateral globus ed. Stamford [CT]: Medhumor Medical Publications; 2000:286.) pallidus infarction. Management of methylmalonic acid-

emia consists of vitamin B12 supplementation and dietary protein restriction. Maple Syrup Urine Disease Maple syrup urine disease (MSUD) is caused by a Glutaric Acidemia Type I deficiency in branched-chain α-ketoacid dehydroge- Glutaric acidemia type I is caused by a deficiency in nase, which is responsible for the metabolism of glutaryl CoA dehydrogenase, which results in dystonia, leucine, isoleucine, and valine. The classic form pre- ataxia, cognitive disability, and spasticity. Metabolic aci- sents in the first week of life with poor feeding, lethargy, dosis is not a prominent feature even with acute and vomiting, quickly progressing to coma, seizures and decompensation. Diagnostic studies are often normal death if untreated. An intermittent form may present when affected individuals are healthy. Neuroimaging later in life with attacks of transient ataxia, sometimes shows frontotemporal atrophy with basal ganglia le- accompanied by cerebral edema.21 These attacks are sions. Basal ganglia injury can appear even with a first triggered by intercurrent illness or stresses. Urine, attack. Macrocephaly is common. Chronic manage- sweat, and cerumen often smell like maple syrup. ment consists of carnitine supplementation and pro- Acidosis and hyperammonemia are uncommon. tein restriction.18 In the United States, many states screen newborns for MSUD. Testing during an attack shows elevated AMINOACIDOPATHIES leucine, isoleucine, and valine in blood as well as Classic Phenylketonuria branched-chain metabolites in urine, but these levels Classic phenylketonuria (PKU) is caused by a defi- may be normal in the immediate neonatal period ciency in the enzyme phenylalanine hydroxylase, before branched-chain amino acids have accumulated which converts phenylalanine to tyrosine. Neurotoxic and in the intermittent form between attacks. Acute phenylketones then accumulate. Testing shows elevat- management includes aggressive high calorie intra- ed levels of blood phenylalanine and urine phenylke- venous or nasogastric feeds, sometimes with intra- tones. Infants are normal at birth but in the first year venous insulin to help induce an anabolic state. Special of life manifest progressive cognitive delay, micro- MSUD total parenteral nutrition is available with the cephaly, spasticity, recurrent eczematous rash, and a proper mixture of amino acids. Chronic management mousy odor. Seizures occur in 25% of untreated PKU relies on dietary restriction of branched-chain amino patients.19 Newborn screening and early treatment can acids. With early diagnosis and tight metabolic control, prevent these symptoms. Treatment in classic PKU con- the prognosis is for normal development. sists of dietary restriction of phenylalanine and close monitoring of blood phenylalanine levels. Women with Classic Homocystinuria PKU should have phenylalanine levels under control Classic homocystinuria is an autosomal recessive dis- before attempting to conceive. Fetuses exposed to high order caused by a defect in the enzyme cystathionine levels of phenylalanine are at risk for congenital heart β-synthetase, resulting in elevations of homocystine and disease, intrauterine growth restriction, mental retar- methionine. Infants are usually asymptomatic, but men- dation, and microcephaly. Approximately 2% of PKU tal retardation can develop in untreated patients. Adults patients have normal phenylalanine hydroxylase ac- are often tall and thin, and most have significant myopia. tivity but are deficient in the cofactor tetrahydro- Lens dislocation (ectopia lentis) may develop later in life, biopterin.20 These patients require biopterin supple- but the lens is usually dislocated inferiorly, which is the mentation. opposite of what is seen in Marfan syndrome. Untreated

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UREA CYCLE DISORDERS HCO + NH + 2 ATP 3 4 Mitochondrion The urea cycle converts ammonia, which is a toxic CPSI N-acetylglutamate byproduct of protein metabolism, into urea (Figure 3). Cytoplasm All urea cycle disorders are autosomal recessive with the Carbamly Asparate phosphate exception of ornithine transcarbamylase deficiency, which is X-linked. Citrulline Citrulline OTC Clinical Features

