9783642157196

Table of Contents


I	DIAGNOSIS AND TREATMENT: GENERAL PRINCIPLES	2
1	Clinical Approach to Inborn Errors of Metabolism in Pediatrics Jean-Marie Saudubray	3
1.1	Classification	4
1.1.1	Pathophysiology	4
1.1.2	Clinical Presentation	5
1.2	Antenatal Symptoms	5
1.3	Symptoms in the Neonatal Period and Early Infancy (<1 year)	6
1.3.1	Clinical Presentations	6
1.3.2	Metabolic Derangements and Diagnostic Tests	12
1.4	Metabolic Emergencies from Late Infancy to Adolescence	15
1.4.1	Clinical Presentations	15
1.4.2	Metabolic Derangements and Diagnostic Tests	22
1.5	Chronic and Progressive Neurological Symptoms (Mental Retardation, Developmental Delay, Epilepsy, Neurological Deterioration and Psychiatric Symptoms)	27
1.5.1	Diagnostic Approach to Neurological and Mental Deterioration Related to Age	28
1.5.2	Diagnostic Approach to Neuromental Deterioration According to Neurophysiological and Neuroradiological Signs	36
1.6	Specific Organ Signs and Symptoms	41
1.6.1	Cardiology	41
1.6.2	Dermatology	41
1.6.3	Dysmorphology, Malformations, Dysplasia	43
1.6.4	Endocrinology	43
1.6.5	Gastroenterology	44
1.6,1	Haematology	45
1.6.1	Hepatology	48
1.6.2	Immunology	49
1.6.3	Myology	49
1.6.4	Nephrology	49
1.6.5	Neurology and Psychiatry	49
1.6.6	Ophthalmologic Signs	49
1.6.7	Osteology	51
1.6.8	Pneumology	51
1.6.9	Psychiatry	52
1.6.10	Rheumatology	52
1.6.17	Stomatology	52
	References	52
2	Inborn Errors of Metabolism in Adults: A Diagnostic Approach to Neurological and Psychiatric Presentations Fr�d�ric Sedel	55
2.1	Introduction	56
2.2	Differences Between Paediatric and Adult Phenotypes	56
2.3	General Approach to JEM in Adulthood	58
2.3.1	Energy Metabolism Defects	59
2.3.2	Disorders of Lipid Metabolism	60
2.3.3	Intoxication Syndromes	60
2.3.4	Disorders of Neurotransmitter Metabolism	60
2.3.5	Metal Storage Disorders	60
2.4	Specific Approaches to Neurometabolic Presentations in Adults	60
2.4.1	Encephalopathies/Comas	60
2.4.2	Strokes and Pseudo-strokes	61
2.4.3	Movement Disorders	61
2.4.4	Peripheral Neuropathies	64
2.4.5	Leukoencephalopathies	64
2.4.6	Epilepsy	64
2.4.7	Psychiatric Disorders	66
2.4.8	Spastic Paraparesis	69
2.4.9	Cerebellar Ataxia	69
2.4.10	Myopathy	70
2.4.11	Others	72
	References	74
3	Newborn Screening for Inborn Errors of Metabolism Bridget Wilcken, Piero Rinaldo, Dietrich Matern	75
3.1	Introduction	76
3.2	General Aspects of Newborn Screening	76
3.2.1	Aims and Criteria	76
3.2.2	Sensitivity, Specificity and Positive Predictive Value	76
3.2.3	Technical Aspects of Newborn Screening Tests	77
3.2.4	Range of Possibilities from Early Detection	78
3.2.5	Follow-up	78
3.3	Screening for Individual Inborn Errors of Metabolism	82
3.3.1	Aminoacidopathies	82
3.3.2	Galactosaemias	83
3.3.3	Organic Acid Disorders	83
3.3.4	Fatty Acid Oxidation Disorders	84
3.3.5	Lysosomal Storage Disorders	84
3.3.6	Other Conditions	85
	References	85
4	Diagnostic Procedures: Functional Tests and Post-mortem Protocol Guy Touati, Fanny Mochel, Daniel Rabier	87
4.1	Introduction	88
4.2	Basal Investigation	88
4.2.1	Amino and Organic acids Analyses	88
4.2.2	Metabolic Profile over the Course of the Day	88
4.3	In Vitro ^�H-NMR Spectroscopy of Body Fluids	95
4.4	Functional Tests	96
4.4.1	Fasting Test	96
4.4.2	Glucose Loading Test	98
4.4.3	Protein and Allopurinol Loading Tests	98
4.4.4	Exercise Test	99
4.5	Post-mortem Protocol	100
4.5.1	Cells and Tissues for Enzyme Assays	100
4.5.2	Ceils and Tissues for Chromosome and DNA Investigations	100
4.5.3	Skin Fibroblasts	100
4.5.4	Body Fluids for Chemical Investigations	101
4.5.5	Autopsy	101
	References	101
5	Emergency Treatments Carlo Dionisi-Vici, H�l�ne Ogier de Baulny	103
5.1	General Principles	104
5.1.1	Supportive Care	104
5.1.2	Nutrition	104
5.1.3	Specific Therapies	104
5.1.4	Extracorporeal Procedures for Toxin Removal	105
5.2	Emergency Management of Particular Clinical Presentations	105
5.2.1	Neurological Deterioration	105
5.2.2	Liver Failure	108
5.2.3	Neonatal Hypoglycaemia	108
5.2.4	Cardiac Failure	109
5.2.5	Primary Hyperlactataemia	109
5.2.6	Intractable Convulsions	109
5.3	Final Considerations	110
	References	110
II	DISORDERS OF CARBOHYDRATE METABOLISM
6	The Glycogen Storage Diseases and Related Disorders Pascal Lafor�t, David A. Weinstein, G. Peter, A. Smit	115
6.1	Liver Glycogenoses	117
6.1.1	Glycogen Storage Disease Type I (Glucose-6-Phosphatasefor Translocase Deficiency)	117
6.1.2	Glycogen Storage Disease Type III (Debranching Enzyme Deficiency)	122
