Metabolic Disorders in Pediatric Neurology


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Metabolic Disorders in Pediatric Neurology

  1. 1. ® NEUROLOGY BOARD REVIEW MANUAL STATEMENT OF EDITORIAL PURPOSE Metabolic Disorders in The Hospital Physician Neurology Board Review Manual is a study guide for residents and Pediatric Neurology practicing physicians preparing for board examinations in neurology. Each quarterly Editor: Catherine Gallagher, MD manual reviews a topic essential to the cur- Assistant Professor of Neurology, University of Wisconsin Movement rent practice of neurology. Disorders Program, Staff Physician, Middleton VA Hospital, PUBLISHING STAFF Madison, WI PRESIDENT, GROUP PUBLISHER Contributors: Bruce M. White Gregory M. Rice, MD EDITORIAL DIRECTOR Fellow in Clinical and Biochemical Genetics, Departments of Medical Debra Dreger Genetics and Pediatrics, University of Wisconsin, Madison, WI ASSOCIATE EDITOR Rita E. Gould David Hsu, MD, PhD Assistant Professor of Neurology, Department of Neurology, University EXECUTIVE VICE PRESIDENT of Wisconsin, Madison, WI Barbara T. White EXECUTIVE DIRECTOR OF OPERATIONS Table of Contents Jean M. Gaul PRODUCTION DIRECTOR Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Suzanne S. Banish Disorders Caused by Energy Failure . . . . . . . . . . . . . . . . . 2 PRODUCTION ASSISTANT Kathryn K. Johnson Disorders of Amino Acid Metabolism. . . . . . . . . . . . . . . . 6 ADVERTISING/PROJECT MANAGER Disorders of Carbohydrate Metablism . . . . . . . . . . . . . . . 9 Patricia Payne Castle Lysosomal Storage Disorders . . . . . . . . . . . . . . . . . . . . . 10 SALES & MARKETING MANAGER Deborah D. Chavis Peroxisomal Biogenesis Disorders . . . . . . . . . . . . . . . . . 11 NOTE FROM THE PUBLISHER: White Matter Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 12 This publication has been developed without Gray Matter Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 14 involvement of or review by the American Board of Psychiatry and Neurology. Other Metabolic Disorders . . . . . . . . . . . . . . . . . . . . . . . 14 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Endorsed by the Association for Hospital Medical Education Cover Illustration by Kathryn K. Johnson Copyright 2005, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or oth- erwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of appropriate topics and preparation of editorial content. The authors are solely responsible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inac- curacies. Information contained within this publication should not be used as a substitute for clinical judgment. www.turner - Neurology Volume 9, Part 2 1
  2. 2. NEUROLOGY BOARD REVIEW MANUAL Metabolic Disorders in Pediatric Neurology Gregory M. Rice, MD, and David Hsu, MD, PhD INTRODUCTION DISORDERS CAUSED BY ENERGY FAILURE This manual reviews metabolic diseases that affect the nervous system, focusing on the usual presentations GLYCOGEN STORAGE DISORDERS (GSD) from the perspective of a pediatric neurologist. Many of Glycogen is an important source of stored glucose these disorders also have milder presentations in later found primarily in liver and muscle. Defects in glycogen life, which are not discussed here. This review presents mobilization can lead to energy failure during times of sufficient information to begin a workup and to insti- fasting and exercise. tute initial interventions. A beginning neurologist will need to learn more about each disorder as he or she GSD Type II closes in on the definitive diagnosis. If a diagnosis is not GSD type II (Pompe’s disease) is caused by deficiency of readily apparent by clinical presentation (Table 1), one the lysosomal enzyme acid maltase (α-1-4-glucosidase).1 must resort to a more systematic approach. The infantile form presents as severe hypotonia and car- In this review, disorders are generally grouped diomyopathy and is usually fatal before 12 months of age. according to defects of the various biochemical path- The childhood form affects only skeletal muscle and pre- ways (Figure 1). Metabolic disorders caused by energy sents as progressive weakness. Creatine kinase (CK) levels failure can involve defects in the mobilization of glyco- are markedly elevated, and muscle biopsy demonstrates gen (ie, glycogen storage diseases) or fats (ie, fatty acid oxi- glycogen storage in muscle fibers and absence of acid mal- dation defects) or defects in the citric acid cycle or respi- tase. Hypoglycemia is not seen in GSD type II. ratory chain (ie, mitochondrial disorders). These disorders tend to present as decompensations with stress or in- GSD Type V creased energy demand. Metabolic disorders caused by GSD type V (McArdle’s disease) is caused by defi- defects in amino acid metabolism include the organic ciency of myophosphorylase and presents in adolescents acidemias, aminoacidopathies, and urea cycle defects. These as cramps and muscle fatigue shortly after initiating disorders tend to present in infancy as increasing lethar- exercise. A “second wind” effect can occur (ie, renewed gy and vomiting with initiation of feeds. Lysosomal disor- ability to continue exercising if patients rest briefly after ders result in the accumulation of large carbohydrate– the onset of fatigue). Laboratory studies show elevated lipid complexes and present as dysmorphism with CK levels, post-exertional myoglobinuria, and a failure organomegaly, psychiatric symptoms, or white matter of the normal rise in lactate levels with exercise. The disease. Aside from the glycogen storage disorders, the forearm ischemic test is the classic exercise test but is dif- disorders of carbohydrate metabolism are rather heteroge- ficult to perform reliably. Muscle biopsy shows glycogen neous. Finally, some primarily white matter disorders are storage in muscle and absence of myophosphorylase. suggested by clinical presentation, such as increasing Moderate exercise with careful warmup is advisable. spasticity and abnormalities in white matter on mag- Dietary treatments have been disappointing. netic resonance imaging (MRI), whereas primarily gray matter disorders present as seizures and cognitive decline. FATTY ACID OXIDATION DISORDERS In the United States, most states screen newborns for Fatty acid oxidation disorders consist of autosomal phenylketonuria, galactosemia, hypothyroidism, con- recessive defects in either the transport of fatty acids into genital adrenal hyperplasia, hemoglobinopathies, and mitochondria or in the intramitochondrial β-oxidation maple syrup urine disease. Some states employ tandem of fatty acids. A prolonged fast or significant stress (eg, ill- mass spectroscopy, which gives amino acid and acylcar- ness, surgery) may deplete liver stores of glycogen. If fatty nitine profiles. These tests are useful for diagnosing stores fail to be mobilized for fuel, the result is the classic many metabolic disorders, as described below. laboratory finding of hypoketotic hypoglycemia.2 A mild to 2 Hospital Physician Board Review Manual www.turner -
