Inborn Metabolic Diseases (eBook)

Jean-Marie Saudubray, M.D., is Emeritus Professor of Pediatrics and Expert Metabolic Consultant at the adult neuro-metabolic unit in the Hôpital La Pitié Salpétrière from the Université Pierre et Marie Curie, Paris. Matthias R. Baumgartner, M.D., Professor of Paediatrics and Inherited Metabolic Medicine, University of Zurich, is Head of the Division of Metabolism and the Swiss Newborn Screening Programme at the University Children’s Hospital, Zurich. John Walter, M.D. is Honorary Clinical Professor of Inherited Metabolic Medicine, Manchester Academic Health Science Centre, Willink Unit, Manchester.

Preface to the 6th edition 5
Content 6
List of Contributors 26
Section I Diagnosis and Treatment: General Principles 32
1Clinical Approach to Inborn Errors of Metabolism in Pediatrics 33
Classification 34
Pathophysiology 34
Clinical Presentation 35
Antenatal Symptoms 36
Neonatal and Early Infancy Presentation (< 1 year)
Clinical Presentation 38
Metabolic Derangements and Diagnostic Tests 44
Later Onset Acute and Recurrent Attacks (Late Infancy and Beyond) 48
Clinical Presentations 48
Metabolic Derangements and Diagnostic Tests 56
Chronic and Progressive Neurological Symptoms (Mental Retardation , Developmental Delay , Epilepsy , Neurological Deterioration 62
Diagnostic Approach to Neurological and Mental Deterioration Related to Age 62
Specific Neurosensorial, Neuro-physiological and Neuroradiological Signs and Symptoms (at any Age) 75
Recommended Laboratory Tests in Neurological Syndromes 82
Specific Organ Signs and Symptoms 85
Cardiology 85
Dermatology 85
Endocrinology (. Table 1.34) 87
Gastroenterology and Nutritional Findings 88
Haematology 91
Hepatology 93
Immunology (see also 94
Section 1.6 Neutropenia) 94
Myology 95
Nephrology (. Table 1.39) 95
Neurology and Psychiatry 95
Ophthalmologic Signs 95
Orthopedy (. Table 1.42) 96
Pneumology 98
Psychiatry 98
Rheumatology 98
Stomatology 99
References 99
2Inborn Errors of Metabolism in Adults : A Diagnostic Approach to Neurological and Psychiatric Presentations 101
Differences Between Paediatric and Adult Phenotypes 102
General Approach to IEM in Adulthood 102
Disorders of Energy Metabolism 102
Disorders of Lipid Metabolism 102
Intoxication Syndromes 105
Disorders of Neurotransmitter Metabolism 106
Metal Storage Disorders 106
Specific Approaches to Neuro-metabolic Presentations in Adults 106
Encephalopathies /Coma s 106
Strokes and Pseudostrokes 107
Movement Disorders 107
Peripheral Neuropathies 107
Leukoencephalopathies 109
Epilepsy 111
Psychiatric Disorders 112
Spastic Paraparesis 114
Cerebellar Ataxia 114
Myopathy 115
Others 117
References 119
3Diagnostic Procedures 120
Introduction 121
Basal Metabolic Investigation 121
Amino and organic acids 121
Metabolic Profile over the Course of the Day 121
Metabolomic Approaches :the Example of In Vitro 1H-NMRSpectroscopy of Body Fluids 129
Functional Tests 130
Fasting Test 130
Oral Glucose Loading Test 132
Glucagon Test 132
Protein and Allopurinol Loading Test 132
Exercise Test 133
Next Generation Sequencing and Gene panels 133
Postmortem Protocol 134
Cells and Tissues for Enzyme Assays 134
Cells and Tissues for Chromosome and DNA Investigations 134
Skin Fibroblasts 134
Body Fluids for Chemical Investigations 134
Autopsy 135
References 136
4Emergency Treatments 137
Introduction 138
General Principles 138
Supportive Care 138
Nutrition 138
Specific Therapies 138
Extracorporeal Procedures for Toxin Removal 138
Emergency Management of Particular Clinical Presentations 139
Neurological Deterioration 139
Liver Failure 142
Neonatal Hypoglycaemia 142
Cardiac Failure 143
Primary Hyperlactataemia 143
Intractable Seizures 143
Final Considerations 143
References 143
Section II Disorders of Carbohydrate Metabolism 146
5The Glycogen Storage Diseases and Related Disorders 147
Hepatic Glycogenoses 149
Liver Glycogen Storage Disease Type 0 (GSD 0a) 149
Glycogen Storage Disease Type I(GSD I) 149
Glycogen Storage Disease Type III (GSD III) 153
Glycogen Storage Disease Type IV (GSD IV) 154
Glycogen Storage Disease Type VI (GSD VI) 155
Glycogen storage disease type IX (GSD IX) 155
Fanconi-Bickel Syndrome 155
Muscle and Cardiac Glycogenoses 156
Glycogen Storage Disease Type V (Myophosphorylase Deficiency , McArdle Disease ) 156
Disorders of Glycolysis 157
Glycogen Storage Disease Type II (Pompe Disease ) 157
Danon Disease (LAMP-2 Deficiency ) 158
Glycogen Depletion Syndromes : Muscle Glycogen Synthase Deficiency (Muscle GSD Type 0, GSD 0b) and Glycogenin 1 Deficiency 159
Muscle and Cardiac Glycogenosis with Polyglucosan Bodies Due to RBCK1 and GYG1 Mutations 159
AMP-activated Protein Kinase (AMPK) Deficiency 160