6.1.3	Glycogen Storage Disease Type IV (Branching Enzyme Deficiency)	123
6.1.4	Glycogen Storage Disease Type VI (Glycogen Phosphorylase Deficiency)	125
6.1.5	Glycogen Storage Disease Type IX (Phosphorylase Kinase Deficiency)	125
6.1.6	Glycogen Storage Disease Type 0 (Glycogen Synthase Deficiency)	126
6.2	Muscle and Cardiac Glycogenoses	127
6.2.1	GSDs With Exercise Intolerance Without Cardiac Involvement	127
6.2.2	GSDs with Cardiac Involvement	130
6.3	Brain Glycogenoses	133
6.3.1	Lafora Disease (Neuronal Laforin/Malin Defects)	133
6.3.2	Adult Polyglucosan Body Disease (Astrocytes Branching Enzyme Deficiency)	134
	References	134
7	Disorders of Galactose Metabolism Gerard T. Berry, John H. Walter	141
7.1	Galactose-1-Phosphate Uridyltransferase Deficiency	143
7.1.1	Clinical Presentation	143
7.1.2	Metabolic Derangement	143
7.1.3	Genetics	144
7.1.4	Diagnostic Tests	144
7.1.5	Treatment and Prognosis	144
7.2	Uridine Diphosphate-Galactose4�-Epimerase Deficiency	147
7.2.1	Clinical Presentation	147
7.2.2	Metabolic Derangement	147
7.2.3	Genetics	147
7.2.4	Diagnostic Tests	147
7.2.5	Treatment and Prognosis	147
7.3	Galactokinase Deficiency	148
7.3.1	Clinical Presentation	148
7.3.2	Metabolic Derangement	148
7.3.3	Genetics	148
7.3.4	Diagnostic Tests	148
7.3.5	Treatment and Prognosis	148
7.4	Fanconi-Bickel Syndrome	149
7.5	Portosystemic Venous Shunting and Hepatic Arteriovenous Malformations	149
	References	149
8	Disorders of the Pentose Phosphate Pathway Mirjam M.C. Wamelink, Vassili Valayannopoulos, Cornelis Jakobs	151
8.1	Ribose-5-Phosphate Isomerase Deficiency	153
8.1.1	Clinical Presentation	153
8.1.2	Metabolic Derangement	153
8.1.3	Genetics	153
8.1.4	Diagnostic Tests	153
8.1.5	Treatment and Prognosis	153
8.2	Transaldolase Deficiency	153
8.2.1	Clinical Presentation	153
8.2.2	Metabolic Derangement	154
8.2.3	Genetics	154
8.2.4	Diagnostic Tests	155
8.2.5	Treatment and Prognosis	155
	References	155
9	Disorders of Fructose Metabolism Beat Steinmann, Ren� Santer	157
9.1	Essential Fructosuria	159
9.1.1	Clinical Presentation	159
9.1.2	Metabolic Derangement	159
9.1.3	Genetics	159
9.1.4	Diagnosis	159
9.1.5	Treatment and Prognosis	159
9.2	Hereditary Fructose Intolerance	159
9.2.1	Clinical Presentation	159
9.2.2	Metabolic Derangement	160
9.2.3	Genetics	160
9.2.4	Diagnosis	161
9.2.5	Differential Diagnosis	161
9.2.6	Treatment and Prognosis	161
9.3	Fructose-1,6-Bisphosphatase Deficiency	162
9.3.1	Clinical Presentation	162
9.3.2	Metabolic Derangement	162
9.3.3	Genetics	163
9.3.4	Diagnosis	163
9.3.5	Differential Diagnosis	164
9.3.6	Treatment and Prognosis	164
	References	164
10	Persistent Hyperinsulinaemic Hypoglycaemia Pascale de Lonlay, Jean-Marie Saudubray	167
10.1	Clinical Presentation	169
10.2	Metabolic Derangement	169
10.3	Genetics	169
10.4	Diagnostic Tests	170
10.4.1	Diagnostic Criteria	170
10.4.2	Differentiation of Focal from Diffuse Forms	171
10.5	Treatment and Prognosis	171
10.5.1	Medical Treatment	171
10.5.2	Surgical Treatment	171
10.5.3	Prognosis	172
10.6	Conclusion	172
	References	172
11	Disorders of Glucose Transport Ren� Santer, J�rg Klepper	175
11.1	Congenital Glucose/Galactose Malabsorption (SGLT1 Deficiency)	177
11.1.1	Clinical Presentation	177
11.1.2	Metabolic Derangement	177
11.1.3	Genetics	177
11.1.4	Diagnostic Tests	177
11.1.5	Treatment and Prognosis	178
11.2	Renal Glucosuria (SGLT2 Deficiency)	178
11.2.1	Clinical Presentation	178
11.2.2	Metabolic Derangement	178
11.2.3	Genetics	178
11.2.4	Diagnostic Tests	178
11.2.5	Treatment and Prognosis	178
11.3	Glucose Transporter Deficiency Syndrome (GLUT1 Deficiency)	178
11.3.1	Clinical Presentation	178
11.3.2	Metabolic Derangement	179
11.3.3	Genetics	179
11.3.4	Diagnostic Tests	179
11.3.5	Treatment and Prognosis	179
11.4	Fanconi-Bickel Syndrome (GLUT2 Deficiency)	180
11.4.1	Clinical Presentation	180
11.4.2	Metabolic Derangement	180
11.4.3	Genetics	180
11.4.4	Diagnostic Tests	180
11.4.5	Treatment and Prognosis	181
11.5	Arterial Tortuosity Syndrome (GLUT10 Deficiency)	181
11.5.1	Clinical Presentation	181
11.5.2	Metabolic Derangement	181
11.5.3	Genetics	181
11.5.4	Treatment and Prognosis	181
	References	181
III	DISORDERS OF MITOCHONDRIAL ENERGY METABOLISM
12	Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle Linda J. De Meirleir, Mich�le Brivet, Angeles Garcia-Cazorla	187
12.1	Pyruvate Carboxylase Deficiency	189
12.1.1	Clinical Presentation	189
12.1.2	Metabolic Derangement	189
12.1.3	Genetics	190
12.1.4	Diagnostic Tests	190
12.1.5	Treatment and Prognosis	190