  3. 3. Metabolic Disorders in Pediatric Neurology Table 1. Clinical Presentations and Differential Diagnosis of Metabolic Disorders Stroke/stroke-like episodes Cardiomyopathy Progressive myoclonic epilepsies Mitochondrial myopathy, encephalomyelopa- VLCAD deficiency Myoclonic epilepsy with ragged red fibers thy, and lactic acidosis with stroke-like LCHAD deficiency (MERRF) episodes (MELAS) Unverricht-Lundborg disease (Baltic Carnitine transporter deficiency Homocystinuria myoclonus) Infantile CPT2 deficiency Propionic acidemia Neuronal ceroid lipofuscinosis GSD II (Pompe’s disease) Methylmalonic acidemia Lafora’s disease GSD III (Cori’s disease) Isovaleric acidemia Sialidosis type 1 Mitochondrial disorders Glutaric acidemia type I Psychiatric/behavioral change Cherry red spots on the macula Urea cycle disorders Wilson’s disease Tay-Sachs disease Congenital disorders of glycosylation Neuronal ceroid lipofuscinosis Sandhoff’s disease Menkes’ syndrome X-Linked adrenoleukodystrophy GM1 gangliosidosis Fabry’s disease Juvenile- and adult-onset metachromatic Niemann-Pick disease Leigh disease leukodystrophy Sialidosis Electron transport chain defects Late-onset GM2 gangliosidosis Multiple sulfatase deficiency Pyruvate dehydrogenase complex deficiency Lesch-Nyhan syndrome Rhabdomyolysis/myoglobinuria Biotinidase deficiency Porphyria (episodic) GSD type V (McArdle’s disease) Reye-like syndrome Urea cycle disorders (episodic) Adult CPT2 deficiency Fatty acid oxidation disorders Sanfilippo’s syndrome (mucopolysaccharido- VLCAD deficiency sis III) Urea cycle disorders LCHAD deficiency Hunter’s syndrome (mucopolysaccharidosis II) Organic acidemias Carnitine transporter deficiency Mitochondrial disorders CPT = carnitine palmitoyl transferase; GSD = glycogen storage disease; LCHAD = long-chain hydroxy acyl coenzyme A dehydrogenase; VLCAD = very-long-chain acyl coenzyme A dehydrogenase. (Adapted from Nyhan WL, Ozand PT. Atlas of metabolic diseases. New York: Chapman and Hall; 1998; and Clarke JT. A clinical guide to inherited metabolic diseases. 2nd ed. New York: Cambridge University Press; 2002.) moderate hyperammonemia may also be seen. Organs Carbohydrates 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 Fructose Amino acids Fatty acids demand and because fatty fuels spare proteolysis), and the liver (which relies on energy derived from fatty acid NH3 Urea oxidation for gluconeogenesis and ureagenesis). Man- Pyruvate Lactate Urea agement for all fatty acid oxidation disorders includes cycle avoiding prolonged fasts and aggressive use of dextrose- Acetyl CoA containing fluids during decompensations. β-oxidation Krebs Ketones Carnitine must bind to long-chain fatty acids for fatty cycle acid transport across the mitochondrial double mem- brane. Carnitine enters the cell through a carnitine ATP ADP transporter. It is bound to the fatty acyl group by carni- Mitochondrion Respiratory chain Cytosol tine palmitoyl transferase 1 (CPT1) at the outer mito- chondrial membrane. Acylcarnitine is then transported Figure 1. Basic pathways of intermediary metabolism. Glucose- to the inner mitochondrial membrane by acylcarnitine 6-P = glucose-6-phosphate. (Adapted with permission from translocase. At the inner mitochondrial membrane, acyl- Hoffmann GF, Nyhan WL, Zschocke J. Inherited metabolic dis- carnitine is disassembled into acyl coenzyme A (CoA) eases. Philadelphia: Lippincott Williams & Wilkins; 2002:6.) and free carnitine by carnitine palmitoyl transferase 2 (CPT2). Acyl CoA then enters β-oxidation while free carnitine is recirculated to the cell cytoplasm. The first www.turner - Neurology Volume 9, Part 2 3
  4. 4. Metabolic Disorders in Pediatric Neurology 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 hydroxy acyl coenzyme A dehydrogenase; M = skeletal muscle; MCAD = medium-chain acyl coenzyme A dehydrogenase; N = neonate; nl = normal. (Adapted from Nyhan WL, Ozand PT. Atlas of metabolic diseases. New York: Chapman and Hall; 1998.) step in β-oxidation is performed by acyl CoA dehydro- form presents in the teens to twenties as episodic rhab- genases, which are distinct depending on the acyl group domyolysis and myoglobinuria with elevated CK levels chain length. following prolonged exercise, cold exposure, infection, Carnitine also acts as a scavenger of potentially toxic or fasting. acyl CoA metabolites, forming acylcarnitine esters that are excreted in the urine. A secondary carnitine defi- Disorders of β-Oxidation and Ketogenesis ciency results when urinary acylcarnitine loss is ex- Medium-chain acyl CoA dehydrogenase (MCAD) cessive. Blood carnitine levels then show an elevated deficiency is the most common of the fatty acid oxida- acylcarnitine ester-to-free carnitine ratio (ie, > 0.4).2 Val- tion disorders. MCAD helps metabolize medium-chain proic acid therapy can cause secondary carnitine defi- fatty acids to ketones, which are used as fuel during ciency in this way by forming valproyl carnitine ester. times of stress and fasting. Acute presentation consists Screening laboratory tests include plasma free and of lethargy, vomiting, seizure, and progressive enceph- total carnitines, plasma acylcarnitine profile, and urine alopathy after fasting or physical stress. An initial attack acylglycines. Laboratory findings are summarized in may result in sudden infant death. Management in- Table 2. Interpretation of urine acylglycines is complex cludes moderate dietary fat restriction and carnitine and is omitted in this review. supplementation. Very-long-chain acyl CoA dehydrogenase (VLCAD) Carnitine Disorders deficiency and long-chain 3-hydroxy acyl CoA dehy- Carnitine transporter deficiency leads to total body drogenase (LCHAD) deficiency are associated with carnitine depletion secondary to increased renal loss. cardiomyopathy, skeletal myopathy, post-exertional Symptoms include muscle weakness and cardiomyopa- rhabdomyolysis, and hypoketotic hypoglycemia with de- thy. Carnitine given in high doses reverses symptoms compensations. Children with VLCAD deficiency can pre- and can be lifesaving.2 sent with a Reye-like syndrome, which can be fatal. CPT1 deficiency presents as a Reye-like syndrome, Mothers carrying a fetus with LCHAD deficiency can pre- with progressive encephalopathy, seizures secondary to sent with hemolysis, elevated liver function tests, and low hypoglycemia, hepatomegaly, moderate hyperammo- platelet counts (HELLP syndrome). Diagnosis is by acyl- nemia, and elevated liver enzymes. Skeletal and cardiac carnitine profile, which shows elevated long-chain acyl- muscle are not involved. Acylcarnitine profile shows de- carnitines and hydroxy-acylcarnitines, respectively, in creased long-chain acylcarnitines (C16, C18). Chronic patients with VLCAD deficiency and LCHAD deficiency. treatment with medium-chain fatty acids may be of ben- Medium-chain triglycerides (MCT oil) are supplemented. efit. Glutaric acidemia type II (multiple acyl CoA CPT2 deficiency has an infantile (liver) and adult dehydrogenase deficiency) involves defects in the flavin (muscle) form. The infantile form presents as hep- adenine dinucleotide (FAD)–dependent electron atomegaly, liver failure, cardiomegaly, arrhythmias, and transfer from dehydrogenase enzymes to the electron seizures, with hypoketotic hypoglycemia. The adult transport chain. This disorder affects both fatty acid 4 Hospital Physician Board Review Manual www.turner -
