Inborn Metabolic Diseases: Diagnosis and Treatment 5th Ed

Cover......Page 1
Front-matter......Page 2
Preface to the 5th edition......Page 5
Contents......Page 6
List of Contributors......Page 19
Abbreviation List......Page 24
I Diagnosis and Treatment:General Principles......Page 25
1 \rClinical Approach to Inborn Errorsof Metabolism in Paediatrics......Page 26
X Organelle-Related Disorders:Lysosomes, Peroxisomes, and Golgiand Pre-Golgi Systems......Page 0
1.1.1 Pathophysiology......Page 27
1.2 Antenatal Symptoms......Page 28
1.3.1 Clinical Presentations......Page 29
1.3.2 Metabolic Derangementsand Diagnostic Tests......Page 35
1.4.1 Clinical Presentations......Page 38
1.4.2 Metabolic Derangementsand Diagnostic Tests......Page 45
1.5 Chronic and Progressive NeurologicalSymptoms (Mental Retardation ,Developmental Delay , Epilepsy ,Neurological Deterioration andPsychiatric Symptoms )......Page 50
1.5.1 Diagnostic Approach toNeurological and MentalDeterioration Related to Age......Page 51
1.5.2 Diagnostic Approach to NeuromentalDeterioration According toNeurophysiological andNeuroradiological Signs......Page 59
1.6.2 Dermatology......Page 64
1.6.4 Endocrinology......Page 66
1.6.5 Gastroenterology......Page 67
1.6.6 Haematology......Page 68
1.6.7 Hepatology......Page 71
1.6.12 Ophthalmologic Signs......Page 72
1.6.14 Pneumology......Page 74
References......Page 75
2 Inborn Errors of Metabolism in Adults:A Diagnostic Approach to Neurologicaland Psychiatric Presentations \r......Page 78
2.2 Differences Between Paediatric andAdult Phenotypes......Page 79
2.3 General Approach to IEMIn Adulthood......Page 81
2.3.1 Energy Metabolism Defects......Page 82
2.4.1 Encephalopathies /Coma s [4]......Page 83
2.4.3 Movement Disorders [5]......Page 84
2.4.6 Epilepsy [12]......Page 87
2.4.7 Psychiatric Disorders [13, 14]......Page 90
2.4.9 Cerebellar Ataxia......Page 92
2.4.10 Myopathy......Page 93
2.4.11 Others......Page 95
References......Page 97
3 Newborn Screening for Inborn Errorsof Metabolism \r......Page 98
3.2.2 Sensitivity, Specificity and PositivePredictive Value......Page 99
3.2.3 Technical Aspects of NewbornScreening Tests......Page 100
3.2.5 Follow-up......Page 101
3.3.1 Aminoacidopathies......Page 105
3.3.3 Organic Acid Disorders......Page 106
3.3.5 Lysosomal Storage Disorders......Page 107
References......Page 108
4 Diagnostic Procedures: Functional Tests andPost-mortem Protocol \r......Page 110
4.2.2 Metabolic Profile over the Courseof the Day......Page 111
4.3 In Vitro 1H-NMR Spectroscopyof Body Fluids......Page 118
4.4.1 Fasting Test......Page 119
4.4.3 Protein and Allopurinol LoadingTest s......Page 121
4.4.4 Exercise Test......Page 122
4.5.3 Skin Fibroblasts......Page 123
4.5.5 Autopsy......Page 124
References......Page 125
5 Emergency Treatments \r......Page 126
5.1.3 Specific Therapies......Page 127
5.2.1 Neurological Deterioration......Page 128
5.2.3 Neonatal Hypoglycaemia......Page 131
5.2.6 Intractable Convulsions......Page 132
References......Page 133
II Disorders of Carbohydrate Metabolism......Page 135
6 The Glycogen Storage Diseases and RelatedDisorders \r......Page 136
