AtlAs of InherIted MetAbolIc dIseAses AtlAs of InherIted MetAbolIc dIseAses thIrd edItIon William L Nyhan, MD PhD Professor of Pediatrics Biochemical Genetics Program University of California, San Diego USA Bruce A Barshop, MD PhD Professor of Pediatrics Biochemical Genetics Program University of California, San Diego USA and Aida I Al-Aqeel, MD DCH FRCP FACMG Consultant and Head Pediatrics, Medical Genetics and Consultant Endocrinology Riyadh Military Hospital Riyadh Saudi Arabia CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2011 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Version Date: 20130417 International Standard Book Number-13: 978-1-4441-5042-1 (eBook - PDF) This book contains information obtained from authentic and highly regarded sources. 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Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com Contents Contributor ix Foreword xi Preface xii Part 1 Organic acidemias 1 Introduction 3 2 Propionicacidemia 8 3 Methylmalonicacidemia 19 4 Methylmalonicaciduriaandhomocystinuria(cobalaminCandDdisease) 33 5 Multiplecarboxylasedeficiency/holocarboxylasesynthetasedeficiency 40 6 Multiplecarboxylasedeficiency/biotinidasedeficiency 47 7 Isovalericacidemia 57 8 Glutaricaciduria(typeI) 64 9 3-MethylcrotonylCoAcarboxylasedeficiency/3-methylcrotonylglycinuria 74 10 D-2-Hydroxyglutaricaciduria 79 11 L-2-Hydroxyglutaricaciduria 85 12 4-Hydroxybutyricaciduria 89 13 Mitochondrialacetoacetyl-CoAthiolase(3-oxothiolase)deficiency 95 Part 2 disOrders Of aminO acid metabOlism 14 Alkaptonuria 105 15 Phenylketonuria 112 16 Hyperphenylalaninemiaanddefectivemetabolismoftetrahydrobiopterin 123 17 Biogenicamines 136 18 Homocystinuria 144 19 Maplesyrupurinedisease(branched-chainoxoaciduria) 152 20 Oculocutaneoustyrosinemia/tyrosineaminotransferasedeficiency 164 21 Hepatorenaltyrosinemia/fumarylacetoacetatehydrolasedeficiency 171 22 Nonketotichyperglycinemia 180 Part 3 HyPerammOnemia and disOrders Of tHe urea cycle 23 Introductiontohyperammonemiaanddisordersoftheureacycle 191 24 Ornithinetranscarbamylasedeficiency 197 25 Carbamylphosphatesynthetasedeficiency 205 26 Citrullinemia 210 27 Argininosuccinicaciduria 216 28 Argininemia 223 29 Hyperornithinemia,hyperammonemia,homocitrullinuriasyndrome 229 30 Lysinuricproteinintolerance 235 31 Glutaminesynthetasedeficiency 241 vi Contents Part 4 disOrders Of fatty acid OxidatiOn 32 Introductiontodisordersoffattyacidoxidation 247 33 Carnitinetransporterdeficiency 253 34 Carnitine-acylcarnitinetranslocasedeficiency 260 35 CarnitinepalmitoyltransferaseIdeficiency 267 36 CarnitinepalmitoyltransferaseIIdeficiency,lethalneonatal 273 37 CarnitinepalmitoyltransferaseIIdeficiency,lateonset 277 38 MediumchainacylCoAdehydrogenasedeficiency 281 39 VerylongchainacylCoAdehydrogenasedeficiency 289 40 LongchainL-3-hydroxyacylCoAdehydrogenase–(trifunctionalproteindeficiency) 295 41 Short-chainacylCoAdehydrogenasedeficiency 302 42 3-HydroxyacylCoAdehydrogenase(short-chain3-hydroxyacylCoAdehydrogenase)deficiency 309 43 Short/branchedchainacyl-CoAdehydrogenase(2-methylbutyrylCoAdehydrogenase)deficiency 312 44 MultipleacylCoAdehydrogenasedeficiency/glutaricaciduriatypeII/ethylmalonic-adipicaciduria 316 45 3-Hydroxy-3-methylglutarylCoAlyasedeficiency 325 Part 5 tHe lactic acidemias and mitOcHOndrial disease 46 Introductiontothelacticacidemias 337 47 Pyruvatecarboxylasedeficiency 347 48 Fructose-1,6-diphosphatasedeficiency 354 49 Deficiencyofthepyruvatedehydrogenasecomplex 359 50 Lacticacidemiaanddefectiveactivityofpyruvate,2-oxoglutarate,andbranchedchainoxoaciddehydrogenases 368 51 Mitochondrialencephalomyelopathy,lacticacidosis,andstroke-likeepisodes(MELAS) 374 52 Myoclonicepilepsyandraggedredfiber(MERRF)disease 382 53 Neurodegeneration,ataxia,andretinitispigmentosa(NARP) 388 54 Kearns-Sayresyndrome 393 55 Pearsonsyndrome 398 56 ThemitochondrialDNAdepletionsyndromes:mitochondrialDNApolymerasedeficiency 404 Part 6 disOrders Of carbOHydrate metabOlism 57 Galactosemia 415 58 Glycogenstoragediseases:introduction 425 59 GlycogenosistypeI–VonGierkedisease 428 60 