12.2	Phosphoenolpyruvate Carboxykinase Deficiency	191
12.3	Pyruvate Dehydrogenase Complex Deficiency	192
12.3.1	Clinical Presentation	192
12.3.2	Metabolic Derangement	192
12.3.3	Genetics	193
12.3.4	Diagnostic Tests	193
12.3.5	Treatment and Prognosis	194
12.4	Dihydrolipoamide Dehydrogenase Deficiency	194
12.4.1	Clinical Presentation	194
12.4.2	Metabolic Derangement	194
12.4.3	Genetics	194
12.4.4	Diagnostic Tests	194
12.4.5	Treatment and Prognosis	194
12.5	2-Ketoglutarate Dehydrogenase Complex Deficiency	195
12.5.1	Clinical Presentation	195
12.5.2	Metabolic Derangement	195
12.5.3	Genetics	195
12.5.4	Diagnostic Tests	195
12.5.5	Treatment and Prognosis	195
12.6	Fumarase Deficiency	195
12.6.1	Clinical Presentation	195
12.6.2	Metabolic Derangement	196
12.6.3	Genetics	196
12.6.4	Diagnostic Tests	196
12.6.5	Treatment and Prognosis	196
12.7	Succinate Dehydrogenase Deficiency	196
12.7.1	Clinical Presentation	196
12.7.2	Metabolic Derangement	196
12.7.3	Genetics	197
12.7.4	Diagnostic Tests	197
12.7.5	Treatment and Prognosis	197
12.8	Other Krebs Cycle Disorders	197
12.9	Pyruvate Transporter Defect	197
12.9.1	Clinical Presentation	197
12.9.2	Metabolic Derangement	197
12.9.3	Diagnostic Tests	197
12.9.4	Genetics	197
12.9.5	Treatment and Prognosis	198
12.10	Protein-bound lipoid acid defect	198
	References	198
13	Disorders of Mitochondria I Fatty Acid Oxidation and Related Metabolic Pathways Andrew AM. Morris, Ute Spiekerkoetter	201
13.1	Introduction	203
13.2	Clinical Presentations	203
13.2.1	Fatty Acid Transport Defects	203
13.2.2	Carnitine Cycle Defects	203
13.2.3	β-Oxidation Defects	205
13.2.4	Electron Transfer Defects	206
13.3	Metabolic Derangement	207
13.4	Genetics	207
13.5	Diagnostic Tests	208
13.5.1	Abnormal Metabolites	208
13.5.2	In Vitro Studies	210
13.5.3	Fasting Studies	210
13.5.4	Prenatal Diagnosis	210
13.5.5	Newborn Screening	211
13.6	Treatment and Prognosis	211
13.6.1	Management of Acute Illness	211
13.6.2	Long-term Dietary Management	211
13.6.3	Drug Treatment	212
13.6.4	Monitoring	212
13.6.5	Prognosis	212
13.7	Related Defects	214
13.7.1	Defects of Leukotriene (LT) Metabolism	214
13.7.2	Sj�gren-Larsson Syndrome	214
	References	214
14	Disorders of Ketogenesis and Ketolysis Andrew A.M. Morris	217
14.1	Clinical Presentation	219
14.1.1	Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency	219
14.1.2	3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency	219
14.1.3	Succinyl-CoA 3-Oxoacid CoA Transferase Deficiency	219
14.1.4	Mitochondrial Acetoacetyl-CoA Thiolase Deficiency	219
14.2	Metabolic Derangement	220
14.3	Genetics	220
14.4	Diagnostic Tests	220
14.4.1	Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency	220
14.4.2	3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency	220
14.4.3	Succinyl-CoA 3-Oxoacid CoA Transferase Deficiency	220
14.4.4	Mitochondrial Acetoacetyl-CoA Thiolase Deficiency	221
14.4.5	Prenatal Diagnosis	221
14.5	Treatment and Prognosis	221
14.6	Cytosolic Acetoacetyl-CoA Thiolase Deficiency	221
	References	222
15	Defects of the Respiratory Chain Arnold Munnich, Agn�s R�tig, Marl�ne Rio	223
15.1	Clinical Presentation	224
15.1.1	Fetuses	226
15:1.2	Neonates	226
15.1.3	Infants	226
15.1.4	Children and Adults	227
15.2	Metabolic Derangement	227
15.3	Genetics	228
15.3.1	Mitochondrial DNA Mutations	229
15.3.2	Large-scale mtDNA Rearrangements	229
15.3.3	Nuclear DNA Mutations	229
153.4	Genetic Counselling and Prenatal Diagnosis	231
15.4	Diagnostic Tests	231
15.4.1	Screening Tests	231
15.4.2	Enzyme Assays	232
15.4.3	Histopathological Studies	234
15.4.4	Magnetic Resonance Imaging (MRI) and Spectroscopy of Muscle and Brain	234
15.4.5	Molecular Genetic Tests	234
15.5	Treatment and Prognosis	235
	References	236
16	Creatine Deficiency Syndromes Sylvia St�ckler-Ipsirogiu, Saadet Mercimek-Mahmutoglu, Gajja S. Salomons	239
16.1	Clinical Presentation	241
16.1.1	Guanidinoacetate Methyltransferase Deficiency	241
16:1.2	Arginine:Glycine Amldinotransferase Deficiency	241
16.1.3	SLC6A8 Deficiency	241
16.2	Metabolic Derangement	242
16.3	Genetics	243
16.4	Diagnostic Tests	243
16.4.1	MRS of Brain	243
16.4.2	Metabolite Screening	243
16.4.3	DNA Diagnostics	244
16.4.4	Functional Tests/Enzymatic Diagnostics	244
16.4.5	Prenatal Diagnosis	244
16.5	Treatment and Prognosis	244
16.5.1	GAMT Deficiency	244
16.5.2	AGAT Deficiency	244
16.5.3	SLC6A8 Deficiency	245
	References	245
IV	DISORDERS OF AMINO ACID METABOLISM AND TRANSPORT
17	Hyperphenylalaninaemia John H. Walter, Robin H. Lachmann, Peter Burgard	251