6.1.1 Glycogen Storage Disease Type I(Glucose-6-Phosphatase orTranslocase Deficiency )......Page 138
6.1.2 Glycogen Storage Disease Type III(Debranching Enzyme Deficiency )......Page 143
6.1.3 Glycogen Storage Disease Type IV(Branching Enzyme Deficiency )......Page 144
6.1.5 Glycogen Storage DiseaseType IX (Phosphorylase KinaseDeficiency )......Page 146
6.1.6 Glycogen Storage Disease Type 0(Glycogen Synthase Deficiency )......Page 147
6.2.1 GSDs With Exercise IntoleranceWithout Cardiac Involvement......Page 148
6.2.2 GSDs with Cardiac Involvement......Page 151
6.3.1 Lafora Disease(Neuronal Laforin/Malin Defects )......Page 154
References......Page 155
7 Disorders of Galactose Metabolism \r......Page 161
7.1.3 Genetics......Page 163
7.1.5 Treatment and Prognosis......Page 164
7.2.5 Treatment and Prognosis......Page 167
7.3.5 Treatment and Prognosis......Page 168
References......Page 169
8 Disorders of the Pentose Phosphate Pathway \r......Page 171
8.2.1 Clinical Presentation......Page 173
8.2.3 Genetics......Page 174
References......Page 175
9 Disorders of Fructose Metabolism \r......Page 176
9.2.1 Clinical Presentation......Page 178
9.2.3 Genetics......Page 179
9.2.6 Treatment and Prognosis......Page 180
9.3.2 Metabolic Derangement......Page 181
9.3.4 Diagnosis......Page 182
References......Page 183
10 Persistent Hyperinsulinaemic Hypoglycaemia \r......Page 185
10.3 Genetics......Page 187
10.4.1 Diagnostic Criteria......Page 188
10.5.2 Surgical Treatment......Page 189
References......Page 190
11 Disorders of Glucose Transport \r......Page 193
11.1.4 Diagnostic Tests......Page 195
11.3.1 Clinical Presentation......Page 196
11.3.5 Treatment and Prognosis......Page 197
11.4.4 Diagnostic Tests......Page 198
References......Page 199
III Disorders of Mitochondrial EnergyMetabolism......Page 202
12 Disorders of Pyruvate Metabolismand the Tricarboxylic Acid Cycle \r......Page 203
12.1.2 Metabolic Derangement......Page 205
12.1.5 Treatment and Prognosis......Page 206
12.2 PhosphoenolpyruvateCarboxykinase Deficiency......Page 207
12.3.2 Metabolic Derangement......Page 208
12.3.4 Diagnostic Tests......Page 209
12.4.5 Treatment and Prognosis......Page 210
12.6.1 Clinical Presentation......Page 211
12.7.2 Metabolic Derangement......Page 212
12.9.4 Genetics......Page 213
References......Page 214
13 of Mitochondrial FattyAcid Oxidation and Related MetabolicPathways \r......Page 217
13.2.2 Carnitine Cycle Defects......Page 219
13.2.3 ß-Oxidation Defects......Page 221
13.2.4 Electron Transfer Defects......Page 222
13.4 Genetics......Page 223
13.5.1 Abnormal Metabolites......Page 224
13.5.4 Prenatal Diagnosis......Page 226
13.6.2 Long-term Dietary Management......Page 227
13.6.5 Prognosis......Page 228
References......Page 230
14 Disorders of Ketogenesis and Ketolysis \r......Page 233
14.1.4 Mitochondrial Acetoacetyl-CoAThiolase Deficiency......Page 235
14.4.3 Succinyl-CoA 3-Oxoacid CoATransferase Deficiency......Page 236
14.6 Cytosolic Acetoacetyl-CoA ThiolaseDeficiency......Page 237
References......Page 238
15 Defects of the Respiratory Chain \r......Page 239
15.1 Clinical Presentation......Page 240
15.1.3 Infants......Page 242
15.2 Metabolic Derangement......Page 243
15.3 Genetics......Page 244