Ornithine Similar to the organic acidemias, urea cycle disorders ASS classically present in neonates as lethargy, poor feeding, and vomiting soon after initiating protein feeds.25 What Ornithine Argininosuccinate distinguishes the urea cycle disorders from the organic acidemias, however, is hyperammonemia without acidosis ASL (Table 5). In an acute crisis, encephalopathy quickly pro- Urea Arginine ARG gresses to coma, seizures, and death if left untreated. Fumarate Cerebral edema (with a bulging fontanelle and tachyp- Figure 3. The urea cycle and its disorders. ARG = arginase defi- nea) can occur early and progresses rapidly. Metabolic ciency; ASL = arginosuccinic acid lyase deficiency; ASS = argino- strokes may also occur. All urea cycle disorders with the succinic acid synthetase deficiency; CPS-I = carbamyl phosphate exception of argininemia are accompanied by hyperam- µ synthetase I deficiency; OTC = ornithine transcarboxylase defi- monemia. Ammonia levels exceeding 200 g/dL cause µ ciency. (Adapted with permission from Summar ML, Tuchman M. lethargy and vomiting, levels greater than 300 g/dL µ Urea cycle disorders overview. GeneReviews. Available at www. result in coma, and levels exceeding 500 g/dL cause 17 geneclinics.org/profiles/ucd-overview. Accessed 8 Apr 2005.) seizures. Any catabolic state, including the immediate postnatal period before initiation of feeding, can provoke a crisis because of associated proteolysis. Permanent neu- patients are at risk for seizures, psychiatric disorders, and rologic sequelae can occur after a single crisis. Ammonia thromboembolic events including stroke, myocardial in- levels greater than 350 µg/dL26 and coma for longer than farction, and pulmonary emboli.22 Treatment involves 24 hours27 are correlated with death or profound mental µ protein restriction, supplementation with vitamin B12 retardation. Ammonia levels less than 180 g/dL usually and folate, and stroke prophylaxis with aspirin. results in normal development or only mild mental retardation.26 Milder forms including female carriers of Nonketotic Hyperglycinemia ornithine transcarbamylase deficiency can have a more Nonketotic hyperglycinemia (glycine encephalopa- subtle presentation. thy) is caused by a defect in glycine cleavage.23 This defect results in elevated glycine levels in the blood, Treatment urine, and cerebrospinal fluid (CSF). The neonatal Hyperammonemia in an encephalopathic infant is a form presents as lethargy and poor feeding after the ini- medical emergency. In addition to determining ammo- tiation of protein feeds, quickly progressing to persistent nia levels and acid-base status, laboratory studies should seizures, encephalopathy, and coma. Apnea is common be ordered for electrolytes, calcium, glucose, lactate, and persistent hiccups have also been seen. Diagnosis liver enzymes, free and total carnitine, quantitative plas- depends on simultaneous measurement of CSF and ma amino acids, and urine organic acids. Acute man- plasma glycine levels. A CSF-to-plasma glycine ratio agement for all urea cycle disorders consists of (1) stop- greater than 0.06 supports this diagnosis.24 Acute man- ping all protein intake; (2) starting an intravenous agement includes use of sodium benzoate to help nor- infusion of 10% glucose plus lipid to promote the ana- malize plasma glycine level. Dextromethorphan, an bolic state; and (3) starting arginine HCl, sodium ben- NMDA (N-methyl-D-aspartate) receptor antagonist, zoate, and sodium phenylacetate with intravenous load- may be beneficial. Valproic acid, which inhibits metabo- ing doses followed by maintenance infusions. Peritoneal lism of glycine, is contraindicated. The prognosis for the dialysis or hemodialysis should be considered if there is neonatal form is poor. Survivors often have spastic quad- clinical deterioration and ammonia levels are not riplegia, intractable seizures, and severe mental retarda- responding. Chronic management typically includes tion. Infantile, childhood, and adult-onset forms exist protein restriction, and oral sodium benzoate and sodi- but are uncommon; these forms have milder outcomes. um phenylacetate supplementation.25 Because the urea