Brain Glycogenoses 160
Lafora Disease (Neuronal Laforin/ Malin Defects ) 160
Adult Polyglucosan Body Disease 161
References 161
6Disorders of Galactose Metabolism 164
Galactose-1-Phosphate Uridylyl-transferase (GALT) Deficiency 166
Clinical Presentation of GALT Deficiency 166
Metabolic Derangement in GALT Deficiency 167
Genetics of GALT Deficiency 167
Diagnostic Tests for GALT Deficiency 167
Treatment and Prognosis for GALT Deficiency 168
Uridine Diphosphate Galactose 4’-Epimerase (GALE) Deficiency 169
Clinical Presentation of GALE Deficiency 169
Metabolic Derangement in GALE Deficiency 169
Genetics of GALE Deficiency 170
Diagnostic Tests for GALE Deficiency 170
Treatment and Prognosis for GALE Deficiency 170
Galactokinase (GALK) Deficiency 170
Clinical Presentation of GALK Deficiency 170
Metabolic Derangement in GALK Deficiency 170
Genetics of GALK Deficiency 170
Diagnostic Tests for GALK Deficiency 171
Treatment and Prognosis for GALK Deficiency 171
Fanconi-Bickel Syndrome 171
Portosystemic Venous Shunting and Hepatic Arteriovenous Malformations 171
References 171
7Disorders of Glycolysis and the Pentose Phosphate Pathway 173
Muscle Phosphofructokinase (PFKM) Deficiency 175
Clinical Presentation 175
Metabolic Derangement 175
Genetics 175
Diagnostic Tests 176
Aldolase A (ALDOA) Deficiency 176
Clinical Presentation 176
Metabolic Derangement 176
Genetics 176
Diagnostic Tests 176
Treatment and Prognosis 176
Triosephosphate Isomerase (TPI) Deficiency 176
Clinical Presentation 176
Metabolic Derangement 176
Genetics 177
Diagnostic Tests 177
Treatment and Prognosis 177
Phosphoglycerate Kinase (PGK) Deficiency 177
Clinical Presentation 177
Metabolic Derangement 177
Genetics 177
Diagnostic Tests 177
Treatment and Prognosis 177
Phosphoglycerate Mutase (PGAM) Deficiency 178
Clinical Presentation 178
Metabolic Derangement 178
Genetics 178
Diagnostic Tests 178
Treatment and Prognosis 178
Enolase Deficiency 178
Clinical Presentation 178
Metabolic Derangement 178
Genetics 178
Diagnostic Tests 178
Treatment and Prognosis 179
Lactate Dehydrogenase (LDH) Deficiency 179
Clinical Presentation 179
Metabolic Derangement 179
Genetics 179
Diagnostic Tests 179
Treatment and Prognosis 179
Glycerol Kinase Deficiency (GKD) 179
Clinical Presentation 179
Metabolic Derangement 179
Genetics 180
Diagnostic Tests 180
Treatment and Prognosis 180
Ribose-5-Phosphate Isomerase (RPI) Deficiency 180
Clinical Presentation 180
Metabolic Derangement 180
Genetics 181
Diagnostic Tests 181
Treatment and Prognosis 181
Transaldolase (TALDO) Deficiency 181
Clinical Presentation 181
Metabolic Derangement 181
Genetics 181
Diagnostic Tests 181
Treatment and Prognosis 182
Transketolase (TKT) Deficiency 182
Clinical Presentation 182
Metabolic Derangement 182
Genetics 182
Diagnostic Tests 182
Treatment and Prognosis 182
Sedoheptulokinase (SHPK) Deficiency 182
Clinical Presentation 182
Metabolic Derangement 183
Genetics 183
Diagnostic Tests 183
Treatment and Prognosis 183
References 183
8Disorders of Fructose Metabolism 185
Essential Fructosuria 187
Clinical Presentation 187
Metabolic Derangement 187
Genetics 187
Diagnosis 187
Treatment and Prognosis 187
Hereditary Fructose Intolerance 187
Clinical Presentation 187
Metabolic Derangement 188
Genetics 188
Diagnosis 188
Differential Diagnosis 189
Treatment and Prognosis 189
Fructose-1,6-Bisphosphatase Deficiency 189
Clinical Presentation 189
Metabolic Derangement 190
Genetics 190
Diagnosis 190
Differential Diagnosis 191
Treatment and Prognosis 191
References 191
9Congenital Hyperinsulinism 193
Clinical Presentation 195
Metabolic Derangement 196
Genetics 196
Diagnostic Tests 196
Treatment and Prognosis 197
Long-term Medical Management 198
Prognosis 198
References 198
10Disorders of Glucose Transport 199
Congenital Glucose/Galactose Malabsorption (SGLT1 Deficiency ) 201
Clinical Presentation 201
Metabolic Derangement 201
Genetics 201
Diagnostic Tests 201
Treatment and Prognosis 202
Renal Glucosuria (SGLT2 Deficiency ) 202
Clinical Presentation 202
Metabolic Derangement 202
Genetics 202
Diagnostic Tests 202
Treatment and Prognosis 202
Glucose Transporter-1 Deficiency (GLUT1 Deficiency ) 202
Clinical Presentation 202
Metabolic Derangement 203
Genetics 203
Diagnostic Tests 203
Treatment and Prognosis 203
Fanconi-Bickel Syndrome (GLUT2 Deficiency ) 204
Clinical Presentation 204
Metabolic Derangement 204
Genetics 204
Diagnostic Tests 204
Treatment and Prognosis 205
Arterial Tortuosity Syndrome (GLUT10 Deficiency ) 205
Clinical Presentation 205
Metabolic Derangement 205
Genetics 205
Diagnostic Tests 205
Treatment and Prognosis 205
References 206
Section III Disorders of Mitochondrial Energy Metabolism 208
11Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle 209
Pyruvate Carboxylase Deficiency 211
Metabolic Derangement 211
Clinical Presentation 211
Genetics 212
Diagnostic Tests 212
Treatment and Prognosis 212
Phosphoenolpyruvate Carboxykinase Deficiency 214
Pyruvate Dehydrogenase Complex Deficiency 214
Clinical Presentation 214
Metabolic Derangement 215
Genetics 215
Diagnostic Tests 215
Treatment and Prognosis 216
Dihydrolipoamide Dehydrogenase Deficiency (DLD) 216
Clinical Presentation 216
Metabolic Derangement 216
Genetics 216
Diagnostic Tests 216
Treatment and Prognosis 216
2-Ketoglutarate Dehydrogenase Complex Deficiency (KDHC) 217
Clinical Presentation 217
Metabolic Derangement 217
Genetics 217
Diagnostic Tests 217
Treatment and Prognosis 217
Fumarase Deficiency 217
Clinical Presentation 217
Metabolic Derangement 217
Genetics 218
Diagnostic Tests 218
Treatment and Prognosis 218
Succinate Dehydrogenase Deficiency 218
Clinical Presentation 218
Metabolic Derangement 218
Other Krebs Cycle Disorders 218
Pyruvate Transporter Defect 219
Protein-bound lipoic acid defect and defects in cof actors 219
References 219
12Disorders of Mitochondrial Fatty Acid Oxidation & Riboflavin Metabolism
Disorders of Mitochondrial Fatty Acid Oxidation 224
Clinical Presentations 224
Fatty Acid Transport Defects 224
Carnitine Cycle Defects 224
ß-Oxidation Defects 226
Electron Transfer Defects 227
Other Potential Defects 227
Metabolic Derangement 227
Genetics 228
Diagnostic Tests 228
Abnormal Metabolites 228
Studies 230
Fasting Studies 230
Prenatal Diagnosis 230
Newborn Screening 230
Treatment and Prognosis 230
Management of Acute Illness 230
Long Term Dietary Management 230
Drug Treatment 231
Monitoring 231
Prognosis 232
Defects of Riboflavin Transport & Metabolism
Brown-Vialetto-van Laere Syndrome 232
RFVT1 Deficiency 233
FAD Synthase and Mitochondrial FAD Transporter Deficiencies 233
References 233
13Disorders of Ketogenesis and Ketolysis 235
Ketogenesis Defects 237
Clinical Presentation 237
Metabolic Derangement 237
Genetics 237
Diagnostic Tests 237
Treatment and Prognosis 238
Defects of Ketone Body Utilization or Transport 238
Clinical Presentation 238
Metabolic Derangement 239
Genetics 239
Diagnostic Tests 239
Treatment and Prognosis 239
Cytosolic Acetoacetyl-CoA Thiolase Deficiency 240
Ketogenic Diets 240
References 240
14Disorders of Oxidative Phosphorylation 242
Clinical Presentation 244
Neonatal and Infantile Presentations 245
Presentation in Childhood and Adolescence 249
Adult-Onset Disorders 250
Metabolic Derangement 250
Genetics 251
Mitochondrial DNA Mutations 251
Nuclear Gene Defects 251
Frequency of Mutations 252
Diagnostic Tests 252
Screening Tests 252
Muscle and Other Tissue Biopsies 254
Molecular Genetic Investigations 257
Treatment and Prognosis 257
Treatable Disorders 257
Supportive Management 259
Vitamin and Cofactor Cocktails 259
Experimental Approaches 259
Genetic Counselling and Prenatal and Preimplantation Genetic Diagnosis 259
Prognosis 259
References 260
15Creatine Deficiency Syndromes 262
Clinical Presentation 264
Arginine Glycine Amidinotransferase (AGAT) Deficiency 264
Guanidinoacetate Methyltransferase (GAMT) Deficiency 264
Creatine Transporter (CRTR) Deficiency 264
Metabolic Derangement 264
Genetics 265
Diagnostic Tests 265
Brain MRS 265
Metabolite Analysis 265
DNA Analysis 265
Functional Tests 266
Prenatal Diagnosis 266
Newborn Screening 266
Treatment and Prognosis 266
Deficiency 266
GAMT Deficiency 266
CRTR Deficiency 266
References 266
Section IV Disorders of Amino Acid Metabolism and Transport 268
16Hyperphenylalaninaemia 270
Phenylalanine Hydroxylase Deficiency 272
Clinical Presentation 272
Metabolic Derangement 272
Genetics 272
Diagnostic Tests 272
Treatment and Prognosis 273
Maternal PKU 277
Clinical Presentation 277
Metabolic Derangement 277
Treatment and Prognosis 277
HPA and Disorders of Biopterin Metabolism 278
Clinical Presentation 278
Metabolic Derangement 278
Genetics 278
Diagnostic and Confirmatory Tests 278
Treatment and Prognosis 279
References 280
17Disorders of Tyrosine Metabolism 283
Hereditary Tyrosinaemia Type I (Hepatorenal Tyrosinaemia ) 285
Clinical Presentation 285
Metabolic Derangement 285
Genetics 286
Diagnostic Tests 286
Treatment and Prognosis 287
Hereditary Tyrosinaemia Type II (Oculocutaneous Tyrosinaemia , Richner-Hanhart Syndrome ) 288
Clinical Presentation 288
Metabolic Derangement 288
Genetics 289
Diagnostic Tests 289
Treatment and Prognosis 289
Hereditary Tyrosinaemia Type III 289
Clinical Presentation 289
Metabolic Derangement 289
Genetics 289
Diagnostic Tests 290
Treatment and Prognosis 290
Transient Tyrosinaemia 290