15.3.3 Nuclear DNA Mutations......Page 245
15.4.1 Screening Tests......Page 247
15.4.2 Enzyme Assays......Page 248
15.4.5 Molecular Genetic Tests......Page 250
15.5 Treatment and Prognosis......Page 251
References......Page 252
16 Creatine Deficiency Syndromes \r......Page 255
16.1.3 SLC6A8 Deficiency......Page 257
16.2 Metabolic Derangement......Page 258
16.4.2 Metabolite Screening......Page 259
16.5.2 AGAT Deficiency......Page 260
References......Page 261
IV Disorders of Amino Acid Metabolismand Transport......Page 264
17 Hyperphenylalaninaemia \r......Page 265
17.2.3 Genetics......Page 267
17.2.5 Treatment and Prognosis......Page 268
17.3.2 Metabolic Derangement......Page 272
17.3.3 Treatment and Prognosis......Page 273
17.4.2 Metabolic Derangement......Page 274
17.4.4 Diagnostic and Confirmatory Tests......Page 275
17.4.5 Treatment and Prognosis......Page 276
References......Page 277
18 Disorders of Tyrosine Metabolism \r......Page 279
18.1.2 Metabolic Derangement......Page 281
18.1.4 Diagnostic Tests......Page 282
18.1.5 Treatment and Prognosis......Page 283
18.2.4 Diagnostic Tests......Page 285
18.3.5 Treatment and Prognosis......Page 286
18.5.2 Metabolic Derangement......Page 287
18.6.4 Diagnostic Tests......Page 288
References......Page 289
19 Branched-chain OrganicAcidurias /Acidaemias \r......Page 291
19.1.1 Clinical Presentation......Page 293
19.1.2 Metabolic Derangement......Page 295
19.1.3 Genetics......Page 297
19.1.5 Treatment and Prognosis......Page 298
19.2.5 Treatment and Prognosis......Page 304
19.3 3-Methylglutaconic Aciduria......Page 305
19.7 3-Hydroxyisobutyric Aciduria......Page 306
References......Page 307
20 Disorders of the Urea Cycle and RelatedEnzymes \r......Page 311
20.1.2 Presentation in Infants......Page 313
20.1.4 Newborn Screening......Page 314
20.2.3 CNS Toxicity in Urea Cycle Defects......Page 315
20.3 Genetics of Urea Cycle Defects......Page 316
20.5 Diagnostic Tests and DifferentialDiagnosis......Page 317
20.6.1 Treatment in Acute Presentations......Page 318
20.6.2 Maintenance Therapy......Page 320
20.8 Pregnancy......Page 322
References......Page 323
21 Disorders of Sulfur Amino Acid Metabolism \r......Page 325
21.1.1 Clinical Presentation......Page 327
21.1.3 Genetics......Page 328
21.1.4 Diagnostic Tests......Page 329
21.1.5 Treatment and Prognosis......Page 330
21.2.3 Genetics......Page 331
21.4.1 Clinical Presentation......Page 332
21.6.1 Clinical Presentation......Page 333
References......Page 334
22 Disorders of Ornithine Metabolism \r......Page 336
22.1.1 Clinical Presentation......Page 338
22.1.4 Diagnostic Tests......Page 339
22.1.5 Treatment and Prognosis......Page 340
22.2.3 Genetics......Page 341
22.3.1 Clinical Presentation......Page 342
References......Page 343
23 Cerebral Organic Acid Disorders and OtherDisorders of Lysine Catabolism \r......Page 346
23.1 Introduction......Page 348
23.2.4 Diagnostic Tests......Page 349
23.5.1 Clinical Presentation......Page 350
23.5.3 Genetics......Page 352
23.5.5 Treatment and Prognosis......Page 353
23.7.3 Genetics......Page 355
23.8.1 Clinical Presentation......Page 356
23.8.5 Treatment and Prognosis......Page 357