  5. 5. Metabolic Disorders in Pediatric Neurology Table 3. Mitochondrial Disorders Disorder 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 deletions; only skeletal muscle affected Kearns-Sayre syndrome4 CPEO, retinitis pigmentosa, and one of following: cerebellar ataxia, Multiple mtDNA deletions; all tissues affect- conduction block, CSF protein > 100 mg/dL ed; check serial ECGs Leigh disease, 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; multiple mutations encephalomyelopathy7 associated Leber’s hereditary optic Acute: optic nerve hyperemia, vascular tortuosity Painless; initially asymmetric; progresses over neuropathy8 Chronic: optic atrophy weeks to months Uncommon: cardiac conduction abnormalities NARP7 Neuropathy, ataxia, retinitis pigmentosa, proximal weakness, men- Can go years without exacerbation; tal retardation mtATPase affected Friedreich’s 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 imag- ing; mt = mitochondrial; NARP = neurogenic muscle weakness, ataxia, and retinitis pigmentosa. oxidation and amino acid metabolism. The classic neo- Table 4. Clinical Features of Mitochondrial Disorders natal 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’s syndrome) is significant overlap with a complex relationship be- Endocrine system: diabetes, hypoparathyroidism tween identified genetic defects and classic mitochon- drial syndromes3 (Table 3).4 – 9 Adapted from Cohen BH, Gold DR. Mitochondrial cytopathy in adults: What we know so far. Cleveland Clin J Med 2001;68:625–41 Clinical Features with permission from The Cleveland Clinic Foundation. Copyright © 2001, all rights reserved. Mitochondrial disorders are highly variable in pre- sentation. Suspicion for a mitochondrial defect increas- lactate levels at rest. Furthermore, mitochondrial DNA es if there is multisystem involvement of high energy sys- panels are abnormal in only 10% of patients.11 Thus, tems3,10 (Table 4). Diagnosis of mitochondrial disorders muscle biopsy remains a key to diagnosis. Muscle biop- begins with analysis of serum lactate, pyruvate, and CK sy 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, 50–250). However, 40% of patients have normal mitochondrial respiratory chain protein synthesis. www.turner - Neurology Volume 9, Part 2 5
  6. 6. Metabolic Disorders in Pediatric Neurology A B C Figure 2. Mitochondrial myopathy, encephalomyelopathy, and lactic acidosis with stroke-like episodes (MELAS) syndrome in a 10-year- old boy with migrating infarction. (A) Initial T2-weighted magnetic resonance image (MRI) shows a high signal intensity lesion in the left occipital lobe (arrows). Follow-up MRI 15 months later showed resolution of the occipital lesion but with new left temporal lesion (not shown). (B) Photomicrograph (original magnification, ×40; Gomori methenamine silver stain) of the muscle biopsy reveals scattered ragged red fibers (arrows). (C) Electron micrograph reveals an increased number of mitochondria (arrows), which are irregular and enlarged. (Adapted with permission from Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in children: a pictorial review of MR imag- ing features. Radiographics 2002;22:470. Radiological Society of North America.) Biochemical analysis of muscle can reveal decreases in Treatment involves supplementation with thiamine, activity of the respiratory chain complexes I to IV. Elec- which is a cofactor for PDHC, and a high fat, low carbo- tron microscopy shows overabundant, enlarged, and hydrate diet. Acetazolamide may abort attacks.17 bizarrely shaped mitochondria with paracrystalline inclu- sions. Brain MRI may show lesions of the basal ganglia, thalamus, midbrain, or cerebral white matter. In the cere- DISORDERS OF AMINO ACID METABOLISM bral white matter, recurrent stroke-like events may occur, with transitory migrating lesions that cross vascular terri- tories (Figure 2). Magnetic resonance (MR) spectros- ORGANIC ACIDEMIAS copy may show elevated lactate peaks in these lesions.12,13 Organic acidemias are caused by autosomal recessive Impaired autoregulation of cerebral vasculature has disorders of amino acid metabolism. The usual presenta- been suggested as the etiology of stroke-like events.14 tion is that of nonspecific poor feeding, lethargy, and vom- iting in the neonatal period, eventually progressing to Treatment coma. Symptoms are often initially mistaken for sepsis. Treatment is with L-carnitine, B vitamins (riboflavin Laboratory findings include metabolic acidosis with an and thiamine), and coenzyme Q or idebenone. Biotin, elevated anion gap, sometimes with ketosis and hyper- antioxidants (vitamins A and C), folate, and lipoic acid ammonemia (Table 5). Diagnosis during the acute illness are also used.15 Dichloroacetic acid may lower lactate depends on plasma amino acids, plasma acylcarnitine levels in some patients.16 Response to treatment is vari- profile, urine organic acids, and urine acylglycine profile. able, with some patients experiencing improvement in The detailed analysis of these profiles is often complex energy and function but many experiencing no dis- and is not discussed here. Acute treatment involves with- cernible improvement. holding protein feeds and aggressively pushing dextrose- containing fluids, to induce an anabolic state. Chronic PYRUVATE DEHYDROGENASE COMPLEX DEFICIENCY treatment consists of specific dietary protein restriction. Pyruvate dehydrogenase complex (PDHC) deficien- Carnitine supplementation can be helpful.18 cy blocks entry of pyruvate into the citric acid cycle, resulting in elevated lactate and pyruvate levels. PDHC Propionic Acidemia deficiency presents similarly to the mitochondrial disor- Propionic acidemia is caused by a deficiency in propi- ders. The severe neonatal form is fatal in infancy. Leigh onyl CoA carboxylase. Most children have some cognitive disease can develop later in infancy. Diagnosis is based disability even with optimal therapy. Cardiomyopathy, on finding elevated lactate and pyruvate levels with pancreatitis, osteoporosis, and movement disorders are preservation of the lactate-to-pyruvate ratio (ie, < 20). late complications. 6 Hospital Physician Board Review Manual www.turner -