Alkaptonuria 290
Clinical Presentation 290
Metabolic Derangement 290
Genetics 291
Diagnostic Tests 291
Treatment and Prognosis 291
Hawkinsinuria 291
Clinical Presentation 291
Metabolic Derangement 291
Genetics 291
Diagnostic Tests 291
Treatment and Prognosis 292
References 292
18Branched-chain Organic Acidurias /Acidaemias 294
Maple Syrup Urine Disease , Isovaleric Aciduria , Propionic Aciduria , Methylmalonic Aciduria 296
Clinical Presentation 296
Metabolic Derangement 298
Genetics 299
Diagnostic Tests 300
Treatment and Prognosis 300
3-Methylcrotonyl Glycinuria 305
Clinical Presentation 305
Metabolic Derangement 305
Genetics 305
Diagnostic Tests 306
Treatment and Prognosis 306
3-Methylglutaconic Aciduria 306
Short/Branched Chain Acyl-CoA Dehydrogenase Deficiency 307
2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency 307
Isobutyryl-CoA Dehydrogenase Deficiency 307
3-Hydroxyisobutyric Aciduria 307
Malonyl-CoA Decarboxylase Deficiency 308
ACSF3 Deficiency 308
Enoyl-CoA Hydratase or ECHS1 Deficiency 308
References 308
19Disorders of the Urea Cycle and Related Enzymes 312
Mitochondrial Urea Cycle Disorders 314
Clinical Presentation 314
Genetics 315
Diagnostic Tests 315
Metabolic Derangements 315
Treatment and Prognosis 317
Cytosolic Urea Cycle Disorders 318
Clinical Presentation 318
Metabolic Derangements 319
Genetics 319
Diagnostic Tests 319
Treatment and Prognosis 320
Urea Cycle Mitochondrial Transporter Defects 320
Hyperornithinemia , Hyperammonaemia and Homocitrullinuria (HHH) Syndrome 320
Citrin Deficiency 320
Urea Cycle Defects due to Deficiencies of Ancillary Enzymes 322
.1-Pyrroline-5-Carboxylate Synthetase (P5CS) Deficiency 322
Carbonic Anhydrase Va (CAVA) Deficiency 322
References 323
20Disorders of Sulfur Amino Acid Metabolism 326
Methionine S-Adenosyltransferase Deficiency (Mudd’s Disease ) 328
Clinical Presentation 328
Metabolic Derangement 328
Genetics 328
Diagnostic Tests 328
Treatment and Prognosis 330
Glycine N-Methyltransferase Deficiency 330
Clinical Presentation 330
Metabolic Derangement 330
Genetics 330
Diagnostic Tests 330
Treatment and Prognosis 330
S-Adenosylhomocysteine Hydrolase Deficiency 330
Clinical Presentation 330
Metabolic Derangement 330
Genetics 330
Diagnostic Tests 330
Treatment and Prognosis 331
Adenosine Kinase Deficiency 331
Cystathionine ß-Synthase Deficiency 331
Clinical Presentation 331
Metabolic Derangement 331
Genetics 331
Diagnostic Tests 332
Treatment and Prognosis 333
Cystathionine .-Lyase Deficiency 334
Clinical Presentation 334
Metabolic Derangement 334
Genetics 334
Diagnostic Tests 334
Treatment and Prognosis 334
Molybdenum Cofactor Deficiency 334
Clinical Presentation 334
Metabolic Derangement 334
Genetics 334
Diagnostic Tests 334
Treatment and Prognosis 334
Isolated Sulfite Oxidase Deficiency 335
Clinical Presentation 335
Metabolic Derangement 335
Genetics 335
Diagnostic Tests 335
Treatment and Prognosis 335
Ethylmalonic Encephalopathy 335
Clinical Presentation 335
Metabolic Derangement 335
Genetics 335
Diagnostic Tests 335
Treatment and Prognosis 335
References 336
21Disorders of Ornithine and Proline Metabolism 338
Hyperornithinaemia Due to Ornithine Aminotransferase Deficiency (Gyrate Atrophy of the Choroid and Retina ) 340
Hyperornithinaemia , Hyperammonaemia and Homocitrullinuria (HHH) Syndrome 342
.1-Pyrroline-5-Carboxylate Synthetase Deficiency 344
.1-Pyrroline-5-Carboxylate Reductase Deficiency 1 (PYCR1) and 2 (PYCR2) 345
Proline Oxidase Deficiency (Hyperprolinaemia Type I ) 345
.1-Pyrroline-5-Carboxylate Dehydrogenase Deficiency (Hyperprolinaemia Type II) 346
Prolidase Deficiency 346
Spermine Synthase Deficiency (Snyder Robinson Syndrome ) 347
References 347
22Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism 349
Introduction 351
Hyperlysinaemia /Saccharopinuria 353
Clinical Presentation 353
Metabolic Derangement 353
Genetics 354
Diagnostic Tests 354
Treatment and Prognosis 354
Hydroxylysinuria 354
2-Amino -/2-Oxoadipic Aciduria 354
Clinical Presentation 354
Metabolic Derangement 354
Genetics 355
Diagnostic Tests 355
Treatment and Prognosis 355
Glutaric Aciduria Type I 355
Clinical Presentation 355
Metabolic Derangement 356
Genetics 356
Diagnostic Tests 356
Treatment and Prognosis 357
Glutaric Aciduria Type III 358
Clinical Presentation 358
Metabolic Derangement 358
Genetics 358
Diagnostic Tests 358
Treatment and Prognosis 358
L-2-Hydroxyglutaric Aciduria 358
Clinical Presentation 358
Metabolic Derangement 359
Genetics 359
Diagnostic Tests 359
Treatment and Prognosis 359
D-2-Hydroxyglutaric Aciduria 359
Clinical Presentation 359
Metabolic Derangement 359
Genetics 360
Diagnostic Tests 360
Treatment and Prognosis 360