23.9.5 Treatment and Prognosis......Page 358
Reference......Page 359
24 Nonketotic Hyperglycinaemia(Glycine Encephalopathy ) \r......Page 361
24.1.1 Neonatal NKH......Page 362
24.2 Metabolic Derangement......Page 364
24.4 Diagnostic Tests......Page 365
References......Page 366
25 Disorders of Proline and Serine Metabolism \r......Page 369
25.1.2 Δ1-Pyrroline 5-CarboxylateDehydrogenase Deficiency(Hyperprolinaemia Type II)......Page 371
25.2.1 3-PhosphoglycerateDehydrogenase Deficiency......Page 372
References......Page 373
26 Transport Defects of Amino Acids at theCell Membrane: Cystinuria , Lysinuric ProteinIntolerance and Hartnup Disorder \r......Page 375
26.1.5 Treatment and Prognosis......Page 377
26.2.1 Clinical Presentation......Page 378
26.2.5 Treatment and Prognosis......Page 379
26.3.2 Metabolic Derangement......Page 380
26.4 Asymptomatic Aminoacidurias......Page 381
References......Page 382
V Vitamin-Responsive Disorders......Page 385
27 Biotin-responsive Disorders \r......Page 386
27.1.2 Biotinidase Deficiency......Page 388
27.2 Metabolic Derangement......Page 389
27.3.3 Biotin-responsive Basal GangliaDisease......Page 390
27.4.4 Prenatal Diagnosis......Page 391
27.5.2 Biotinidase Deficiency......Page 392
References......Page 393
28 Disorders of Cobalamin and Folate Transportand Metabolism \r......Page 396
28.1.2 Defective Transport of Cobalaminby Enterocytes (Imerslund-GräsbeckSyndrome )......Page 398
28.1.4 Transcobalamin Deficiency......Page 399
28.2 Disorders of Intracellular Utilisationof Cobalamin......Page 400
28.2.1 Combined Deficiencies of Adenosylcobalaminand Methylcobalamin......Page 401
28.2.2 Adenosylcobalamin Deficiency......Page 403
28.2.3 Methylcobalamin Deficiency......Page 404
28.3.2 Cerebral Folate Deficiency......Page 406
28.3.4 MethylenetetrahydrofolateReductase Deficiency......Page 407
28.3.5 Dihydrofolate Reductase Deficiency......Page 408
References......Page 409
VI Neurotransmitter and SmallPeptide Disorders......Page 414
29 Disorders of Neurotransmission \r......Page 415
29.1.2 Succinic SemialdehydeDehydrogenase Deficiency......Page 417
29.2.1 Hyperekplexia......Page 418
29.2.3 Mitochondrial GlutamateTransporter Defect......Page 420
29.3.2 Aromatic L-AminoacidDecarboxylase Deficiency......Page 422
29.3.4 Monoamine Oxidase-A Deficiency......Page 423
29.3.5 Guanosine TriphosphateCyclohydrolase-I Deficiency......Page 424
29.3.8 Other Inborn Defects Involved inMonoamine Metabolism......Page 425
29.4.1 Pyridoxine-responsive Epilepsy......Page 427
29.4.2 Pyridox(am)ine 5’-PhosphateOxidase Deficiency......Page 429
References......Page 430
30 Disorders in the Metabolism of Glutathioneand Imidazole Dipeptide s \r......Page 433
30.1.2 Glutathione Synthetase Deficiency......Page 435
30.1.4 5-Oxoprolinase Deficiency......Page 437
30.2.1 Serum Carnosinase Deficiency......Page 438
30.2.3 Prolidase Deficiency......Page 439
References......Page 440
31 Trimethylaminuria and DimethylglycineDehydrogenase Deficiency \r......Page 441
31.1.5 Treatment......Page 443
References......Page 444
VII Disorders of Lipid and BileAcid Metabolism......Page 446
32 Dyslipidaemias \r......Page 447
32.1 Overview of Plasma Lipidand Lipoprotein Metabolism......Page 449