17.1	Introduction	253
17.2	Phenylalanine Hydroxylase Deficiency	253
17.2.1	Clinical Presentation	253
17.2.2	Metabolic Derangement	253
17.2.3	Genetics	253
17.2.4	Diagnostic Tests	254
17.2.5	Treatment and Prognosis	254
17.3	Maternal PKU	258
17.3.1	Clinical Presentation	258
17.3.2	Metabolic Derangement	258
17.3.3	Treatment and Prognosis	259
17.4	HPA and Disorders of Biopterin Metabolism	260
17.4.1	Clinical Presentation	260
17.4.2	Metabolic Derangement	260
17.4.3	Genetics	261
17.4.4	Diagnostic and Confirmatory Tests	261
17.4.5	Treatment and Prognosis	262
	References	263
18	Disorders of Tyrosine Metabolism Anupam Chakrapani, Paul Gissen, Patrick McKiernan	265
18.1	Hereditary Tyrosinaemia Type I (Hepatorenal Tyrosinaemia)	267
18.1.1	Clinical Presentation	267
18.1.2	Metabolic Derangement	267
18.1.3	Genetics	268
18.1.4	Diagnostic Tests	268
18.1.5	Treatment and Prognosis	269
18.2	Hereditary Tyrosinaemia Type II (Oculocutaneous Tyrosinaemia, Richner-Hanhart Syndrome)	271
18.2.1	Clinical Presentation	271
18.2.2	Metabolic Derangement	271
18.2.3	Genetics	271
18.2.4	Diagnostic Tests	271
18.2.5	Treatment and Prognosis	272
18.3	Hereditary Tyrosinaemia Type III	272
18.3.1	Clinical Presentation	272
18.3.2	Metabolic Derangement	272
18.3.3	Genetics	272
18.3.4	Diagnostic Tests	272
18.3.5	Treatment and Prognosis	272
18.4	Transient Tyrosinaemia	273
18.5	Alkaptonuria	273
18.5.1	Clinical Presentation	273
18.5.2	Metabolic Derangement	273
18.5.3	Genetics	274
18.5.4	Diagnostic Tests	274
18.5.5	Treatment and Prognosis	274
18.6	Hawkinsinuria	274
18.6.1	Clinical Presentation	274
18.6.2	Metabolic Derangement	274
18.6.3	Genetics	274
18.6.4	Diagnostic Tests	274
18.6.5	Treatment and Prognosis	275
	References	275
19	Branched-chain Organic AciduHas/ Acidaemias H�l�ne Ogier de Baulny, Carlo Dionisi-Vici, Udo Wendel	277
19.1	Maple Syrup Urine Disease, Isovaleric Aciduria, Propionic Aciduria, Methylmalonic Aciduria	279
19.1.1	Clinical Presentation	279
19.1.2	Metabolic Derangement	281
19.1.3	Genetics	283
19.1.4	Diagnostic Tests	284
19.1.5	Treatment and Prognosis	284
19.2	3-Methylcrotonyl Glycinuria	289
19.2.1	Clinical Presentation	289
19.2.2	Metabolic Derangement	290
19.2.3	Genetics	290
19.2.4	Diagnostic Tests	290
19.2.5	Treatment and Prognosis	290
19.3	3-Methylglutaconic Aciduria	291
19.4	Short-/Branched-chain Acyl-CoA Dehydrogenase Deficiency	292
19.5	2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency	292
19.6	Isobutyryl-CoA Dehydrogenase Deficiency	292
19.7	3-Hydroxyisobutyric Aciduria	292
19.8	Malonic Aciduria	293
19.8.1	Clinical Presentation	293
19.8.2	Metabolic Derangement	293
19.8.3	Genetics	293
19.8.4	Diagnostic Tests	293
19.8.5	Treatment and Prognosis	293
	References	293
20	Disorders of the Urea Cycle and Related Enzymes Frits A. Wijburg, Marie-C�cile Nassogne	297
20.1	Clinical Presentation	299
20.1.1	Neonatal Presentation	299
20.1.2	Presentation in Infants	299
20.1.3	Presentation in Older Children and Adults	300
20.1.4	Newborn Screening	300
20.2	Metabolic Derangement	301
20.2.1	The Urea Cycle, Its Connections and Regulation	301
20.2.2	Sources of Ammonia and Inter-organ Fluxes	301
20.2.3	CNS Toxicity in Urea Cycle Defects	301
20.3	Genetics of Urea Cycle Defects	302
20.4	Prenatal Diagnosis	303
20.5	Diagnostic Tests and Differential Diagnosis	303
20.6	Treatment	304
20.6.1	Treatment in Acute Presentations	304
20.6.2	Maintenance Therapy	306
20.7	Outcome	308
20.8	Pregnancy	308
	References	309
21	Disorders of Sulfur Amino Acid Metabolism Generoso Andria, Brian Fowler, Gianfranco Sebastio	311
21.1	Homocystinuria Due to Cystathionine β-Synthase Deficiency	313
21.1.1	Clinical Presentation	313
21.1.2	Metabolic Derangement	314
21.1.3	Genetics	314
21.1.4	Diagnostic Tests	315
21.1.5	Treatment and Prognosis	316
21.2	Methionine S-Adenosyltransferase Deficiency	317
21.2.1	Clinical Presentation	317
21.2.2	Metabolic Derangement	317
21.2.3	Genetics	317
21.2.4	Diagnostic Tests	318
21.2.5	Treatment and Prognosis	318
21.3	Glycine N-Methyltransferase Deficiency	318
21.3.1	Clinical Presentation	318
21.3.2	Metabolic Derangement	318
21.3.3	Genetics	318
21.3.4	Diagnostic Tests	318
21.3.5	Treatment and Prognosis	318
21.4	S-Adenosylhomocysteine Hydrolase Deficiency	318
21.4.1	Clinical Presentation	318
21.4.2	Metabolic Derangement	319
21.4.3	Genetics	319
21.4.4	Diagnostic Tests	319
21.4.5	Treatment and Prognosis	319
21.5	γ-Cystathioninase Deficiency	319
21.5.1	Clinical Presentation	319