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cycle takes place in the liver, liver transplantation is cura- tion. With age, acute episodes of hyperammonemia tive for the metabolic disorder but does not reverse accu- become less frequent. Developmental delays are com- mulated neurologic injury. In the severe forms of the urea mon even with good compliance. cycle disorders (eg, carbamyl phosphate synthetase I Argininemia is caused by a defect in arginase. [CPS1] deficiency, ornithine transcarbamylase [OTC] Argininemia is unique among the urea cycle disorders deficiency), liver transplantation before 1 year of age is in that it rarely causes acute hyperammonemic crisis. associated with better survival into the childhood years Ammonias may chronically be mildly elevated. Spastic- with mild (rather than profound) mental retardation.28 ity and developmental regression develop early in childhood, often with cyclic vomiting, seizures, and fail- Specific Disorders ure to thrive. Children are often misdiagnosed as hav- CPS1 deficiency blocks formation of carbamyl phos- ing cerebral palsy. Diagnosis is based on elevated argi- phate and has the classic presentation described above. nine in plasma, although levels can be normal in the Orotic acid is a metabolite of carbamyl phosphate. immediate newborn period. Treatment involves an Thus, CPS1 deficiency is the only urea cycle disorder arginine-restricted diet. The prognosis includes mental without elevated urine orotic acid. Plasma amino acids retardation, seizures, and spastic diparesis. show decreased citrulline and arginine. Chronic management is as described above plus arginine supplementation. Prognosis is poor with neonatal presenta- DISORDERS OF CARBOHYDRATE METABOLISM tions. Recurrent exacerbations occur even with optimal therapy. Survivors are generally profoundly mentally retarded. Initial presentation is usually in the neonatal GALACTOSEMIA period but can be delayed into childhood. The out- Galactosemia results from a deficiency in galactose- come in later onset cases can be milder but still includes 1-phosphate uridyltransferase.30 Neonates present with mental retardation, motor deficits, and death. vomiting, poor feeding, and lethargy following the ini- OTC deficiency is identical to CPS1 deficiency in tiation of breast or bottle feeding. Jaundice and hepato- presentation except that urine orotic acids are elevated. megaly are seen, and simultaneous Escherichia coli sepsis Plasma amino acids show decreased citrulline and argi- is associated. Untreated infants develop profound men- nine. Due to skewed X-inactivation, 15% of females will tal retardation and often renal failure. Lenticular cata- develop hyperammonemia.29 Many of these females racts develop after only 1 month if untreated. Those learn to avoid meat. A protein load can induce symp- with suboptimal control are at risk for behavioral and toms. The catabolic postpartum state can also provoke learning problems. Even with good dietary control, a crisis. Chronic management involves protein restric- patients may have subtle cognitive delays or learning tion and oral sodium benzoate, phenylacetate, and cit- disabilities. Action tremor may become a prominent rulline supplementation. Prognosis is the same as for complaint, refractory to medical therapy. Females are at CPS1 deficiency. risk for premature ovarian failure, even if treated. The Citrullinemia is caused by a defect in argininosuc- diagnosis is suggested by finding reducing substances in cinic acid synthetase. The presentation is similar to that urine and confirmed by elevations in serum galactose- of CPS1 deficiency, but prognosis for survivors of the 1-phosphate. Treatment is based on dietary restriction initial episode is somewhat better, with future exacerba- of galactose. tions becoming easier to manage with age. A milder, late-onset form of citrullinemia exists. Plasma amino CONGENITAL DISORDERS OF GLYCOSYLATION acids show elevated citrulline and reduced arginine. Congenital disorders of glycosylation (CDG, former- Chronic management is the same as for CPS1 deficien- ly called carbohydrate-deficient glycoprotein syn- cy, but arginine supplementation is essential. drome) are a heterogenous group of mostly autosomal Argininosuccinic aciduria is caused by deficiency of recessive disorders with deficient glycosylation of glyco- argininosuccinic acid lyase. Affected children may proteins.31 CDG Ia is the most common type and demonstrate failure to thrive, hepatomegaly, and un- involves deficiency of phosphomannomutase. CDG Ib usual hair, including alopecia and trichorrhexis is unique in presenting as hypoglycemia and protein- nodosa. Plasma amino acids show elevated citrulline losing enteropathy, without neurologic features. CDG with decreased arginine. Argininosuccinic acid is ele- as a group is suggested in an infant or a child with some vated in plasma and present in urine. Treatment in- combination of failure to thrive, stroke-like episodes, a volves protein restriction and arginine supplementa- clotting or bleeding tendency, hypotonia, psychomotor