GlycogenosistypeII/Pompe/lysosomala-glucosidasedeficiency 438 61 GlycogenosistypeIII/amylo-1,6-glucosidase(debrancher)deficiency 447 Part 7 PerOxisOmal disOrders 62 Adrenoleukodystrophy 459 63 Neonataladrenoleukodystrophy/disordersofperoxisomalbiogenesis 469 Part 8 disOrders Of Purine metabOlism 64 Lesch-Nyhandiseaseandvariants 483 65 Adeninephosphoribosyl-transferasedeficiency 498 66 Phosphoribosylpyrophosphatesynthetaseanditsabnormalities 503 67 Adenosinedeaminasedeficiency 507 68 Adenylosuccinatelyasedeficiency 514 69 Oroticaciduria 518 Contents vii Part 9 disOrders Of transPOrt and mineral metabOlism 70 Cystinuria 525 71 Cystinosis 532 72 Hartnupdisease 540 73 Histidinuria 544 74 Menkesdisease 546 Part 10 mucOPOlysaccHaridOses 75 Introductiontomucopolysaccharidoses 555 76 Hurlerdisease/mucopolysaccharidosistypeIHa-L-iduronidasedeficiency 558 77 ScheieandHurler-Scheiediseases/mucopolysaccharidosisISandIHS/a-iduronidasedeficiency 566 78 Hunterdisease/mucopolysaccharidosistypeII/iduronatesulfatasedeficiency 572 79 Sanfilippodisease/mucopolysaccharidosistypeIII 580 80 Morquiosyndrome/mucopolysaccharidosistypeIV/keratansulfaturia 588 81 Maroteaux-Lamydisease/mucopolysaccharidosisVI/N-acetylgalactosamine-4-sulfatasedeficiency 597 82 Slydisease/b-glucuronidasedeficiency/mucopolysaccharidosisVII 605 Part 11 mucOliPidOses 83 I-celldisease/mucolipidosisII 613 84 MucolipidosisIII/pseudo-Hurlerpolydystrophy/N-acetyl-glucosaminyl-l-phosphotransferasedeficiency 621 Part 12 disOrders Of cHOlesterOl and neutral liPid metabOlism 85 Familialhypercholesterolemia 631 86 Mevalonicaciduria 642 87 Lipoproteinlipasedeficiency/typeIhyperlipoproteinemia 648 Part 13 liPid stOrage disOrders 88 Fabrydisease 659 89 GMgangliosidosis/b-galactosidasedeficiency 666 1 90 Tay-Sachsdisease/hexosaminidaseAdeficiency 678 91 Sandhoffdisease/GMgangliosidosis/deficiencyofhexosaminidaseAandB/hex-Bsubunitdeficiency 686 2 92 GMactivatordeficiency/GMgangliosidosis–deficiencyoftheactivatorprotein 694 2 2 93 Gaucherdisease 698 94 Niemann-Pickdisease 708 95 Niemann-PicktypeCdisease/cholesterol-processingabnormality 718 96 Krabbedisease/galactosylceramidelipidosis/globoidcellleukodystrophy 726 97 Wolmandisease/cholesterylesterstoragedisease 733 98 Fucosidosis 740 99 a-Mannosidosis 745 100 Galactosialidosis 752 101 Metachromaticleukodystrophy 760 102 Multiplesulfatasedeficiency 769 Part 14 miscellaneOus 103 Congenitaldisorderofglycosylation,typela 781 104 Otherformsofcongenitaldisordersofglycosylation 787 viii Contents 105 a-Antitrypsindeficiency 803 1 106 Canavandisease/aspartoacylasedeficiency 811 107 Ethylmalonicencephalopathy 819 108 Disordersofcreatinesynthesisortransport 827 Appendix 833 Index 847 Contributor Chapter 41 Zarazuela Zolkipli MD Fellow in Biochemical Genetics and Mitochondrial Disease, and Assistant Adjunct (Clinical) Professor, Neurosciences University of California, San Diego, USA Foreword We must not cease from exploration, newborn population screening with subsequent early And at the end of all our exploring, treatment is the most successful approach. Tandem mass spectrometry has recently been implemented in newborn Will be to arrive where we started, screening programs in an increasing number of countries And know the place for the first time. and other diagnostic high-throughput techniques T.S. Elliot, Four Quartets, 1942. including primary molecular diagnostics are at the edge. Handicap and suffering can be prevented from thousands of children and their families. Although novel diagnostic In 1942 only a handful of inborn errors of metabolism, and therapeutic possibilities never come for free, extended sometimes called orphan diseases, were recognised with newborn screening is far more cost-effective than other little to no treatment available. Destiny would take its medical advances. The costs of screening programs are course and genetic counselling was virtually all that greatly outnumbered by the costs for direct health and could be offered. Phenylketonuria was then shown by social costs in childhood. Horst Bickel from the Children’s