32.1.2 Endogenous LipoproteinMetabolism......Page 450
32.1.3 Reverse Cholesterol Transport andHigh-density Lipoproteins......Page 451
32.2.1 Lipoprotein Lipase Deficiency......Page 453
32.3.1 Disorders of VLDL Overproduction......Page 454
32.3.2 Disorders of LDL Removal......Page 456
32.4.1 Dysbetalipoproteinaemia(Type III Hyperlipoproteinaemia )......Page 458
32.5.2 Hypobetalipoproteinaemia......Page 459
32.6.2 Apolipoprotein A-I Mutations......Page 460
32.6.6 Scavenger Receptor Class B Type I......Page 461
32.7.1 Clinical Evaluation......Page 462
32.7.3 Goals for Dietary and HygienicTherapy......Page 463
32.7.4 Low-density-Lipoprotein-loweringDrugs......Page 464
References......Page 466
33 Disorders of Cholesterol Synthesis \r......Page 469
33.1.3 Genetics......Page 471
33.2.2 Metabolic Derangement......Page 472
33.3.1 Clinical Presentation......Page 473
33.4.2 Metabolic Derangement......Page 474
33.5.5 Treatment and Prognosis......Page 475
33.7.2 Metabolic Derangement......Page 476
References......Page 477
34 Disorders of Bile Acid Synthesis \r......Page 480
34.2.2 Metabolic Derangement......Page 482
34.2.5 Treatment and Prognosis......Page 483
34.3.4 Diagnostic Tests......Page 484
34.4.2 Metabolic Derangement......Page 485
34.5.1 Clinical Presentation......Page 486
34.6.3 Genetics......Page 487
34.8.1 Clinical Presentation......Page 488
34.9.4 Diagnostic Tests......Page 489
References......Page 490
35 Disorders of Phospholipid andGlycosphingolipid Synthesis \r......Page 492
35.1.1 LIPN1 Deficiency (PhosphatidatePhosphatase 1 Deficiency )......Page 494
35.1.2 Cardiolipin Remodelling EnzymeDeficiency : Barth Syndrome......Page 495
35.1.3 Phospholipase A2 Deficiency(Infantile Neuroaxonal Dystrophyand Neurodegeneration with BrainIron Accumulation......Page 496
35.1.4 α-/β-Hydrolase 12 (ABHD12)Deficiency (Polyneuropathy, HearingLoss, Ataxia, Retinitis Pigmentosaand Cataracts: PHARC Syndrome )......Page 497
35.1.5 Choline Kinase Deficiency(Congenital Muscular Dystrophywith Mito chondrial StructuralAbnormalities)......Page 498
35.2.1 Serine Palmitoyl CoA TransferaseDeficiency......Page 500
References......Page 501
VIII Disorders of Nucleic Acidand Heme Metabolism......Page 503
36 Disorders of Purine and PyrimidineMetabolism \r......Page 504
36.1.1 Phosphoribosyl PyrophosphateSynthetase Superactivity......Page 506
36.1.3 Adenylosuccinase (AdenylosuccinateLyase ) Deficiency......Page 507
36.1.5 Muscle Adenosine MonophosphateDeaminase Deficiency......Page 508
36.1.7 Adenosine Deaminase Deficiency......Page 509
36.1.10 Xanthine Oxidase Deficiency......Page 511
36.1.11 Hypoxanthine-guaninePhosphoribosyltransferaseDeficiency......Page 512
36.1.14 Thiopurine MethyltransferaseDeficiency......Page 514
36.1.15 Inosine Triphosphatase Deficiency......Page 515
36.2.2 Miller Syndrome......Page 517
36.2.4 Dihydropyrimidinase Deficiency......Page 518
36.2.9 Cytidine Deaminase Deficiency......Page 519
References......Page 520
37 Disorders of Haem Biosynthesis \r......Page 524
37.2 The Porphyrias......Page 526
37.2.1 Classification and Diagnosis......Page 527
37.3 5-Aminolevulinic Acid DehydratasePorphyria......Page 528