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Table 6. Mucopolysaccharidoses (MPS) Affected Syndrome MPS Type Features Compound Defect Comments α Hurler IH MR, CF, CC DS, HS -L-iduronidase Cardiac disease; motor weakness; dysostosis multiplex α Scheie IS CF, CC DS, HS -L-iduronidase Dysostosis multiplex; milder than Hurler α Hurler/ Scheie IHS CF, CC, ± MR DS, HS -L-iduronidase Intermediate between Hurler and Scheie Hunter II MR, CF DS, HS Iduronate sulfatase Motor weakness; aggressive

Sanfilippo types A–D IIIA–D MR HS Distinct for each type Severe behavior problems; speech delay

Morquio types A IVA, IVB CC, ± MR KS and Distinct for each type Odontoid hypoplasia; bony abnormalities and 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.)

retardation, strabismus, retinitis pigmentosa, hypogo- forms of MPS are autosomal recessive except MPS type II nadism, ataxia, and cerebellar hypoplasia. There may (Hunter syndrome), which is X-linked recessive. Neo- be inverted nipples and unusual fat deposits in the nates appear normal. Onset of disease is insidious. Other suprapubic and supragluteal regions. Peripheral neu- features are listed in Table 6. Urinary testing for MPS sug- ropathy may occur. Severity of symptoms is highly vari- gests the diagnosis, which is confirmed by enzyme assays able. Most adults are wheelchair bound. Diagnosis and from leukocytes or fibroblasts. separation into subtypes is by transferrin electrophore- sis. Coagulation studies may show deficiencies of factor SPHINGOLIPIDOSES XI, proteins C and S, and antithrombin. Oral mannose The sphingolipidoses involve abnormal metabolism is effective in CDG Ib, but no treatment exists for the and accumulation of sphingolipids. Deficiency of hex- 31 other types of CDG. osaminidase A alone results in GM2 gangliosidosis, the classic form of which is Tay-Sachs disease. Tay-Sachs dis- LAFORA BODY DISEASE ease is more common in Ashkenazi Jews than in the gen- Lafora body disease is an autosomal recessive eral population and is autosomal recessive. Onset of polyglucosan storage disorder that presents as symptoms is between 3 and 6 months of age. The initial myoclonic seizures in the mid-teens, with rapid neu- sign is an excessive startle reflex. A macular cherry red rocognitive deterioration. Neurons show Lafora bodies spot (see Table 1) almost always is present at this stage, with a core that stains very dark with periodic acid and psychomotor regression then begins. By age 1 year, Schiff, with a lighter outer “halo.” Skin, liver, or muscle the child is unresponsive and spastic. Seizures and biopsy can also be diagnostic.32 macrocephaly soon follow, and most children die by 4 to

5 years of age. Late-onset GM2 gangliosidosis, also more common in Ashkenazi Jews, presents in childhood and LYSOSOMAL STORAGE DISORDERS adulthood. Symptoms include weakness, personality change, tongue atrophy and fasciculations, tremor, and Lysosomes are involved in the degradation of large mixed upper and lower motor neuron signs. Dysarthria, molecules, including mucopolysaccharides, sphin- ataxia, and progressive spasticity and dementia follow. A golipids, sphingomyelin, and several others. Progressive cherry red macula is not present in late-onset disease.

organomegaly, dysmorphism, and neurodegeneration Diagnosis of both forms of GM2 gangliosidosis is by are typical. assays of hexosaminidase A activity in serum, leukocytes, or cultured fibroblasts. No treatment is available. MUCOPOLYSACCHARIDOSES In the mucopolysaccharidoses (MPS), impaired degra- SANDHOFF DISEASE dation of various mucopolysaccharides (also known as gly- Sandhoff disease is a rare autosomal recessive disor- cosaminoglycans) cause variable combinations of coarse der caused by deficiencies in both hexosaminidase A facies, short stature, bony defects, stiff joints, mental retar- and B. It is not more prevalent in Ashkenazi Jews. dation, hepatosplenomegaly, and corneal clouding. All Clinical features are identical to those of Tay-Sachs

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disease, with additional findings of hepatosplenomegaly and bony deformities. Diagnosis is by enzyme assays of hexosaminidase. Foamy histiocytes are sometimes seen in bone marrow. No treatment is available.