Hospital, Heidelberg, The field of inborn errors of metabolism or Metabolic Germany, to be a treatable “genetic” disease in which Medicine is continuing to increase, both by its size and early diagnosis and dietary treatment prevented impaired fortunately even more by our knowledge. Clinical expertise mental development. Subsequently, many other inborn and a good cooperation between the referring physician errors of metabolism became manageable in a similar and the metabolic specialist and a broad spectrum of way, i.e. with substrate deprivation strategies: maple syrup metabolic investigations in the respective center are the urine disease, galactosemia, fructosemia, tyrosinemia type key to successful diagnosis and treatment. Each disease and 2, and others. Pharmacological doses of vitamins proved each patient is different from each other. When molecular useful in defects of cobalamin and biotin metabolism, genetics came to medicine, there was a widely held belief, in distinct forms of homocystinuria, and some others. that knowing the genotype at the particular locus would Avoiding of fasting was recognized as the cornerstone predict the corresponding phenotype and assist counseling of successful therapy for defects of fatty acid oxidation, and treatment. It has become clear that this has been ketogenesis and glycogenolysis. Initially progress had been rather naive. Although genotype-phenotype correlation slow but has begun to explode over the last decennium is strong in some diseases, there is a huge number of as current progress in understanding the molecular and examples where the phenotype cannot be explained by pathophysiological bases of inborn errors of metabolism the mutations found. Even more, it has become obvious funnels into the development of successful rational that, in addition to mutations of the affected gene and therapies: new treatment protocols - new therapeutic environment, many other factors influence the phenotype. agents (drugs and foods) - improved tissue transplantation, The role of numerous factors affecting post-transcriptional enzyme replacement and gene therapy by other means. events, (including transport of RNA, protein synthesis, The world health organisation (WHO) as well as the folding, and degradation.) and their mutual relationships European Union (EU) have now announced genetic and are at best partly understood. orphan diseases as a major health challenge of the future. The “‘Atlas of Inherited Metabolic Diseases” is now set Among those the by now more than 500 inborn errors in its 3rd edition and has become the in-depth clinical of metabolism are especially important because of their reference resource for inborn errors of metabolism, relatively high frequency and because successful rationale combining in numerous details clinical presentation, therapy is already available or will become so in the near treatment, monitoring and course. After brief but solid future. As a group, they account for approx. 1 in 100 biochemical and molecular background information births worldwide. Scientific and technological advances physicians will find the most comprehensive clinical offer enormous benefit to patients suffering from inborn reference book for Metabolic Medicine with instructive errors of metabolism often completely preventing life- descriptions of clinical situations and the possibility of long burden and suffering. Early diagnosis by extended a visual double check on a metabolic syndrome with xii Foreword physical characteristics through the great photos found the care for their patients. Reflecting their experience nowhere else. The content of this book draws from decades in the details and advice found in the “Atlas of Inherited long clinical experiences in its best way, always asking what Metabolic Diseases” they may often find themselves could have been done better. It has been and will continue remembering the beautiful lines of T.S. Elliot. to be an invaluable source for metabolic physicians in Georg F. Hoffmann, MD Chairman of Pediatrics University Children`s Hospital Heidelberg, Germany