21.5.2	Metabolic Derangement	319
21.5.3	Genetics	319
21.5.4	Diagnostic Tests	319
21.5.5	Treatment and Prognosis	319
21.6	Isolated Sulfite Oxidase Deficiency	319
21.6.1	Clinical Presentation	319
21.6.2	Metabolic Derangement	320
21.6.3	Genetics	320
21.6.4	Diagnostic Tests	320
21.6.5	Treatment and Prognosis	320
	References	320
22	Disorders of Ornithine Metabolism Matthias R. Baumgartner, David Valle	323
22.1	Hyperornithinaemia Due to Ornithine Aminotransferase Deficiency (Gyrate Atrophy of the Choroid and Retina)	325
22.1.1	Clinical Presentation	325
22.1.2	Metabolic Derangement	326
22.1.3	Genetics	326
22.1.4	Diagnostic Tests	326
22.1.5	Treatment and Prognosis	327
22.2	Hyperornithinaemia, Hyperammonaemia and Homocitrullinuria (HHH) Syndrome	328
22.2.1	Clinical Presentation	328
22:2.2	Metabolic Derangement	328
22.2.3	Genetics	328
22.2.4	Diagnostic Tests	329
22.2.5	Treatment and Prognosis	329
22.3	Δ¹-Pyrroline-5-Carboxylate Synthase Deficiency	329
22.3.1	Clinical Presentation	329
22.3.2	Metabolic Derangement	330
22.3.3	Genetics	330
22.3.4	Diagnostic Tests	330
22.3.5	Treatment and Prognosis	330
22.4	Δ¹-Pyrroiine-5-Carboxylate Reductase Deficiency	330
	References	330
23	Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism Georg F. Hoffmann, Stefan K�lker	333
23.1	Introduction	335
23.2	Hyperlysinaemia/Saccharopinuria	336
23.2.1	Clinical Presentation	336
23.2.2	Metabolic Derangement	336
23.2.3	Genetics	336
23.2.4	Diagnostic Tests	336
23.2.5	Treatment and Prognosis	337
23.3	Hydroxyiysinuria	337
23.4	2-Amino-/2-Oxoadipic Aciduria	337
23.4.1	Clinical Presentation	337
23.4.2	Metabolic Derangement	337
23.4.3	Genetics	337
23.4.4	Diagnostic Tests	337
23.4.5	Treatment and Prognosis	337
23.5	Glutaric Aciduria Type I	337
23.5.1	Clinical Presentation	337
23.5.2	Metabolic Derangement	339
23.5.3	Genetics	339
23.5.4	Diagnostic Tests	340
23.5.5	Treatment and Prognosis	340
23.6	Glutaric Aciduria Type III	342
23.6.1	Clinical Presentation	342
23.6.2	Metabolic Derangement	342
23.6.3	Genetics	342
23.6.4	Diagnostic Tests	342
23.6.5	Treatment and Prognosis	342
23.7	L-2-Hydroxyglutaric Aciduria	342
23.7.1	Clinical Presentation	342
23.7.2	Metabolic Derangement	342
23.7.3	Genetics	342
23.7.4	Diagnostic Tests	343
23.7.5	Treatment and Prognosis	343
23.8	D-2-Hydroxyglutaric Aciduria	343
23.8.1	Clinical Presentation	343
23.8.2	Metabolic Derangement	344
23.8.3	Genetics	344
23.8.4	Diagnostic Tests	344
23.8.5	Treatment and Prognosis	344
23.9	N-Acetylaspartic Aciduria (Canavan Disease)	345
23.9.1	Clinical Presentation	345
23.9.2	Metabolic Derangement	345
23.9.3	Genetics	345
23.9.4	Diagnostic Tests	345
23.9.5	Treatment and Prognosis	345
23.10	Hypoacetylaspartia	346
	References	346
24	Nonketotic Hyperglycinaemia (Glycine Encephalopathy) Olivier Dulac, Marie-Odile Rolland	349
24.1	Clinical Presentation	350
24.1.1	Neonatal NKH	350
24.1.2	Late-onset NKH	352
24.2	Metabolic Derangement	352
24.3	Genetics	353
24.4	Diagnostic Tests	353
24.5	Differential Diagnosis	354
24.6	Prenatal Diagnosis	354
24.7	Treatment	354
	References	354
25	Disorders of Proline and Serine Metabolism Jaak Jaeken	357
25.1	Inborn Errors of Proline Metabolism	359
25.1.1	Proline Oxidase Deficiency (Hyperprolinaemia Type I)	359
25.1.2	Δ¹-Pyrroline 5-Carboxylate Dehydrogenase Deficiency (Hyperprolinaemia Type II)	359
25.1.3	Δ¹-Pyrroline 5-Carboxylate Reductase Deficiency	360
25.2	Inborn Errors of Serine Metabolism	360
25.2.1	3-Phosphoglycerate Dehydrogenase Deficiency	360
25.2.2	Phosphoserine Aminotransferase Deficiency	361
25.2.3	Phosphoserine Phosphatase Deficiency	361
25.2.4	Serine Deficiency with Ichthyosis and Polyneuropathy	361
25.2.5	Serine Palmitoyltransferase Defects	361
	References	361
26	Transport Defects of Amino Acids at the Cell Membrane: Cystinuria, Lysinuric Protein Intolerance and Hartnup Disorder Kirsti N�snt�-Salonen, Harri Niinikoski, Olli G. Simell	363
26.1	Cystinuria	364
26.1.1	Clinical Presentation	364
26.1.2	Metabolic Derangement	365
26.1.3	Genetics	365
26.1.4	Diagnostic Tests	365
26.1.5	Treatment and Prognosis	365
26.2	Lysinuric Protein Intolerance	366
26.2.1	Clinical Presentation	366
26.2.2	Metabolic Derangement	367
26.2.3	Genetics	367
26.2.4	Diagnostic Tests	367
26.2.5	Treatment and Prognosis	367
26.3	Hartnup Disorder	368
26.3.1	Clinical Presentation	368
26.3.2	Metabolic Derangement	368
26.3.3	Genetics	369
26.3.4	Diagnostic Tests	369
26.3.5	Treatment and Prognosis	369
26.4	Asymptomatic Aminoacidurias	369
	References	370
V	VITAMIN-RESPONSIVE DISORDERS