FABRY DISEASE Fabry disease is an X-linked recessive disorder caused by α-galactosidase deficiency. Presentation is usually during adolescence or early adulthood with painful crises in the extremities and paresthesias. Angiokeratomas and gastrointestinal complaints are often present. There is an increased risk for stroke, heart disease, renal failure, pulmonary complications, and hearing loss. Intelligence A is normal. Diagnosis is by enzyme assay showing decreased activity. α-Galactosidase replacement therapy is available and appears promising.33

NIEMANN-PICK DISEASE Niemann-Pick Type A Niemann-Pick type A is caused by sphingomyelinase deficiency, which results in accumulation of lipids, mainly sphingomyelin. Infants are normal at birth but develop feeding problems, hepatomegaly, and psychomotor regression in the first several months of life. In half of cases, children have cherry red spots. Opis- thotonus and hyperreflexia are common, whereas B seizure is uncommon. Death occurs between ages 2 and Figure 4. Alexander disease in a 5-year-old boy with macro- 4 years. Diagnosis is based on enzyme assay. Foamy cells cephaly. (A) T2-weighted magnetic resonance image (MRI) shows are observed in bone marrow and blood. symmetric demyelination in the frontal lobe white matter includ- Niemann-Pick Type C ing the subcortical U fibers. (B) Photomicrograph (original magnification, ×100; hematoxylin and eosin stain) of the pathologic spec- Niemann-Pick type C is an autosomal recessive dis- imen shows deposition of Rosenthal fibers (arrows). (Adapted with order that may present in neonates as severe liver or permission from Cheon JE, Kim IO, Hwang YS, et al. Leukodys- lung disease or in children as upgaze palsy or apraxia, trophy in children: a pictorial review of MR imaging features. Ra- ataxia, seizures, dementia, dysarthria, dysphagia, and diographics 2002;22:473. Radiological Society of North America.) dystonia. Adults present with psychiatric symptoms. Diagnosis is suggested by finding impaired cholesterol esterification and is confirmed by genetic testing for the Zellweger syndrome presents at birth as severe hypoto- NPC1 and NPC2 genes. Foamy cells are observed in nia, high forehead, wide-open fontanelles, hepato- liver, spleen, and marrow. Sea-blue histocytes are seen megaly, and hyporeflexia. Intractable seizures, liver dys- in marrow in advanced disease. Cholesterol-lowering function, renal cysts, cardiac defects, retinal dystrophy, drugs reduce cholesterol levels, but no treatment and sensorineural hearing loss are common. Brain MRI improves neurologic symptoms.34 demonstrates severe hypomyelination of the hemispheres, with neuronal migrational defects (eg, polymi- crogyria, pachygyria, periventricular heterotopias). PEROXISOMAL BIOGENESIS DISORDERS Plasma very-long-chain fatty acids (C26:0 and C26:1) are elevated. After the neonatal period, phytanic acid also is Peroxisomes degrade very-long-chain fatty acids elevated. Specific genetic testing is available for 6 known (C24, C26). The classic peroxisomal biogenesis disorder mutations, the most common affecting the PEX1 gene. is Zellweger syndrome (cerebrohepatorenal syndrome), The majority of affected infants die in the first year. an autosomal recessive disorder caused by deficiency of Severe psychomotor retardation develops in survivors.35 multiple proteins responsible for peroxisomal assembly. Milder presentations of peroxisomal biogenesis