  7. 7. Metabolic Disorders in Pediatric Neurology 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 hyperammo- Elevated Normal nemia can be severe, and a single attack can cause per- Acid-Base Status Ammonia Ammonia manent cognitive disability. Seizures, spasticity, behav- Acidemia with elevated Organic acidemia Organic acidemia ioral problems, and ataxia are common. Metabolic anion gap (neonate) (older child) stroke with an acute decompensation can occur. Many No acidemia Urea cycle disorder Galactosemia, patients will develop renal failure and require renal MSUD transplantation. Methylmalonic acid can also be elevat- MSUD = maple syrup urine disease. (Adapted with permission from ed in disorders of cobalamin (vitamin B12) metabolism, Silverstein S. Laughing your way to passing the pediatric boards. 2nd and megaloblastic anemia can be seen. Brain MRI may ed. Stamford [CT]: Medhumor Medical Publications; 2000:286). show bilateral globus pallidus infarction. Management Copyright © 2000. of methylmalonic acidemia consists of vitamin B12 sup- plementation 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 leu- glutaryl CoA dehydrogenase, which results in dystonia, cine, isoleucine, and valine. The classic form presents in ataxia, cognitive disability, and spasticity. Metabolic aci- the first week of life as poor feeding, lethargy, and vom- dosis is not a prominent feature even with acute de- iting, quickly progressing to coma, seizures, and death compensation. Diagnostic studies are often normal if untreated. An intermittent form may present later in when affected individuals are healthy. Neuroimaging life as attacks of transient ataxia, sometimes accompa- shows frontotemporal atrophy with basal ganglia le- nied by cerebral edema.21 These attacks are triggered by sions. Basal ganglia injury can appear even with a first intercurrent illness or stresses. Urine, sweat, and ceru- attack. Macrocephaly is common. Chronic manage- men often smell like maple syrup. Acidosis and hyper- ment consists of carnitine supplementation and pro- ammonemia 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. As a result, and in the intermittent form between attacks. Acute neurotoxic phenylketones accumulate. Testing shows management includes aggressive high calorie intra- elevated levels of blood phenylalanine and urine venous or nasogastric feeds, sometimes with intra- phenylketones. Infants are normal at birth, but in the venous insulin to help induce an anabolic state. Special first year of life manifest progressive cognitive delay, MSUD total parenteral nutrition is available with the microcephaly, spasticity, recurrent eczematous rash, proper mixture of amino acids. Chronic management and a mousy odor. Seizures occur in 25% of untreated relies on dietary restriction of branched-chain amino PKU patients.19 Newborn screening and early treat- acids. With early diagnosis and tight metabolic control, ment can prevent these symptoms. Treatment in classic the prognosis is for normal development. PKU consists of dietary restriction of phenylalanine and close monitoring of blood phenylalanine levels. Classic Homocystinuria Women with PKU should have phenylalanine levels Classic homocystinuria is an autosomal recessive dis- under control before attempting to conceive. Fetuses order caused by a defect in the enzyme cystathionine exposed to high levels of phenylalanine are at risk for β-synthetase, resulting in elevations of homocystine and congenital heart disease, intrauterine growth restric- methionine. Infants are usually asymptomatic, but men- tion, mental retardation, and microcephaly. Approx- tal retardation can develop in untreated patients. Adults imately 2% of PKU patients have normal phenylala- are often tall and thin, and most have significant myopia. nine hydroxylase activity but are deficient in the Lens dislocation (ectopia lentis) may develop later in life, cofactor tetrahydrobiopterin.20 These patients require but the lens is usually dislocated inferiorly, which is the biopterin supplementation. opposite of what is seen in Marfan syndrome. Untreated www.turner - Neurology Volume 9, Part 2 7
  8. 8. Metabolic Disorders in Pediatric Neurology UREA CYCLE DISORDERS HCO3 + NH4 + 2 ATP 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 Carbamyl Asparate phosphate e e exception of ornithine transcarbamylase (OTC) defi- in in tr ull ull ciency, which is X-linked. Ci tr Ci 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 ARG Arginine gresses to coma, seizures, and death if left untreated. Fumarate Cerebral edema (with a bulging fontanelle and tachy- Figure 3. The urea cycle and its disorders. ARG = arginase defi- pnea) can occur early and progresses rapidly. Metabolic ciency; ASL = argininosuccinic acid lyase deficiency; ASS = argin- strokes may also occur. All urea cycle disorders, with the inosuccinic acid synthetase deficiency; CPSI = carbamyl phosphate exception of argininemia, are accompanied by hyperam- synthetase I deficiency; OTC = ornithine transcarboxylase defi- monemia. Ammonia levels exceeding 200 µg/dL cause ciency. (Adapted with permission from Summar ML, Tuchman M. lethargy and vomiting, levels greater than 300 µg/dL Urea cycle disorders overview. GeneReviews. Available at www. result in coma, and levels exceeding 500 µg/dL cause Accessed 8 Apr 2005.) seizures.17 Any catabolic state, including the immediate postnatal period before initiation of feeding, can provoke a crisis because of associated proteolysis. Permanent neu- patients are at risk for seizures, psychiatric disorders, and rologic sequelae can occur after a single crisis. Ammonia thromboembolic events, including stroke, myocardial in- levels greater than 350 µg/dL26 and coma for longer than farction, and pulmonary emboli.22 Treatment involves 3 days27 are correlated with death or profound mental protein restriction; supplementation with vitamin B6, vit- retardation. Ammonia levels less than 180 µg/dL usually amin B12, and folate; and stroke prophylaxis with aspirin. result in normal development or only mild mental retar- dation.26 Milder forms, as seen with female carriers of Nonketotic Hyperglycinemia OTC deficiency, can have a more subtle presentation. Nonketotic hyperglycinemia (glycine encephalopa- thy) is caused by a defect in glycine cleavage.23 This Treatment defect results in elevated glycine levels in the blood, Hyperammonemia in an encephalopathic infant is a urine, and cerebrospinal fluid (CSF). The neonatal medical emergency. In addition to determining ammo- form presents as lethargy and poor feeding after the ini- nia levels and acid-base status, laboratory studies tiation of protein feeds, quickly progressing to persistent should be ordered for electrolytes, calcium, glucose, lac- seizures, encephalopathy, and coma. Apnea is common tate, liver enzymes, free and total carnitine, quantitative and persistent hiccups have also been seen. Diagnosis plasma amino acids, and urine organic acids. Acute depends on simultaneous measurement of CSF and management for all urea cycle disorders consists of plasma glycine levels. A CSF-to-plasma glycine ratio (1) stopping all protein intake; (2) starting an intra- greater than 0.06 supports this diagnosis.24 Acute man- venous infusion of 10% glucose plus lipid to promote agement includes use of sodium benzoate to help nor- the anabolic state; and (3) starting arginine hydrochlo- malize plasma glycine level. Dextromethorphan, an ride, sodium benzoate, and sodium phenylacetate with NMDA (N-methyl-D-aspartate) receptor antagonist, may intravenous loading doses, followed by maintenance be beneficial. Valproic acid, which inhibits metabolism infusions. Peritoneal dialysis or hemodialysis should be of glycine, is contraindicated. The prognosis for the considered if there is clinical deterioration and ammo- neonatal form is poor. Survivors often have spastic quad- nia levels are not responding. Chronic management riplegia, intractable seizures, and severe mental retarda- typically includes protein restriction and oral sodium tion. Infantile, childhood, and adult-onset forms exist benzoate and sodium phenylacetate supplementa- but are uncommon; these forms have milder outcomes. tion.25 Because the urea cycle takes place in the liver, 8 Hospital Physician Board Review Manual www.turner -