27	Biotin-responsive Disorders Matthias R. Baumgartner, Terttu Suormala	375
27.1	Clinical Presentation	377
27.1.1	Holocarboxylase Synthetase Deficiency	377
27.1.2	Biotinidase Deficiency	377
27.1.3	Biotin-responsive Basal Ganglia Disease	378
27.2	Metabolic Derangement	378
27.3	Genetics	379
27.3.1	Holocarboxylase Synthetase Deficiency	379
27.3.2	Biotinidase Deficiency	379
27.3.3	Biotin-responsive Basal Ganglia Disease	379
27.4	Diagnostic Tests	380
27.4.1	Holocarboxylase Synthetase Deficiency	380
27.4.2	Biotinidase Deficiency	380
27.4.3	Acquired Biotin Deficiency	380
27.4.4	Prenatal Diagnosis	380
27.5	Treatment and Prognosis	381
27.5.1	Holocarboxylase Synthetase Deficiency	381
27.5.2	Biotinidase Deficiency	381
27.5.3	Biotin-responsive Basal Ganglia Disease	382
	References	382
28	Disorders of Cobalamin and Folate Transport and Metabolism David Watkins, David S. Rosenblatt, Brian Fowler	385
28.1	Disorders of Absorption and Transport of Cobalamin	387
28.1.1	Hereditary Intrinsic Factor Deficiency	387
28.1.2	Defective Transport of Cobalamin by Enterocytes (Imerslund-Gr�sbeck Syndrome)	387
28.1.3	Haptocorrin (R Binder) Deficiency	388
28.1.4	Transcobalamin Deficiency	388
28.1.5	Transcobalamin Receptor Deficiency	389
28.2	Disorders of Intracellular Utilisation of Cobalamin	389
28.2.1	Combined Deficiencies of Adenosylcobalamin and Methylcobalamin	390
28.2.2	Adenosylcobalamin Deficiency	392
28.2.3	Methylcobalamin Deficiency	393
28.3	Disorders of Absorption and Metabolism of Folate	395
28.3.1	Hereditary Folate Malabsorption	395
28.3.2	Cerebral Folate Deficiency	395
28.3.3	Glutamate-Formiminotransferase Deficiency	396
28.3.4	Methylenetetrahydrofolate Reductase Deficiency	396
28.3.5	Dihydrofolate Reductase Deficiency	397
	References	398
VI	NEUROTRANSMITTER AND SMALL PEPTIDE DISORDERS
29	Disorders of Neurotransmission Angels Garda-Cazorla, K. Michael Gibson, Peter T. Clayton	405
29.1	Inborn Errors of Gamma Amino Butyric Acid Metabolism	407
29.1.1	Gamma Amino Butyric Acid Transaminase Deficiency	407
29.1.2	Succinic Semialdehyde Dehydrogenase Deficiency	407
29.1.3	Homocarnosinosrs	408
29.2	Inborn Defects of Receptors and Transporters of Neurotransmitters	408
29.2.1	Hyperekplexia	408
29.2.2	GABA Receptor Mutations	410
29.2.3	Mitochondrial Glutamate Transporter Defect	410
29.3	Inborn Errors of Monoamine Metabolism	412
29.3.1	Tyrosine Hydroxylase Deficiency	412
29.3.2	Aromatic L-Aminoacid Decarboxylase Deficiency	412
29.3.3	Dopamipe β-Hydroxylase Deficiency	413
29.3.4	Monoamine Oxidase-A Deficiency	412
29.3.5	Guanosine Triphosphate Cydohydrolase-I Deficiency	414
29.3.6	Sepiapterine Reductase Deficiency	415
29.3.7	Dopamine Transporter Defect	415
29.3.8	Other Inborn Defects Involved in Monoamine Metabolism	415
29.4	Inborn Disorders Involving Pyridoxine and Pyridoxal Phosphate	417
29.4.1	Pyridoxine-responsive Epilepsy	417
29.4.2	Pyridox(am)ine 5�-Phosphate Oxidase Deficiency	419
	References	420
30	Disorders in the Metabolism of Glutathione and Imidazole Dipeptides Ertan Mayatepek, Jaak Jaeken	423
30.1	Disorders in the Metabolism of Glutathione	425
30.1.1	γ-Glutamylcysteine Synthetase Deficiency	425
30.1.2	Glutathione Synthetase Deficiency	425
30.1.3	γ-Glutamyl Transpeptidase Deficiency	427
30.1.4	5-Oxoprolinase Deficiency	427
30.1.5	Dipeptidase Deficiency	428
30.1.6	Secondary 5-Oxoprolinuria	428
30.2	Disorders of Imidazole Dipeptides	428
30.2.1	Serum Carnosinase Deficiency	428
30.2.2	Homocarnosinosis	429
30.2.3	Prolidase Deficiency	429
	References	430
31	Trimethylaminuria and Dimethylglycine Dehydrogenase Deficiency Valerie Walker, Ron A. Wevers	431
31.1	Trimethylaminuria (Fish Odour Syndrome)	433
31.1.1	Clinical Presentation	433
31.1.2	Metabolic Derangement	433
31.1.3	Genetics	433
31.1.4	Diagnostic Tests	433
31.1.5	Treatment	433
31.2	Dimethylglycine Dehydrogenase Deficiency	434
31.2.1	Clinical Presentation	434
31.2.2	Metabolic Derangement	434
31.2.3	Genetics	434
31.2.4	Diagnostic Tests	434
31.2.5	Treatment	434
	References	434
VII	DISORDERS OF LIPID AND BILE ACID METABOLISM
32	Dyslipidaemias Annabelle Rodriguez-Oquendo, Peter O. Kwiterovich, Jr.	439
32.1	Overview of Plasma Lipid and Lipoprotein Metabolism	441
32.1.1	Exogenous Lipoprotein Metabolism	442
32.1.2	Endogenous Lipoprotein Metabolism	442
32.1.3	Reverse Cholesterol Transport and High-density Lipoproteins	443
32.2	Disorders of Exogenous Lipoprotein Metabolism	445
32.2.1	Lipoprotein Lipase Deficiency	445
32.2.2	Apo C-ll Deficiency	446