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Copyright 2010 by Turner White Communications, Inc., Wayne, PA. All rights reserved. Metabolic Disorders in Pediatric Neurology disorders include neonatal adrenoleukodystrophy (not tified in association with Alexander disease. GFAP is a related to X-linked adrenoleukodystrophy, which is dis- major component of Rosenthal fibers. Juvenile- and cussed below) and Refsum disease. Both conditions adult-onset forms of Alexander disease have a milder can present in infancy or childhood as hypotonia, devel- course, with no macrocephaly or cognitive decline but opmental delay, vitamin K–responsive bleeding tenden- with a higher incidence of bulbar signs, ataxia, and posi- cy (due to liver dysfunction), sensorineural hearing tive family history. Demyelination in late-onset disease is loss, retinitis pigmentosa, neuropathy, and ataxia. The seen posteriorly rather than anteriorly.40,41 spectrum is continuous with no simple phenotype- genotype correlations, and diagnosis can be delayed METACHROMATIC LEUKODYSTROPHY into late adulthood.35 Metachromatic leukodystrophy (sulfatide lipidosis) is an autosomal recessive disorder usually caused by deficiency of arylsulfatase A and, less commonly, by deficien- WHITE MATTER DISORDERS cy of the sphingolipid activator protein, saposin B. Sulfatides then accumulate, leading to myelin destabi- White matter disorders classically present as progres- lization. The late infantile form is most common, with sive spasticity and neurocognitive regression. Hypotonia onset after 1 year of age. This form is characterized by is characteristic in the neonatal period, whereas psychi- ataxia, hypotonia, and peripheral neuropathy followed atric disturbance is typical in children and adults. Dis- later by progressive spasticity and cognitive decline. In cussed below are vanishing white matter disorder, the juvenile and adult forms, central nervous system Alexander disease, metachromatic leukodystrophy, (CNS) symptoms are more prominent, with behavioral Pelizaeus-Merzbacher disease, X-linked adrenoleukodys- disturbances, spasticity, and cognitive decline. Brain MRI trophy, Canavan disease, and Krabbe disease.36,37 A useful shows demyelination of periventricular white matter sym- mnemonic for recalling these disorders is VAMPACK. metrically, with involvement of the corpus callosum, early sparing of the subcortical U fibers, and late atrophy. VANISHING WHITE MATTER DISEASE There is no enhancement with contrast. A tigroid pattern Vanishing white matter disease (childhood ataxia with with patchy white matter sparing (formerly thought central hypomyelination) is an autosomal recessive disor- pathognomic for Pelizaeus-Merzbacher disease) and a der that usually presents in children aged 2 to 6 years as leopard skin pattern have been described. In this case, slowly progressive cerebellar ataxia, spasticity, variable the islands of normal-appearing white matter may en- optic atrophy, and relatively preserved cognitive abilities.38 hance with contrast, but the demyelinated patches do Infections and minor head trauma may lead to altered not (Figure 5). Diagnosis is by testing for arylsulfatase A level of consciousness leading into coma. Brain MRI activity. Bone marrow transplantation may be beneficial shows progressive loss of white matter diffusely with cystic in mildly affected patients with late-onset disease. degeneration. CSF may show elevated glycine. Later- onset (including adult-onset) disease has been described PELIZAEUS-MERZBACHER DISEASE and is associated with a milder clinical course. Mutations Pelizaeus-Merzbacher disease classically presents as have been found in genes that encode eukaryotic initia- neonatal nystagmus, choreoathetosis, progressive atax- tion factor 2B (eIF2B) subunits, which in turn may affect ia, spasticity, and developmental regression, with death the regulation of protein synthesis during cellular stress.39 often by 5 to 7 years of age. The spasticity may affect the legs preferentially. The nystagmus can sometimes ALEXANDER DISEASE resolve. Milder cases present later, and children who Alexander disease classically presents at approximate- present after 1 year of age may live into adulthood. ly 6 months of age as megalencephaly, progressive spas- Brain MRI shows diffusely deficient myelination of the ticity, seizures, and developmental regression. Death is cerebral hemispheres, with a thin corpus callosum and common in infancy and usually occurs before age atrophy of white matter. Histopathology of early disease 10 years. Brain MRI shows frontally dominant demyeli- shows patches or stripes of perivascular white matter nation involving the subcortical U fibers and contrast sparing, resulting in a tigroid pattern, sometimes also enhancement in the deep frontal white matter, basal gan- visible on MRI (see Figure 5). The etiology is duplication glia, and periventricular rim. Pathology shows astrocytic or mutation of the proteolipid protein gene (PLP1) on intracytoplasmic inclusion bodies called Rosenthal fibers the X chromosome, resulting in over- or underproduc- (Figure 4). More than 30 mutations of genes encoding tion of proteolipid protein. Diagnosis is by detecting the glial fibrillary acidic protein (GFAP) have been iden- duplication or mutation of the PLP1 gene.