  9. 9. Metabolic Disorders in Pediatric Neurology liver transplantation is curative for the metabolic disor- age, acute episodes of hyperammonemia become less der but does not reverse accumulated neurologic frequent. Developmental delays are common even with injury. In the severe forms of the urea cycle disorders good compliance. (eg, carbamyl phosphate synthetase 1 [CPS1] deficien- Argininemia is caused by a defect in arginase. cy, OTC deficiency), liver transplantation before 1 year Argininemia is unique among the urea cycle disorders of age is associated with better survival into the child- in that it rarely causes acute hyperammonemic crisis. hood years, with mild (rather than profound) mental Ammonias may chronically be mildly elevated. Spastic- retardation.28 ity and developmental regression develop early in childhood, often with cyclic vomiting, seizures, and fail- Specific Disorders ure to thrive. Children are often misdiagnosed as hav- CPS1 deficiency blocks formation of carbamyl phos- ing cerebral palsy. Diagnosis is based on elevated argi- phate and has the classic presentation described above. nine in plasma, although levels can be normal in the Orotic acid is a metabolite of carbamyl phosphate. immediate newborn period. Treatment involves an Thus, CPS1 deficiency is the only urea cycle disorder arginine-restricted diet. The prognosis includes mental without elevated urine orotic acid. Plasma amino acids retardation, seizures, and spastic diparesis. show decreased citrulline and arginine. Chronic man- agement is as described above plus arginine supple- mentation. Prognosis is poor with neonatal presenta- DISORDERS OF CARBOHYDRATE METABOLISM tions. Recurrent exacerbations occur even with optimal therapy. Survivors are generally profoundly mentally retarded. Initial presentation is usually in the neonatal GALACTOSEMIA period but can be delayed into childhood. The out- Galactosemia results from a deficiency in galactose- come in later-onset cases can be milder but still in- 1-phosphate uridyltransferase.30 Neonates present with cludes mental retardation, motor deficits, and death. vomiting, poor feeding, and lethargy following the ini- OTC deficiency is identical to CPS1 deficiency in tiation of breast or bottle feeding. Jaundice and hepato- presentation, except that urine orotic acids are elevat- megaly are seen, and simultaneous Escherichia coli sepsis ed. Plasma amino acids show decreased citrulline and is associated. Untreated infants develop profound men- arginine. Due to skewed X-inactivation, 15% of females tal retardation and, often, renal failure. Lenticular cata- will develop hyperammonemia;29 many of these females racts develop after only 1 month if untreated. Those learn to avoid meat. A protein load can induce symp- with suboptimal control are at risk for behavioral and toms. The catabolic postpartum state can also provoke learning problems. Even with good dietary control, a crisis. Chronic management involves protein restric- patients may have subtle cognitive delays or learning tion and oral sodium benzoate, phenylacetate, and cit- disabilities. Action tremor may become a prominent rulline supplementation. Prognosis is the same as for complaint, refractory to medical therapy. Females are at CPS1 deficiency. risk for premature ovarian failure, even if treated. The Citrullinemia is caused by a defect in argininosuc- diagnosis is suggested by finding reducing substances in cinic acid synthetase. The presentation is similar to that urine and confirmed by elevations in serum galactose- of CPS1 deficiency, but prognosis for survivors of the 1-phosphate. Treatment is based on dietary restriction initial episode is somewhat better, with future exacerba- of galactose. tions becoming easier to manage with age. A milder, late-onset form of citrullinemia exists. Plasma amino CONGENITAL DISORDERS OF GLYCOSYLATION acids show elevated citrulline and reduced arginine. Congenital disorders of glycosylation (CDG, former- Chronic management is the same as for CPS1 deficien- ly called carbohydrate-deficient glycoprotein syn- cy, but arginine supplementation is essential. drome) are a heterogeneous group of mostly autoso- Argininosuccinic aciduria is caused by deficiency of mal recessive disorders with deficient glycosylation of argininosuccinic acid lyase. Affected children may dem- glycoproteins.31 CDG Ia is the most common type and onstrate failure to thrive, hepatomegaly, and unusual involves deficiency of phosphomannomutase. CDG Ib hair, including alopecia and trichorrhexis nodosa. is unique in presenting as hypoglycemia and protein- Plasma amino acids show elevated citrulline with de- losing enteropathy, without neurologic features. CDG creased arginine. Argininosuccinic acid is elevated in as a group is suggested in an infant or a child with some plasma and present in urine. Treatment involves pro- combination of failure to thrive, stroke-like episodes, a tein restriction and arginine supplementation. With clotting or bleeding tendency, hypotonia, psychomotor www.turner - Neurology Volume 9, Part 2 9
  10. 10. Metabolic Disorders in Pediatric Neurology Table 6. Mucopolysaccharidoses (MPS) Affected Syndrome MPS Type Features Compound Defect Comments Hurler’s IH MR, CF, CC DS, HS α-L-iduronidase Cardiac disease; motor weakness; dysostosis multiplex Scheie’s IS CF, CC DS, HS α-L-iduronidase Dysostosis multiplex; milder than Hurler’s Hurler-Scheie IHS CF, CC, ± MR DS, HS α-L-iduronidase Intermediate between Hurler’s and Scheie’s Hunter’s II MR, CF DS, HS Iduronate sulfatase Motor weakness; aggressive Sanfilippo’s types A–D IIIA–D MR HS Distinct for each type Severe behavior problems; speech delay Morquio’s types A IVA, IVB CC, ± MR KS and Distinct for each type Odontoid hypoplasia; bony abnormalities and B CS (type A); KS (type B) CC = corneal clouding; CF = coarse facial features; CS = chondroitin sulfate; DS = dermatan sulfate; HS = heparan sulfate; KS keratan sulfate; MR = mental retardation. (Adapted with permission from Nyhan WL, Ozand PT. Atlas of metabolic diseases. New York: Chapman and Hall; 1998:441.) retardation, strabismus, retinitis pigmentosa, hypogo- forms of MPS are autosomal recessive except MPS type II nadism, ataxia, and cerebellar hypoplasia. There may (Hunter’s syndrome), which is X-linked recessive. Neo- be inverted nipples and unusual fat deposits in the nates appear normal. Onset of disease is insidious. Other suprapubic and