32.3	Disorders of Endogenous Lipoprotein Metabolism	446
32.3.1	Disorders of VLDL Overproduction	446
32.3.2	Disorders of LDL Removal	448
32.4	Disorders of Endogenous and Exogenous Lipoprotein Transport	450
32.4.1	Dysbetalipoproteinaemia (Type III Hyper-lipoproteinaemia)	450
32.4.2	Hepatic Lipase Deficiency	451
32.5	Disorders of Reduced LDL-Cholesterol Levels	451
32.5.1	Abetalipoproteinaemia	451
32.5.2	Hypobetalipoproteinaemia	451
32.5.3	Chylomicron Retention Disease	452
32.6	Disorders of Reverse Cholesterol Transport	452
32.6.1	Familial Hypoalphalipoproteinaemia	452
32.6.2	Apolipoprotein A-l Mutations	452
32.6.3	Tangier Disease	453
32.6.4	Lecithin-cholesterol Acyltransferase Deficiency	453
32.6.5	Cholesteryl Ester Transfer Protein Deficiency	453
32.6.6	Scavenger Receptor Class B Type I Receptor Deficiency	453
32.6.7	Deficiency of Endothelial Lipase	454
32.6.8	Elevated Lipoprotein (a)	454
32.7	Guidelines for the Clinical Evaluation and Treatment of Dyslipidaemia	454
32.7.1	Clinical Evaluation	454
32.7.2	Dietary Treatment, Weight Reduction and Exercise	455
32.7.3	Goals for Dietary and Hygienic Therapy	455
32.7.4	Low-density-Lipoprotein-lowering Drugs	456
32.7.5	Triglyceride-lowering Drugs	458
32.7.6	Combination Pharmacotherapy	458
32.8	Abbreviations	458
	References	458
33	Disorders of Cholesterol Synthesis Hans R. Waterham, Peter T. Clayton	461
33.1	Mevalonate Kinase Deficiency	463
33.1.1	Clinical Presentation	463
33.1.2	Metabolic Derangement	463
33.1.3	Genetics	463
33.1.4	Diagnostic Tests	464
33.1.5	Treatment and Prognosis	464
33.2	Smith-Lemli-Opitz Syndrome (7-Dehydrocholesterol Reductase Deficiency)	464
33.2.1	Clinical Presentation	464
33.2.2	Metabolic Derangement	464
33.2.3	Genetics	465
33.2.4	Diagnostic Tests	465
33.2.5	Treatment and Prognosis	465
33.3	X-Linked Dominant Chondrodysplasia Punctata 2 or Conradi-H�nermann Syndrome (Sterol Δ8- Δ7 Isomerase Deficiency)	465
33.3.1	Clinical Presentation	465
33.3.2	Metabolic Derangement	466
33.3.3	Genetics	466
33.3.4	Diagnostic Tests	466
33.3.5	Treatment and Prognosis	466
33.4	CHILD Syndrome (3β-Hydroxysteroid C-4 Dehydrogenase Deficiency)	466
33.4.1	Clinical Presentation	466
33.4.2	Metabolic Derangement	466
33.4.3	Genetics	467
33.4.4	Diagnostic Tests	467
33.4.5	Treatment and Prognosis	467
33.5	Desmosterolosis (Desmosterol Reductase Deficiency)	467
33.5.1	Clinical Presentation	467
33.5.2	Metabolic Derangement	467
33.5.3	Genetics	467
33.5.4	Diagnostic Tests	467
33.5.5	Treatment and Prognosis	467
33.6	Lathosterolosis (Sterol Δ5-Desaturase Deficiency)	468
33.6.1	Clinical Presentation	468
33.6.2	Metabolic Derangement	468
33.6.3	Genetics	468
33.6.4	Diagnostic Tests	468
33.6.5	Treatment and Prognosis	468
33.7	Hydrops - Ectopic Calcification - Moth-eaten (HEM) Skeletal Dysplasia or Greenberg Skeletal Dysplasia (Sterol Δ14-Reductase Deficiency)	468
33.7.1	Clinical Presentation	468
33.7.2	Metabolic Derangement	468
33.7.3	Genetics	469
33.7.4	Diagnostic Tests	469
33.7.5	Treatment and Prognosis	469
33.8	Other Disorders	469
	References	469
34	Disorders of Bile Acid Synthesis Peter T. Clayton	473
34.1	Introduction	475
34.2	3β-Hydroxy-Δ5-C27-Steroid Dehydrogenase Deficiency	475
34.2.1	Clinical Presentation	475
34.2.2	Metabolic Derangement	475
34.2.3	Genetics	476
34.2.4	Diagnostic Tests	476
34.2.5	Treatment and Prognosis	476
34.3	Δ4-3-Oxosteroid 5β-Reductase Deficiency	477
34.3.1	Clinical Presentation	477
34.3.2	Metabolic Derangement	477
34.3.3	Genetics	477
34.3.4	Diagnostic Tests	477
34.3.5	Treatment and Prognosis	478
34.4	Cerebrotendinous Xanthomatosis (Sterol 27-Hydroxylase Deficiency)	478
34.4.1	Clinical Presentation	478
34.4.2	Metabolic Derangement	478
34.4.3	Genetics	479
34.4.4	Diagnostic Tests	479
34.4.5	Treatment and Prognosis	479
34.5	α-Methylacyl-CoA Racemase Deficiency	479
34.5.1	Clinical Presentation	479
34.5.2	Metabolic Derangement	480
34.5.3	Genetics	480
34.5.4	Diagnostic Tests	480
34.5.5	Treatment and Prognosis	480
34.6	Oxysterol 7α-Hydroxylase Deficiency	480
34.6.1	Clinical Presentation	480
34.6.2	Metabolic Derangement	480
34.6.3	Genetics	480
34.6.4	Diagnostic Tests	481
34.6.5	Treatment and Prognosis	481
34.7	Bile Acid Amidation Defect 1: Bile Acid CoA: Amino Acid N-Acyl Transferase Deficiency	481
34.7.1	Clinical Presentation	481
34.7.2	Metabolic Derangement	481
34.7.3	Genetics	481
34.7.4	Diagnostic Tests	481
34.7.5	Treatment and Prognosis	481
34.8	Bile Acid Amidation Defect 2: Bile Acid CoA Ligase Deficiency	481