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Figure 5. Metachromatic leukodystrophy. (A) T2-weighted A magnetic resonance image (MRI) shows numerous tubular struc- tures with low signal intensity in a radiating (“tigroid”) pattern within the demyelinated deep white matter. Note sparing of subcortical U fibers. (Adapted with permission from Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in children: a pictorial review of MR imaging features. Radiographics 2002;22:464. Radio- logical Society of North America.)

X-LINKED ADRENOLEUKODYSTROPHY X-Linked adrenoleukodystrophy presents at 5 to 8 years of age as a subacute onset of behavioral problems, visual loss, hyperpigmented skin, and adrenal insufficiency, leading to progressive spasticity, optic atrophy, late seizures, and eventual vegetative state. Death is B typical by 3 years after diagnosis. Brain MRI shows Figure 6. X-Linked adrenoleukodystrophy (ALD) in a 5-year- demyelination, which begins in the splenium of the cor- old boy. (A) T2-weighted magnetic resonance image (MRI) pus callosum and spreads in a posterior to anterior pat- shows symmetric confluent demyelination in the peritrigonal tern. The leading edge of demyelination enhances with white matter and the splenium of the corpus callosum. contrast (Figure 6). The defect is in the ABCD1 gene, (B) Gadolinium-enhanced T1-weighted MRI reveals enhance- which codes for a peroxisomal membrane ATP-binding ment of the leading edge of active demyelination and inflamma- cassette protein transporter. As a result, very-long-chain tion (arrows). (Adapted with permission from Cheon JE, Kim IO, fatty acids are not degraded and, thus, accumulate. Hwang YS, et al. Leukodystrophy in children: a pictorial review Diagnosis is suggested by MRI findings and by elevated of MR imaging features. Radiographics 2002;22:467. Radiological very-long-chain fatty acids in blood, especially C26:0 Society of North America.) but not C26:1 (elevated C26:0 plus C26:1 suggests Zellweger syndrome). lidi and thalami are involved, but the caudate is spared. CANAVAN DISEASE MR spectroscopy shows a large N-acetylaspartic acid Canavan disease (spongiform leukodystrophy) is an (NAA) peak. The deficiency is in aspartoacylase. Diag- autosomal recessive disorder that presents at 2 to nosis is by finding large quantities of NAA in urine. 4 months of age as megalencephaly and hypotonia, leading to developmental regression, progressive spasticity, KRABBE DISEASE and seizures. Brain MRI shows diffuse demyelination that Krabbe disease (globoid cell leukodystrophy) is an begins in subcortical and cerebellar white matter, later autosomal recessive disorder that presents at 1 to involving central white matter (Figure 7). The globus pal- 7 months of age as irritability and hyperreactive startle. www.turner-white.com Neurology Volume 9, Part 2 13

