Table Of ContentAtlAs 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
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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