D-2-/L-2-Hydroxyglutaric Aciduria 360
Clinical Presentation 360
Metabolic Derangement 360
Genetics 360
Diagnostic Tests 360
Treatment and Prognosis 360
N-Acetylaspartic Aciduria (Canavan Disease ) 360
Clinical Presentation 360
Metabolic Derangement 361
Genetics 361
Diagnostic Tests 361
Treatment and Prognosis 361
Aminoacylase 1 Deficiency 361
Diagnostic Tests 362
Treatment and Prognosis 362
Hypoacetylaspartia and AspartateGlutamate Carrier 1 Deficiency 362
References 362
23Nonketotic Hyperglycinemia (Glycine Encephalopathy ) and Lipoate Deficiency Disorders 365
Introduction: Definitions 366
Clinical Presentation 367
Severe Classic NKH 367
Attenuated Classic NKH 367
Lipoate Disorders Including Variant NKH 368
Metabolic Derangement 368
Genetics 369
Diagnostic Tests 369
Treatment 370
Prognosis 371
References 371
24Disorders of Glutamine , Serine and Asparagine Metabolism 373
Glutamine Synthetase Deficiency 375
Inborn Errors of Serine Meta bolism 375
3-Phosphoglycerate Dehydrogenase Deficiency 375
Phosphoserine Aminotransferase Deficiency 376
3-Phosphoserine Phosphatase Deficiency 376
Brain Serine Transporter Deficiency 376
Serine Palmitoyltransferase Defects 377
Asparagine Synthetase Deficiency 377
References 377
25Disorders of Amino Acid Transport at the Cell Membrane 379
Cystinuria 381
Clinical Presentation 381
Metabolic Derangement 381
Genetics 381
Diagnostic Tests 381
Treatment and Prognosis 382
Lysinuric Protein Intolerance 383
Clinical Presentation 383
Metabolic Derangement 383
Genetics 384
Diagnostic Tests 384
Treatment and Prognosis 384
Hartnup Disease 385
Clinical Presentation 385
Metabolic Derangement 385
Genetics 385
Diagnostic Tests 385
Treatment and Prognosis 386
Asymptomatic Aminoacidurias: Iminoglycinuria and Dicarboxylic Aminoaciduria 386
References 386
Section V Vitamin-Responsive Disorders 388
26Biotin-responsive Disorders 389
Clinical Presentation 391
Holocarboxylase Synthetase Deficiency 392
Biotinidase Deficiency 392
Metabolic Derangement 392
Genetics 393
Holocarboxylase Synthetase Deficiency 393
Biotinidase Deficiency 393
Diagnostic Tests 393
Holocarboxylase Synthetase Deficiency 394
Biotinidase Deficiency 394
Acquired Biotin Deficiency 394
Prenatal Diagnosis 394
Treatment and Prognosis 394
Holocarboxylase Synthetase Deficiency 395
Biotinidase Deficiency 395
References 396
27Disorders of Cobalamin and Folate Transport and Metabolism 398
Disorders of Absorption and Transport of Cobalamin 400
Hereditary Intrinsic Factor Deficiency 400
Defective Transport of Cobalamin by Enterocytes (Imerslund-Gräsbeck Syndrome ) 400
Haptocorrin (R Binder) Deficiency 401
Transcobalamin Deficiency 401
Transcobalamin Receptor Deficiency 402
Disorders of Intracellular Utilisation of Cobalamin 402
Combined Deficiencies of Adenosylcobalamin and Methylcobalamin 402
Adenosylcobalamin Deficiency 405
Methylcobalamin Deficiency 405
Disorders of Absorption and Metabolism of Folate 407
Hereditary Folate Malabsorption 407
Cerebral Folate Deficiency 407
Methylenetetrahydrofolate Dehydrogenase (MTHFD1) Deficiency 408
Dihydrofolate Reductase Deficiency 408
Glutamate Formiminotransferase Deficiency 409
Methylenetetrahydrofolate Reductase Deficiency 409
References 410
28Disorders of Thiamine and Pyridoxine Metabolism 413
Disorders of Thiamine (Vitamin B1) Metabolism 414
Thiamine Transporter 1 (THTR1) Deficiency 415
Thiamine Transporter 2 (THTR2) Deficiency 416
Thiamine Pyrophosphokinase Deficiency 416
Mitochondrial TPP Transporter Deficiency 417
Thiamine-Responsive a-Ketoacid Dehydrogenase Deficiencies 417
Thiamine-Responsive Pyruvate Dehydrogenase Deficiency 417
Thiamine-Responsive Maple Syrup Urine Disease 418
Vitamin B6 Metabolism 419
Antiquitin Deficiency 420
Hyperprolinemia Type II 421
Pyridox(am)ine 5’-phosphate Oxidase (PNPO) Deficiency 422
Congenital Hypophosphatasia 422
Hyperphosphatasia-Mental Retardation Syndrome (HPMRS) 422
Other B6 Responsive Disorders 422
References 423
Section VI Neurotransmitter and Small Peptide Disorders 425
29Disorders of Neurotransmission 426
Inborn Errors of Gamma Amino Butyric Acid Metabolism 428
Gamma Amino Butyric Acid Transaminase Deficiency 428
Succinic Semialdehyde Dehydrogenase Deficiency 429
Homocarnosinosis 429
Inborn Errors of Receptors and Trans-porters of Neurotransmitters 430
Hyperekplexia 430
GABA Receptor Mutations 431
Glutamate Receptor Mutations 431
Mitochondrial Glutamate Transporter Defect 431
Dopamine Transporter Defect 432
Brain Dopamine-Serotonin Vesicular Transport Defect 432
Inborn Errors of Monoamine Metabolism 432
Tyrosine Hydroxylase Deficiency 432
Aromatic L-Aminoacid Decarboxylase Deficiency 433
Dopamine ß-Hydroxylase Deficiency 434