supragluteal regions. Peripheral neu- features are listed in Table 6. Urinary testing for MPS sug- ropathy may occur. Severity of symptoms is highly vari- gests the diagnosis, which is confirmed by enzyme assays able. Most adults are wheelchair bound. Diagnosis and from leukocytes or fibroblasts. separation into subtypes is by transferrin electrophore- sis. Coagulation studies may show deficiencies of factor SPHINGOLIPIDOSES XI, proteins C and S, and antithrombin. Oral mannose The sphingolipidoses involve abnormal metabolism is effective in CDG Ib, but no treatment exists for the and accumulation of sphingolipids. Deficiency of hex- other types of CDG.31 osaminidase A alone results in GM2 gangliosidosis, the classic form of which is Tay-Sachs disease. Tay-Sachs dis- LAFORA’S DISEASE ease is more common in Ashkenazi Jews than in the gen- Lafora’s disease is an autosomal recessive poly- eral population and is autosomal recessive. Onset of symp- glucosan storage disorder that presents as myoclonic toms is between 3 and 6 months of age. The initial sign is seizures in the mid-teens, with rapid neurocognitive an excessive startle reflex. A macular cherry red spot deterioration. Neurons show Lafora bodies with a core (Table 1) almost always is present at this stage, and psy- that stains very dark with periodic acid Schiff, with a chomotor regression then begins. By age 1 year, the child lighter outer halo. Skin, liver, or muscle biopsy can also is unresponsive and spastic. Seizures and macrocephaly be diagnostic.32 soon follow, and most children die between 4 and 5 years of age. Late-onset GM2 gangliosidosis, also more com- mon in Ashkenazi Jews, presents in childhood and adult- LYSOSOMAL STORAGE DISORDERS hood. Symptoms include weakness, personality change, tongue atrophy and fasciculations, tremor, and mixed Lysosomes are involved in the degradation of large upper and lower motor neuron signs. Dysarthria, ataxia, molecules, including mucopolysaccharides, sphingo- and progressive spasticity and dementia follow. A cherry lipids, sphingomyelin, and several others. Progressive red macula is not present in late-onset disease. Diagnosis organomegaly, dysmorphism, and neurodegeneration of both forms of GM2 gangliosidosis is by assays of hex- are typical. osaminidase A activity in serum, leukocytes, or cultured fibroblasts. No treatment is available. MUCOPOLYSACCHARIDOSES In the mucopolysaccharidoses (MPS), impaired degra- SANDHOFF’S DISEASE dation of various mucopolysaccharides (also known as gly- Sandhoff’s disease is a rare autosomal recessive dis- cosaminoglycans) cause variable combinations of coarse order caused by deficiencies in both hexosaminidase A facies, short stature, bony defects, stiff joints, mental retar- and B. It is not more prevalent in Ashkenazi Jews. dation, hepatosplenomegaly, and corneal clouding. All Clinical features are identical to those of Tay-Sachs 10 Hospital Physician Board Review Manual www.turner -
  11. 11. Metabolic Disorders in Pediatric Neurology disease, with additional findings of hepatosplenomeg- aly and bony deformities. Diagnosis is by enzyme assays of hexosaminidase. Foamy histiocytes are sometimes seen in bone marrow. No treatment is available. FABRY’S DISEASE Fabry’s disease is an X-linked recessive disorder caused by α-galactosidase deficiency. Presentation is usu- ally during adolescence or early adulthood, with painful crises in the extremities and paresthesias. Angiokera- tomas and gastrointestinal complaints are often present. There is an increased risk for stroke, heart disease, renal failure, pulmonary complications, and hearing loss. In- A telligence is normal. Diagnosis is by enzyme assay show- ing decreased activity. α-Galactosidase replacement ther- apy is available and appears promising.33 NIEMANN-PICK 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 psycho- motor regression in the first several months of life. In half of the cases, children have macular cherry red spots. Opisthotonus and hyperreflexia are common, B whereas seizure is uncommon. Death occurs between Figure 4. Alexander’s disease in a 5-year-old boy with macro- ages 2 and 4 years. Diagnosis is based on enzyme assay. cephaly. (A) T2-weighted magnetic resonance image shows sym- Foamy cells are observed in bone marrow and blood. metric demyelination in the frontal lobe white matter, including the subcortical U fibers. (B) Photomicrograph (original magnifica- Niemann-Pick Type C tion, ×100; hematoxylin and eosin stain) of the pathologic speci- Niemann-Pick type C is an autosomal recessive disor- men shows deposition of Rosenthal fibers (arrows). (Adapted with der that may present in neonates as severe liver or lung permission from Cheon JE, Kim IO, Hwang YS, et al. Leukodys- disease or in children as upgaze palsy or apraxia, ataxia, trophy in children: a pictorial review of MR imaging features. Ra- seizures, dementia, dysarthria, dysphagia, and dystonia. diographics 2002;22:473. Radiological Society of North America.) Adults present with psychiatric symptoms. Diagnosis is suggested by finding impaired cholesterol esterification and is confirmed by genetic testing for the NPC1 and Zellweger’s syndrome presents at birth as severe hypoto- NPC2 genes. Foamy cells are observed in the liver, nia, high forehead, wide-open fontanelles, hepatomegaly, spleen, and marrow. Sea-blue histocytes are seen in the and hyporeflexia. Intractable seizures, liver dysfunction, marrow in advanced disease. Cholesterol-lowering renal cysts, cardiac defects, retinal dystrophy, and sen- drugs reduce cholesterol levels, but no treatment sorineural hearing loss are common. Brain MRI demon- improves neurologic symptoms.34 strates severe hypomyelination of the hemispheres, with neuronal migrational defects (eg, polymicrogyria, pachy- gyria, periventricular heterotopias). Plasma very-long- PEROXISOMAL BIOGENESIS DISORDERS chain fatty acids (C26:0 and C26:1) are elevated. After the neonatal period, phytanic acid also is elevated. Specific Peroxisomes degrade very-long-chain fatty acids (C24, genetic testing is available for 6 known mutations, the C26). The classic peroxisomal biogenesis disorder is most common affecting the PEX1 gene. The majority of Zellweger’s syndrome (cerebrohepatorenal syndrome), affected infants die in the first year. Severe psychomotor an autosomal recessive disorder caused by deficiency of retardation develops in survivors.35 multiple proteins responsible for peroxisomal assembly. Milder presentations of peroxisomal biogenesis www.turner - Neurology Volume 9, Part 2 11