4 years, followed by developmental regression, dementia, pyramidal and extrapyramidal signs, and visual loss; death occurs between ages 6 and 30 years. The juvenile form presents between ages 4 and 10 years as rapidly progressive visual loss leading to total blindness within 2 to 4 years; seizures begin between ages 5 and 18 years and death occurs in the teens to thirties. The adult- onset form presents in the thirties, resulting in death within 10 years later. All of the NCLs are autosomal recessive except the adult form, which is autosomal dominant. The genes involved are PPT1 (at locus CLN1), CLN2 through CLN6, and CLN 8. PPT1 defects can present at any age, whereas CLN3 and CLN4 Figure 7. Canavan disease in a 6-month-old boy with macro- present in children and adults. Electron microscopy of cephaly. T2-weighted magnetic resonance image (MRI) shows white blood cells, skin, conjunctiva, or anal mucosa extensive high-signal intensity areas throughout the white matter. shows fingerprint, curvilinear, or granular osmiophilic Note involvement of the subcortical U fibers. (Adapted with per- deposits. More specific enzyme assays and genetic test- mission from Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy ing are available. Treatment is supportive. Seizures may in children: a pictorial review of MR imaging features. Radio- be worsened by phenytoin and carbamazepine. graphics 2002;22:472. Radiological Society of North America.) Lamotrigine may be the most efficacious and best- tolerated anticonvulsant. Trihexyphenidyl improves dystonia and sialorrhea.42 Developmental regression, spasticity, areflexia, startle myoclonus, seizures, and blindness follow. Most affected infants die by 1 year of age. Brain MRI shows diffuse OTHER METABOLIC DISORDERS demyelination beginning in deep white matter, later involving subcortical white matter. Computed tomography shows calcification in basal ganglia, thalami, and corona SMITH-LEMLI-OPITZ SYNDROME radiata. CSF shows elevated proteins. Motor nerve con- Smith-Lemli-Opitz syndrome is caused by deficiency duction velocities are prolonged. Diagnosis is by demon- of 7-dehydrocholesterol reductase, which leads to im- strating deficient galactocerebroside β-galactosidase activ- paired cholesterol synthesis. Patients have ptosis, antev- ity in leukocytes or cultured fibroblasts. erted nares, micrognathia, microcephaly, hypospadias, and cardiac defects. Syndactyly of the second and third toes is almost always present. Presentation is that of GRAY MATTER DISORDERS poor growth and developmental delay. Diagnosis is based on elevations of 7-dehydrocholesterol and de- Gray matter diseases classically present as seizures creased serum cholesterol. Management is with choles- and loss of function of affected cortex. Prototypical gray terol supplementation. matter diseases include Tay-Sachs disease (discussed previously) and the neuronal ceroid lipofuscinoses. LESCH-NYHAN SYNDROME The neuronal ceroid lipofuscinoses (NCLs) are a Lesch-Nyhan syndrome is an X-linked recessive dis- heterogeneous group of inherited neurodegenerative order caused by deficiency of hypoxanthine-guanine lysosomal storage disorders presenting as some combi- phosphoribosyl transferase (HPRT), an enzyme in- nation of visual loss, behavioral change, movement dis- volved in the metabolism of purines. This defect leads order, and seizures, especially myoclonic seizures.42 The to hyperuricemia and increased urinary excretion of infantile, late infantile, and juvenile forms are more uric acid. Most neonates are normal until 3 months of likely to be accompanied by retinal blindness. The adult age, when they demonstrate hypotonia and global form is usually not associated with visual loss. Those developmental delay. By age 1 to 2 years, choreoatheto- affected by the infantile form are normal at birth. Onset sis and dystonia are apparent, and by age 2 to 3 years, of seizures and visual loss occurs within 2 years and the characteristic severe self-mutilating behavior is death is typical by age 10 years. In the late infantile apparent. Most children never learn to walk. Renal fail- form, initial symptoms are seizures between ages 2 and ure due to urate deposition and gouty arthritis occur

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Copyright 2010 by Turner White Communications, Inc., Wayne, PA. All rights reserved. Metabolic Disorders in Pediatric Neurology later in life. Diagnosis is suggested by an elevated uric copper in blood, works faster than zinc and is also better acid-to-creatinine ratio. Confirmation is by HPRT activ- tolerated than penicillamine.49 ity. Treatment with allopurinol does not improve the neurologic outcome.43 OTHER Pyridoxine-dependent epilepsy presents as neonatal MENKES DISEASE seizures that respond only to pyridoxine.50 Biotinidase Menkes (kinky hair) disease is an X-linked recessive deficiency presents as seizures later in infancy to early disorder of copper transport resulting in low serum cop- childhood, which respond to biotin.51 Glucose trans- per levels, decreased intestinal copper absorption, and porter 1 (GLUT-1) deficiency syndrome presents as reduced activity of copper-dependent enzymes. Affected refractory seizures, acquired microcephaly, ataxia, and males develop normally during the first months of life, low CSF glucose between 1 and 4 months of age. Symp- but development then slows and regression occurs. Myo- toms are due to defective transport of glucose across the clonic seizures in response to stimulation are an early and blood-brain barrier. Seizures respond to the ketogenic almost constant feature. Dysautonomia occurs. The hair diet.52,53 takes on a brittle, steel wool appearance. Other findings on examination include skin laxity, sagging jowls, and ACKNOWLEDGEMENT hypotonia. Cerebral vessels are often tortuous and nar- We thank Justin Stahl, MD, for the white matter mnemonic rowed. Ischemic infarcts and subdural hematomas can VAMPACK. We thank Gregg Nelson, MD, for helpful com- occur. Death usually occurs before age 3 years. Laboratory ments and for Table 2. evaluation shows low serum copper and ceruloplasmin. CSF and plasma catecholamines are abnormal. 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