Monoamine Oxidase-A Deficiency 434
Guanosine Triphosphate Cyclohydrolase-I Deficiency 435
Sepiapterine Reductase Deficiency 436
References 436
30Trimethylaminuria, Dimethyl-glycine Dehydrogenase Deficiency and Disorders in the Metabolism of Glutathione 439
Trimethylaminuria (Fish Malodour Syndrome ) 441
Metabolic Derangement 441
Genetics 441
Clinical Presentation 441
Diagnostic Tests 442
Treatment 442
Dimethylglycine Dehydrogenase Deficiency 442
Clinical Presentation 442
Metabolic Derangement 442
Genetics 442
Diagnostic Tests 442
Treatment 443
Disorders in the Metabolism of Glutathione 443
y-Glutamylcysteine Synthetase Deficiency 443
Glutathione Synthetase Deficiency 444
y-Glutamyl Transpeptidase Deficiency 445
5-Oxoprolinase Deficiency 446
Dipeptidase Deficiency 446
Secondary 5-Oxoprolinuria 446
References 446
Section VII Disorders of Lipid and Bile Acid Metabolism 448
31Inborn Errors of Lipoprotein Metabolism Presenting in Childhood 449
Disorders of Low Density Lipoprotein Metabolism 451
Disorders of Triglyceride (TG) Metabolism 453
Disorders of High Density Lipoprotein Metabolism 461
Disorders of Sterol Storage 461
Conclusion 461
References 461
32Disorders of Isoprenoid/ Cholesterol Synthesis 463
Mevalonate Kinase Deficiency 465
Smith-Lemli-Opitz Syndrome (7-Dehydrocholesterol Reductase Deficiency ) 466
Sterol .8-.7 Isomerase Deficiency 467
X-Linked Dominant Chondrodysplasia Punctata 2 or Conradi-Hünermann Syndrome in Females 467
Hemizygous EBP Deficiency in Males 468
Deficiency of the C4-Demethylase Complex 468
C4-Methyl Sterol Oxidase Deficiency (SMO Deficiency) 468
Sterol 4a-Carboxylate 3-Dehydrogenase Deficiency 468
Desmosterol Reductase Deficiency (Desmosterolosis) 469
Sterol .5-Desaturase Deficiency (Lathosterolosis) 469
Sterol .14-Reductase Deficiency (Hydrops – Ectopic Calcification – Moth-eaten (HEM) Skeletal Dysplasia or Greenberg Skeletal Dys 470
References 471
33Disorders of Bile Acid Synthesis 473
3ß-Hydroxy-.5-C27-Steroid Dehydrogenase Deficiency 475
.4-3-Oxosteroid 5ß-Reductase Deficiency 476
Cerebrotendinous Xanthomatosis (Sterol 27-Hydroxylase Deficiency ) 477
a-Methylacyl-CoA Racemase Deficiency (see also Chapter 40) 479
Oxysterol 7a-Hydroxylase Deficiency 479
Bile Acid Amidation Defect 1 : Bile Acid CoA : Amino Acid N-Acyl Transferase Deficiency 480
Bile Acid Amidation Defect 2 : Bile Acid CoA Ligase Deficiency 480
Cholesterol 7a-Hydroxylase Deficiency 481
Disorders of Peroxisome Biogenesis, Peroxisomal Import and Peroxisomal ß-Oxidation 481
References 481
34Disorders of Intracellular Triglyceride and Phospholipid Metabolism 484
Inborn Errors of the Common Pathway of Acylglycerol and Phospholipid Synthesis 486
Glycerol-3-phosphate Dehydrogenase 1 (GPD1) Deficiency : Autosomal Recessive Hepatic Steatosis and Hypertriglyceridemia 486
Glycerol Kinase Deficiency is described in Chapter 7 486
1-Acylglycerol-3-Phosphate O-Acyltransferase 2 (AGPAT2) Deficiency : Autosomal Recessive Generalized Congenital Lipodystrophy 486
Phosphatidic Acid Phosphatase (PAP LIPIN) Deficiencies
Diacylglycerol Kinase Epsilon (DGKE) Deficiency : Atypical Haemolytic Uremic Syndrome 487
Inborn Errors of Cytoplasmic Triglyceride Metabolism 487
Diacylglycerol O-Acyl Transferase 1 (DGAT1) Deficiency : Congenital Diarrhea 487
Perilipin 1 Deficiency : Autosomal Dominant Partial Lipodystrophy 488
Neutral Lipid Storage Diseases (NLSDs) : ATGL and CGI-58 Deficiencies 488
Hormone-Sensitive Lipase (HSL) Deficiency Insulin Resistance, Diabetes
Inborn Errors of Phospholipid Biosynthesis 490
Choline Kinase ß (CHKß) Deficiency: Congenital Muscular Dystrophy, Megaconial Type 490
Choline-PhosphateCytidylyltrans-ferase a (CCTa) Deficiency : Spondylometaphyseal Dysplasia with Cone-Rod Dystrophy or Congenital 490
PhosphatidylserineSynthase 1 (PSS1) Gain of Function (Lenz-Majewski Hyperostotic Dwarfism ) 490
Acylglycerol Kinase (AGK) Deficiency : Myopathy, Hypertrophic Cardiomyopathy and Congenital Cataract (Sengers Syndrome ) 491
Cardiolipin Remodeling Enzyme Deficiency : X-linked Cardiomyopathy and Neutropenia (Barth Syndrome ) 491
Mutation : Methylglutaconic Aciduria, Deafness, Hepatic I nvolvement, Encephalopathy, and Leigh Syndrome (MEGDHEL Syndrome ) 492
Mitochondrial Calcium Independent Phospholipase A2. (iPLA2.): Autosomal Recessive Myopathy, Dystonia and Convulsions (not shown) 492
Inborn Errors related to Phospholipid Remodeling 492
a/ß Hydrolase Domain-Containing Protein 12 (ABHD12) Deficiency : Polyneuropathy, Hearing loss, Ataxia, Retinitis Pigmentosa and 492
Phospholipase A2 Deficiency (PLA2G6) : Autosomal Recessive Infantile Neuroaxonal Dystrophy, Neurodegeneration with Brain Iron Accumulation 493