  12. 12. Metabolic Disorders in Pediatric Neurology disorders include neonatal adrenoleukodystrophy (not tified in association with Alexander’s disease. GFAP is a related to X-linked adrenoleukodystrophy, which is dis- major component of Rosenthal fibers. Juvenile- and cussed below) and Refsum disease. Both conditions adult-onset forms of Alexander disease have a milder can present in infancy or childhood as hypotonia, devel- course, with no macrocephaly or cognitive decline but opmental delay, vitamin K–responsive bleeding tenden- with a higher incidence of bulbar signs, ataxia, and posi- cy (due to liver dysfunction), sensorineural hearing tive family history. Demyelination in late-onset disease is loss, retinitis pigmentosa, neuropathy, and ataxia. The seen posteriorly rather than anteriorly.40,41 spectrum is continuous with no simple phenotype- genotype correlations, and diagnosis can be delayed METACHROMATIC LEUKODYSTROPHY into late adulthood.35 Metachromatic leukodystrophy (sulfatide lipidosis) is an autosomal recessive disorder usually caused by defi- ciency of arylsulfatase A and, less commonly, by deficien- WHITE MATTER DISORDERS cy of the sphingolipid activator protein, saposin B. Sulfatides then accumulate, leading to myelin destabi- White matter disorders classically present as progres- lization. The late infantile form is most common, with sive spasticity and neurocognitive regression. Hypotonia is onset after 1 year of age. This form is characterized by characteristic in the neonatal period, whereas psychiatric ataxia, hypotonia, and peripheral neuropathy, followed disturbance is typical in children and adults. Discussed later by progressive spasticity and cognitive decline. In below are vanishing white matter disorder, Alexander’s the juvenile and adult forms, central nervous system disease, metachromatic leukodystrophy, Pelizaeus- (CNS) symptoms are more prominent, with behavioral Merzbacher disease, X-linked adrenoleukodystrophy, disturbances, spasticity, and cognitive decline. Brain MRI Canavan’s disease, and Krabbe’s disease.36,37 A useful shows demyelination of periventricular white matter sym- mnemonic for recalling these disorders is VAMPACK. metrically, with involvement of the corpus callosum, early sparing of the subcortical U fibers, and late atrophy. VANISHING WHITE MATTER DISEASE There is no enhancement with contrast. A tigroid pattern Vanishing white matter disease (childhood ataxia with with patchy white matter sparing (formerly thought central hypomyelination) is an autosomal recessive disor- pathognomic for Pelizaeus-Merzbacher disease) and a der that usually presents in children age 2 to 6 years as leopard skin pattern have been described. In this case, slowly progressive cerebellar ataxia, spasticity, variable the islands of normal-appearing white matter may en- optic atrophy, and relatively preserved cognitive abilities.38 hance with contrast, but the demyelinated patches do Infections and minor head trauma may lead to altered not (Figure 5). Diagnosis is by testing for arylsulfatase A level of consciousness, developing into coma. Brain MRI activity. Bone marrow transplantation may be beneficial shows progressive loss of white matter diffusely with cystic in mildly affected patients with late-onset disease. degeneration. CSF may show elevated glycine. Later- onset (including adult-onset) disease has been described PELIZAEUS-MERZBACHER DISEASE and is associated with a milder clinical course. Mutations Pelizaeus-Merzbacher disease classically presents as have been found in genes that encode eukaryotic initia- neonatal nystagmus, choreoathetosis, progressive atax- tion factor 2B (eIF2B) subunits, which in turn may affect ia, spasticity, and developmental regression, with death the regulation of protein synthesis during cellular stress.39 often between 5 and 7 years of age. The spasticity may affect the legs preferentially. The nystagmus can some- ALEXANDER’S DISEASE times resolve. Milder cases present later, and children Alexander’s disease classically presents at approxi- who present after 1 year of age may live into adulthood. mately 6 months of age as megalencephaly, progressive Brain MRI shows diffusely deficient myelination of the spasticity, seizures, and developmental regression. Death cerebral hemispheres, with a thin corpus callosum and is common in infancy and usually occurs before age atrophy of white matter. Histopathology of early disease 10 years. Brain MRI shows frontally dominant demyeli- shows patches or stripes of perivascular white matter nation involving the subcortical U fibers and contrast sparing, resulting in a tigroid pattern, sometimes also enhancement in the deep frontal white matter, basal gan- visible on MRI (Figure 5). The etiology is duplication or glia, and periventricular rim. Pathology shows astrocytic mutation of the proteolipid protein 1 (PLP1) gene on intracytoplasmic inclusion bodies called Rosenthal fibers the X chromosome, resulting in over- or underproduc- (Figure 4). More than 30 mutations of genes encoding tion of proteolipid protein. Diagnosis is by detecting the glial fibrillary acidic protein (GFAP) have been iden- duplication or mutation of the PLP1 gene. 12 Hospital Physician Board Review Manual www.turner -
  13. 13. Metabolic Disorders in Pediatric Neurology Figure 5. Metachromatic leukodystrophy. T2-weighted mag- A netic resonance image shows numerous tubular structures with low-signal intensity in a radiating (“tigroid”) pattern within the demyelinated deep white matter. Note sparing of subcortical U fibers. (Adapted with permission from Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in children: a pictorial review of MR imaging features. Radiographics 2002;22:464. Radiological Society of North America.) X-LINKED ADRENOLEUKODYSTROPHY X-Linked adrenoleukodystrophy presents between 5 and 8 years of age as a subacute onset of behavioral problems, visual loss, hyperpigmented skin, and adren- al insufficiency, leading to progressive spasticity, optic atrophy, late seizures, and eventual vegetative state. B Death is typical by 3 years after diagnosis. Brain MRI Figure 6. X-Linked adrenoleukodystrophy in a 5-year-old boy. shows demyelination, which begins in the splenium of (A) T2-weighted magnetic resonance image (MRI) shows sym- the corpus callosum and spreads in a posterior to ante- metric confluent demyelination in the peritrigonal white matter rior pattern. The leading edge of demyelination en- and the splenium of the corpus callosum. (B) Gadolinium- hances with contrast (Figure 6). The defect is in the enhanced T1-weighted MRI reveals enhancement of the lead- ABCD1 gene, which codes for a peroxisomal mem- ing edge of active demyelination and inflammation (arrows). brane ATP-binding cassette protein transporter. As a (Adapted with permission from Cheon JE, Kim IO, Hwang YS, result, very-long-chain fatty acids are not degraded et al. Leukodystrophy in children: a pictorial review of MR im- and, thus, accumulate. Diagnosis is suggested by MRI aging features. Radiographics 2002;22:467. Radiological Society findings and by elevated very-long-chain fatty acids in of North America.) blood, especially C26:0 but not C26:1 (elevated C26:0 plus C26:1 suggests Zellweger’s syndrome). lidi and thalami are involved, but the caudate is spared. CANAVAN’S DISEASE MR spectroscopy shows a large N-acetylaspartic acid Canavan’s disease (spongiform leukodystrophy) is an (NAA) peak. The deficiency is in aspartoacylase. Diag- autosomal recessive disorder that presents at 2 to nosis is by finding large quantities of NAA in urine. 4 months of age as megalencephaly and hypotonia, lead- ing to developmental regression, progressive spasticity, KRABBE’S DISEASE and seizures. Brain MRI shows diffuse demyelination that Krabbe’s disease (globoid cell leukodystrophy) is an begins in subcortical and cerebellar white matter, later autosomal recessive disorder that presents at 1 to involving central white matter (Figure 7). The globus pal- 7 months of age as irritability and hyperreactive startle. www.turner - Neurology Volume 9, Part 2 13