37.4 Acute Intermittent Porphyria......Page 529
37.5 Congenital Erythropoietic Porphyria(Gunther Disease )......Page 530
37.6 Porphyria Cutanea Tarda......Page 531
37.8 Hereditary Coproporphyriaand Variegate Porphyria......Page 533
37.9 Erythropoietic Protoporphyria......Page 534
References......Page 536
IX Disorders of Metal Transport......Page 538
38 Disorders in the Transport of Copper , Iron ,Magnesium , Manganese , Selenium and Zinc \r......Page 539
38.1.1 Wilson Disease......Page 541
38.1.2 Menkes Disease......Page 543
38.1.3 Other Copper Storage Disorders......Page 544
38.2.1 Systemic Iron Overload Syndromes(Haemochromatosis )......Page 546
38.2.2 Neurodegeneration with Brain IronAccumulation (NBIA)......Page 547
38.3 Magnesium......Page 548
38.3.2 Hypomagnesaemiawith Hypercalciuria andNephrocalcinosis......Page 549
38.4 Manganese......Page 550
38.5 Selenium......Page 551
38.6.1 Acrodermatitis Enteropathica......Page 552
References......Page 553
X Organelle-Related Disorders:Lysosomes, Peroxisomes, and Golgiand Pre-Golgi Systems......Page 556
39 Disorders of Sphingolipid Metabolismand Neuronal Ceroid-Lipofuscinoses \r......Page 557
39.1.1 Clinical Presentation......Page 559
39.1.5 Treatment and Prognosis......Page 560
39.2.1 Clinical Presentation......Page 561
39.2.5 Treatment and Prognosis......Page 562
39.3.2 Metabolic Derangement......Page 563
39.4.1 Clinical Presentation......Page 564
39.5.1 Clinical Presentation......Page 565
39.5.4 Diagnostic Tests......Page 566
39.6.4 Diagnostic Tests......Page 567
39.7.1 Clinical Presentation......Page 568
39.7.5 Treatment and Prognosis......Page 569
39.9.3 Diagnostic Tests......Page 570
39.10.2 Metabolic Derangement......Page 571
39.10.5 Treatment and Prognosis......Page 572
39.12.1 Clinical Presentation......Page 573
39.12.4 Diagnostic Tests......Page 574
39.12.5 Treatment and Prognosis......Page 575
References......Page 576
40 Mucopolysaccharidoses andOligosaccharidoses \r......Page 580
40.1.1 Mucopolysaccharidoses......Page 582
40.1.2 Oligosaccharidoses......Page 588
40.4 Diagnostic Tests......Page 589
References......Page 590
41 Peroxisomal Disorders \r......Page 592
41.1 Clinical Presentation......Page 594
41.1.1 The Neonatal Period......Page 595
41.1.3 Between 6 Months and 4 Years......Page 596
41.1.4 Beyond 4 Years of Age......Page 597
41.2 Metabolic Derangements......Page 598
41.2.2 Deficiencies of Single PeroxisomalEnzymes......Page 600
41.4.1 Diagnostic Group 1......Page 602
41.4.5 Histological Detection......Page 603
References......Page 604
42 Congenital Disorders of Glycosylation \r......Page 607
42.1 Introduction......Page 608
42.2.1 Phosphomannomutase-2 Deficiency(PMM2-CDG)......Page 612
42.2.3 Glucosyltransferase I Deficiency(ALG6-CDG)......Page 613
42.3.2 Walker-Warburg Syndrome(POMT1/POMT2-CDG)......Page 614
42.5.3 ATP6V0A2 (Autosomal RecessiveCutis Laxa Type 2 )......Page 615
References......Page 616
43 Cystinosis \r......Page 617
43.1.1 Clinical Presentation......Page 618
43.1.3 Genetics......Page 620
43.1.5 Treatment......Page 621
References......Page 622
Appendix A: Medications Used in theTreatment of Inborn Errors......Page 625
Subject Index......Page 633