Deficiencies of Neuropathy TargetEsterase (NTE or PNPLA-6) orMitochondrial Calcium-independentPhospholipase A2? (PNPLA6):Peripheral Neuropathy, SpasticParaplegia, ChorioretinalDegeneration, HypogonadotrophicHypogonadism, Trichomegaly(SPG39, Boucher-Neuhauser , Gordon-Holms , Oliver-McFarlane , Laurence-Moon syndromes ) or MitochondrialMyopathy with Dystonia 493
DDHD1 and DDHD2 Mutations :Hereditary Spastic Paraplegias28 and 45 494
CYP2U1 Mutation : Spastic Paraplegiawith Basal Ganglia Calcification(Hereditary Spastic Paraplegia 56,SPG56) 494
Inborn Errors of Polyphosphoinositide Metabolism 495
References 495
Section VIII Disorders of Nucleic Acid and Heme Metabolism 499
35Disorders of Purine and Pyrimidine Metabolism 500
Inborn Errors of Purine Metabolism 502
Phosphoribosyl Pyrophosphate Synthetase Superactivity 502
Phosphoribosyl Pyrophosphate Synthetase Deficiency 502
Adenylosuccinase Deficiency 503
AICA-Ribosiduria 503
Muscle Adenosine Monophosphate Deaminase 1 Deficiency 503
Adenosine Monophosphate Deaminase 2 and 3 Deficiencies 504
Adenosine Deaminase 1 Deficiency 504
Adenosine Deaminase 2 Deficiency 506
Adenosine Deaminase Superactivity 506
Purine Nucleoside Phosphorylase Deficiency 506
Xanthine Oxidase Deficiency 506
Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency 507
Adenine Phosphoribosyl-transferase Deficiency 508
Adenylate Kinase 1 Deficiency 509
Adenylate Kinase 2 Deficiency 509
Adenosine Kinase Deficiency 509
Adenylate Cyclase 5 Mutations 509
IMP Dehydrogenase Mutations 509
Deoxyguanosine Kinase Deficiency 509
Thiopurine Methyltransferase Deficiency 510
Inosine Triphosphatase Deficiency 510
Inborn Errors of Pyrimidine Metabolism 510
CAD (Carbamoylphosphate Synthetase II, Aspartate Transcarba-mylase, Dihydroorotase) Deficiency 510
UMP Synthase Deficiency (Hereditary Orotic Aciduria ) 510
Miller syndrome (Dihydroorotate Dehydrogenase Deficiency ) 512
Dihydropyrimidine Dehydrogenase Deficiency 512
Dihydropyrimidinase Deficiency 513
Ureidopropionase Deficiency 513
Pyrimidine 5’-Nucleotidase Deficiency 513
Cytosolic 5’-Nucleotidase Superactivity 513
Thymidine Phosphorylase Deficiency 513
Cytidine Deaminase Deficiency 514
Thymidine Kinase 2 Deficiency 514
References 514
36Disorders of Haem Biosynthesis 519
X-Linked Sideroblastic Anaemia 521
The Porphyrias 521
Classification and Diagnosis 521
5-Aminolevulinic Acid Dehydratase Porphyria 523
Acute Intermittent Porphyria (AIP) 523
Congenital Erythropoietic Porphyria (CEP) (Gunther Disease ) 525
Porphyria Cutanea Tarda (PCT) 526
Hepatoerythropoietic Porphyria 527
Hereditary Coproporphyria and Variegate Porphyria 527
Erythropoietic Protoporphyria and X-Linked Protoporphyria 528
References 529
Section IX Disorders of Metal Transport and Metabolism 532
37Disorders in the Transport of Copper, Iron, Magnesium, Manganese, Selenium and Zinc 533
Copper 534
Wilson Disease 535
Menkes Disease 537
Other Copper Storage Disorders 538
Other Disturbances of Copper Metabolism with a Low Serum Copper 538
Iron 539
Systemic Iron Overload Syndromes (Haemochromatosis ) 540
Iron Deficiency and Distribution Disorders 541
Neurode generation with Brain Iron Accumulation (NBIA) 542
Magnesium 543
Primary Hypomagnesaemia with Secondary Hypocalcaemia 543
Hypomagnesaemia with Hyper-calciuria and Nephrocalcinosis 544
Isolated Dominant Hypomagnesemia 544
Isolated Autosomal Recessive Hypomagnesaemia 545
Manganese 545
Inherited Manganism Due to Mutations in 545
Manganese Transporter Defect 546
Selenium 546
Zinc 546
Acrodermatitis Enteropathica 547
Zinc Deficiency in Breastfed Babies 548
Hyperzincaemia with Hypercalprotectinaemia 548
Autosomal Dominant Hyperzincaemia without Symptoms 548
References 548
Section X Organelle-Related Disorders: Lysosomes, Peroxisomes, and Golgi and Pre-Golgi Systems 551
38Disorders of Sphingolipid Synthesis, Sphingolipidoses, Niemann-Pick Disease Type C and Neuronal Ceroid Lipofuscinoses 552
Disorders of Sphingolipid Synthesis 554
Serine Palmitoyltransferase (Subunit 1 or 2) Deficiency and HSAN1 554
Defects in Ceramide Synthases 1 and 2 and Myoclonic Epilepsy 555
Fatty Acid 2-Hydroxylase Deficiency (SPG35/FAHN) 556
GM3 Synthase Deficiency and Amish Epilepsy Syndrome 556
GM2/GD2 Synthase Deficiency (SPG26) 556
Nonlysosomal ß-Glucosidase GBA2 Deficiency : SPG46 and Ataxia 556
Ceramide Synthase 3 and Ultra-Long Chain Fatty Acid .-Hydroxylase (CYP4F22) Deficiencies : Autosomal Recessive Congenital Ichthy 556
Mutations in Ceramide Kinase-Like (CERKL) Gene and Retinal Dystrophy 557
Alkaline Ceramidase 3 (ACER3) Deficiency : Infantile Leukodystrophy 557
Sphingolipidoses 557
Gaucher Disease 557
Acid Sphingomyelinase-Deficient Niemann-Pick Disease (Type A, Type B and Intermediate Forms) 560