  14. 14. Metabolic Disorders in Pediatric Neurology ages 2 and 4 years, followed by developmental regres- sion, dementia, pyramidal and extrapyramidal signs, and visual loss; death occurs between ages 6 and 30 years. The juvenile form presents between ages 4 and 10 years as rapidly progressive visual loss leading to total blindness within 2 to 4 years; seizures begin between ages 5 and 18 years and death occurs in the teens to thirties. The adult-onset form presents in the thirties, resulting in death within 10 years. All of the NCLs are autosomal recessive except the adult form, which is autosomal dominant. The genes involved are PPT1 (at locus CLN1), CLN2 through CLN6, and CLN8. PPT1 defects can present at any age, whereas Figure 7. Canavan’s disease in a 6-month-old boy with macro- CLN3 and CLN4 present in children and adults. cephaly. T2-weighted magnetic resonance image shows extensive Electron microscopy of lymphocytes, skin, conjunctiva, high-signal intensity areas throughout the white matter. Note or anal mucosa shows fingerprint, curvilinear, or gran- involvement of the subcortical U fibers. (Adapted with permission ular osmiophilic deposits. More specific enzyme assays from Cheon JE, Kim IO, Hwang YS, et al. Leukodystrophy in chil- and genetic testing are available. Treatment is support- dren: a pictorial review of MR imaging features. Radiographics ive. Seizures may be worsened by phenytoin and car- 2002;22:472. Radiological Society of North America.) bamazepine. Lamotrigine may be the most efficacious and best-tolerated anticonvulsant. Trihexyphenidyl im- proves dystonia and sialorrhea.42 Developmental regression, spasticity, areflexia, startle myoclonus, seizures, and blindness follow. Most affected infants die by 1 year of age. Brain MRI shows diffuse OTHER METABOLIC DISORDERS demyelination beginning in deep white matter, later in- volving subcortical white matter. Computed tomography shows calcification in basal ganglia, thalami, and corona SMITH-LEMLI-OPITZ SYNDROME radiata. CSF shows elevated proteins. Motor nerve con- Smith-Lemli-Opitz syndrome is caused by deficiency duction velocities are prolonged. Diagnosis is by demon- of 7-dehydrocholesterol reductase, which leads to im- strating deficient galactocerebroside β-galactosidase activ- paired cholesterol synthesis. Patients have ptosis, ante- ity in leukocytes or cultured fibroblasts. verted nares, micrognathia, microcephaly, hypospadias, and cardiac defects. Syndactyly of the second and third toes is almost always present. Presentation is that of GRAY MATTER DISORDERS poor growth and developmental delay. Diagnosis is based on elevations of 7-dehydrocholesterol and de- Gray matter disorders classically present as seizures creased serum cholesterol. Management is with choles- and loss of function of affected cortex. Prototypical gray terol supplementation. matter disorders include Tay-Sachs disease (discussed previously) and the neuronal ceroid lipofuscinoses. LESCH-NYHAN SYNDROME The neuronal ceroid lipofuscinoses (NCLs) are a Lesch-Nyhan syndrome is an X-linked recessive dis- heterogeneous group of inherited neurodegenerative order caused by deficiency of hypoxanthine-guanine lysosomal storage disorders presenting as some combi- phosphoribosyl transferase (HPRT), an enzyme in- nation of visual loss, behavioral change, movement dis- volved in the metabolism of purines. This defect leads order, and seizures, especially myoclonic seizures.42 to hyperuricemia and increased urinary excretion of The infantile, late infantile, and juvenile forms are uric acid. Most neonates are normal until 3 months of more likely to be accompanied by retinal blindness. age, when they demonstrate hypotonia and global The adult form is usually not associated with visual loss. developmental delay. By age 1 to 2 years, choreoatheto- Those affected by the infantile form are normal at sis and dystonia are apparent, and by age 2 to 3 years, birth. Onset of seizures and visual loss occurs within the characteristic severe self-mutilating behavior is 2 years and death is typical by age 10 years. In the late apparent. Most children never learn to walk. Renal fail- infantile form, initial symptoms are seizures between ure due to urate deposition and gouty arthritis occur 14 Hospital Physician Board Review Manual www.turner -
  15. 15. Metabolic Disorders in Pediatric Neurology later in life. Diagnosis is suggested by an elevated uric copper in blood, works faster than zinc and is also better acid-to-creatinine ratio. Confirmation is by HPRT activ- tolerated than penicillamine.49 ity. Treatment with allopurinol does not improve the neurologic outcome.43 OTHER Pyridoxine-dependent epilepsy presents as neonatal MENKES’ SYNDROME seizures that respond only to pyridoxine.50 Biotinidase Menkes’ (kinky hair) syndrome is an X-linked reces- deficiency presents as seizures later in infancy to early sive disorder of copper transport resulting in low serum childhood, which respond to biotin.51 Glucose trans- copper levels, decreased intestinal copper absorption, porter 1 (GLUT-1) deficiency syndrome presents be- and reduced activity of copper-dependent enzymes. tween 1 and 4 months of age as refractory seizures, Affected males develop normally during the first months acquired microcephaly, ataxia, and low CSF glucose. of life, but development then slows and regression occurs. Symptoms are due to defective transport of glucose Myoclonic seizures in response to stimulation are an early across the blood-brain barrier. Seizures respond to a and almost constant feature. Dysautonomia occurs. The ketogenic diet.52,53 hair takes on a brittle, steel wool appearance. Other find- ings on examination include skin laxity, sagging jowls, and ACKNOWLEDGEMENT hypotonia. Cerebral vessels are often tortuous and nar- We thank Justin Stahl, MD, for the white matter mnemon- rowed. Ischemic infarcts and subdural hematomas can ic VAMPACK. We thank Gregg Nelson, MD, for helpful com- occur. Death usually occurs before age 3 years. Laboratory ments and for Table 2. evaluation shows low serum copper and ceruloplasmin. CSF and plasma catecholamines are abnormal. Molecular testing is available. Treatment involves subcutaneous or REFERENCES intravenous copper administration. Results are variable, possibly because of poor CNS penetration.44 1. Kishnani PS, Howell RR. Pompe disease in infants and children. J Pediatr 2004;144(5 Suppl):S35–43. 2. Tein I. Role of carnitine and fatty acid oxidation and its defects WILSON’S DISEASE in infantile epilepsy. 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