GM1 Gangliosidosis 561
GM2 Gangliosidoses 562
Krabbe Disease 563
Metachromatic Leukodystrophy 564
Fabry Disease 566
Farber Disease / Acid Ceramidase Deficiency 567
Prosaposin Deficiency 567
Niemann-Pick Disease Type C 567
Clinical Presentation 567
Metabolic Derangement 568
Genetics 569
Diagnostic Tests 569
Treatment and Prognosis 569
Neuronal Ceroid Lipofuscinoses 569
Clinical Presentation 569
Metabolic Derangement 571
Genetics 572
Diagnostic Tests 572
Treatment and Prognosis 572
Re ferences 572
39Mucopolysaccharidoses, Oligosaccharidoses and Sialic Acid Disorders 577
Mucopolysaccharidoses 579
Clinical Presentation 579
Metabolic Derangement 583
Genetics 583
Diagnostic Tests 583
Treatment and Prognosis 583
Oligosaccharidoses and Mucolipidoses 585
Clinical Presentation 585
Metabolic Derangements 587
Genetics 587
Diagnostic Tests 588
Treatment and Prognosis 588
References 588
40Inborn Errors of Non-Mitochondrial Fatty Acid Metabolism Including Peroxisomal Disorders 591
Disorders of Etherphospholipid Biosynthesis 594
Peroxin 7 (PEX7) Deficiency (RCDP Type 1) 594
Glycerone 3-Phosphate Acyltransferase (GNPAT) Deficiency (RCDP type 2) 594
Alkylglycerone 3-Phosphate Synthase (AGPS) Deficiency (RCDP Type 3) 594
PEX5L-Deficiency (RCDP Type 4) 594
Fatty Acyl-CoA Reductase 1 (FAR1) Deficiency 595
Disorders of Peroxisomal ß-Oxidation 595
X-Linked Adrenoleukodystrophy 595
D-Bifunctional Protein (DBP) Deficiency 596
Acyl-CoA Oxidase (ACOX) Deficiency 597
Methyl Acyl-CoA Racemase (AMACR) Deficiency 597
Sterol Carrier Protein-2 (SCPx) Deficiency 598
PMP70 Deficiency 598
Contiguous 598
Syndrome (CADDS) 598
Zellweger Spectrum Disorders (ZSD) 598
Disorders of Peroxisomal Fatty Acid Alpha-Oxidation 599
Adult Refsum Disease (ARD) 599
The Fatty Acid Chain Elongation Disorders 600
ELOVL4 Deficiency 600
ELOVL5 Deficiency 601
Trans-2,3-Enoyl-CoA Reductase (TER) Deficiency 601
3-Hydroxyacyl-CoA Dehydratase1 (HACD1) Deficiency 601
Disorders of Eicosanoid Metabolism 601
Primary Hypertrophic Osteo-arthropathy Type 1 (PHOAR1): 15-Hydroxy Prostaglandin Dehydrogenase (PGDH) Deficiency and Type 2 (PHO 601
LTC4-Synthase Deficiency 603
Remaining Disorders of Fatty Acid Homeostasis 603
Sjögren Larsson Syndrome (SLS) 603
Bile Acid-CoA: Amino Acid N-Acyltransferase (BAAT) Deficiency 604
Other Peroxisomal Disorders not Involving Fatty Acid Metabolism 604
Oxalurias and Oxalosis: Glyoxylate Detoxification Disorders 604
Pipecolic Acidemia 604
Acatalasemia 604
References 605
41Congenital Disorders of Glycosylation, Dolichol and Glycosylphosphatidylinositol Metabolism 607
Introduction 609
Congenital Disorders of Protein N-Glycosylation (. Table 41.1) 611
Phosphomannomutase 2 Deficiency (PMM2-CDG) 611
Mannosephosphate Isomerase Deficiency (MPI-CDG) 612
Glucosyltransferase 1 Deficiency (ALG6-CDG) 612
Mannosyltransferase 1 Deficiency (ALG1-CDG) 613
UDP-GlcNAc:Dol-P-GlcNAc-P Trans-ferase Deficiency (DPAGT1-CDG) 613
Golgi a1-2 Mannosidase 1 Deficiency (MAN1B1-CDG) 614
Congenital Disorders of Protein O-Glycosylation (. Table 41.2) 614
Progeroid Variant of Ehlers-Danlos Syndrome (B4GALT7-CDG) 614
GALNT3 Deficiency (GALNT3-CDG) 614
Hereditary Multiple Exostoses (EXT1/EXT2-CDG) 614
Cerebro-Ocular Dysplasia-Muscular Dystrophy Syndromes , Types A1, B1, C1/A2, B2, C2 (POMT1/POMT2-CDG) 616
Muscle-Eye-Brain Disease, Types A3, B3, C3 (POMGNT1-CDG) 616
O-Fucose-Specific ß-1,3-Glucosyl-trans ferase Deficiency (B3GALTL-CDG) 616
Defects in Lipid Glycosylation and in Glycosylphosphatidylinositol (GPI) Anchor Biosynthesis (. Table 41.3) 616
GM3 Synthase Deficiency (ST3GAL5-CDG) 616
GM2 Synthase Deficiency (B4GALNT1-CDG) 616
PIGA Deficiency (PIGA-CDG) 616
Defects in Multiple Glycosylation Pathways and in Other Pathways I ncluding Dolicholphosphate Biosynthesis Defects (. Table 41.4 616
Hereditary Inclusion Body Myopathy (GNE-CDG) 616
Congenital Myasthenic Syndrome-12 (GFPT1-CDG) 617
Steroid 5-a-Reductase Deficiency (SRD5A3-CDG) 617
COG6 Deficiency (COG6-CDG) 620
Autosomal Recessive Cutis Laxa Type 2 (ATP6V0A2-CDG) 620
Phosphoglucomutase 1 Deficiency (PGM1-CDG) 620
Golgi Homeostasis Disorders: TMEM199 and CCDC115 Deficiencies 620
Manganese and Zinc Transporter Defect : SLC39A8 Deficiency 620
Congenital Disorders of Deglycosylation 621
N-glycanase 1 Deficiency 621
Lysosomal Storage Disorders 621
References 621
42Cystinosis 623
Infantile Cystinosis 624
Clinical Presentation 624
Metabolic Derangement 626
Genetics 626
Diagnostic Tests 626
Treatment 626
Late-Onset Cystinosis 627
Ocular Cystinosis 628
References 628
Section XI Appendix 630
43Medications Used in the Treatment of Inborn Errors 631
Subject Index 640