34.8.1	Clinical Presentation	481
34.8.2	Metabolic Derangement	482
34.8.3	Genetics	482
34.8.4	Diagnostic Tests	482
34.8.5	Treatment and Prognosis	482
34.9	Cholesterol 7α-Hydroxylase Deficiency	482
34.9.1	Clinical Presentation	482
34.9.2	Metabolic Derangement	482
34.9.3	Genetics	482
34.9.4	Diagnostic Tests	482
34.9.5	Treatment and Prognosis	483
34.10	Disorders of Peroxisome Biogenesis and Peroxisomal-β-Oxidation	483
	References	483
35	Disorders of Phospholipid and Glycosphingolipid Synthesis Foudil Lamari, Fr�deric S�del, Jean-Marie Saudubray	485
35.1	Disorders of Phospholipid Synthesis	487
35.1.1	LIPN1 Deficiency (Phosphatidate Phosphatase 1 Deficiency)	487
35.1.2	Cardlolipin Remodelling Enzyme Deficiency: Barth Syndrome	488
35.1.3	Phospholipase A2 Deficiency (Infantile Neuroaxonal Dystrophy and Neurodegeneration with Brain Iron Accumulation)	489
35.1.4	α-/β-Hydrolase 12 (ABHD12) Deficiency (Polyneuropathy, Hearing Loss, Ataxia, Retinitis Pigmentosa and Cataracts: PHARC Syndrome)	490
35.2	Disorders of Glycosphingolipid Synthesis	493
35.2.1	Serine Palmitoyl CoA Transferase Deficiency	493
35.2.2	Fatty Acid 2-Hydroxylase Deficiency	494
35.2 3	GM3 Synthase Deficiency	494
	References	494
VIII	DISORDERS OF NUCLEIC ACID AND HEME METABOLISM
36	Disorders of Purine and Pyrimidine Metabolism Georges van den Berghe, M.-Fran�oise Vincent, Sandrine Marie	499
36.1	Inborn Errors of Purine Metabolism	501
36.1.1	Phosphoribosyl Pyrophosphate Synthetase Superactivity	501
36.1.2	Phosphoribosyl Pyrophosphate Synthetase Deficiency	502
36.1.3	Adenylosuccinase (Adenylosuccinate Lyase) Deficiency	502
36.1.4	AICA-Ribosiduria (ATIC Deficiency)	503
36.1.5	Muscle Adenosine Monophosphate Deaminase Deficiency	503
36.1.6	Adenylate Kinase 2 Deficiency	504
36.1.7	Adenosine Deaminase Deficiency	504
36.1.8	Adenosine Deaminase Superactivity	506
36.1.9	Purine Nucleoside Phosphorylase Deficiency	506
36.1.10	Xanthine Oxidase Deficiency	506
36.1.11	Hypoxanthine-guanine Phosphoribosyl-transferase Deficiency	507
36.1.12	Adenine Phosphoribosyltransferase Deficiency	509
36.1.13	Deoxyguanosine Kinase Deficiency	509
36.1.14	Thiopurine Methyltransferase Deficiency	509
36.1.15	Inosine Triphosphatase Deficiency	510
36.2	Inborn Errors of Pyrimidine Metabolism	512
36.2.1	UMP Synthase Deficiency (Hereditary Orotic Aciduria)	512
36.2.2	Miller Syndrome	512
36.2.3	Dihydropyrimidine Dehydrogenase Deficiency	513
36.2.4	Dihydropyrimidinase Deficiency	513
36.2.5	Ureidopropionase Deficiency	514
36.2.6	Pyrimidine 5�-Nucieotidase Deficiency	514
36.2.7	Cytosol ic 5 �-Nucleotidase Superactivity	514
36.2.8	Thymidine Phosphorylase Deficiency	514
36.2.9	Cytidine Deaminase Deficiency	514
36.2.10	Thymidine Kinase 2 Deficiency	515
	References	515
37	Disorders of Haem Biosynthesis Charles Marquez Louren�o, Chul Lee, Karl E. Anderson	519
37.1	X-Linked Sideroblastic Anaemia	521
37.2	The Porphyrias	521
37.2.1	Classification and Diagnosis	522
37.3	5-Aminolevulinic Acid Dehydratase Porphyria	523
37.4	Acute Intermittent Porphyria	524
37.5	Congenital Erythropoietic Porphyria (Gunther Disease)	525
37.6	Porphyria Cutanea Tarda	526
37.7	Hepatoerythropoietic Porphyria	528
37.8	Hereditary Coproporphyria and Variegate Porphyria	528
37.9	Erythropoietic Protoporphyria	529
	References	531
IX	DISORDERS OF METAL TRANSPORT
38	Disorders in the Transport of Copper, Iron, Magnesium, Manganese, Selenium and Zinc Marc Bierings, Peter Clayton, Roderick H.J. Houwen	535
38.1	Copper	537
38.1.1	Wilson Disease	537
38.1.2	Menkes Disease	539
38.1.3	Other Copper Storage Disorders	540
38.2	Iron	542
38.2.1	Systemic Iron Overload Syndromes (Haemochromatosis)	542
38.2.2	Neurodegeneration with Brain Iron Accumulation (NBIA)	543
38.2.3	Iron Deficiency Syndromes	544
38.3	Magnesium	544
38.3.1	Primary Hypomagnesaemia with Secondary Hypocalcaemia	545
38.3.2	Hypomagnesaemia with Hypercalciuria and Nephrocalcinosis	545
38.3.3	Isolated Dominant Hypomagnesaemia	546
38.3.4	Isolated Autosomal Recessive Hypomagnesaemia	546
38.4	Manganese	546
38.4.1	Isolated Autosomal Recessive Hypermanganesaemia	547
38.4.2	Disorders Affecting Calcium/Manganese Transporters	547
38.5	Selenium	547
38.6	Zinc	548
38.6.1	Acrodermatitis Enteropathica	548
38.6.2	Zinc Deficiency in Breastfed Babies	549
38.6.3	Hyperzincaemia with Hypercalprotectinaemia	549
38.6.4	Autosomal Dominant Hyperzincaemia Without Symptoms	549
	References	549
X	ORGANELLE-RELATED DISORDERS: LYSOSOMES, PEROXISOMES, AND GOLGI AND PRE-GOLGI SYSTEMS
39	Disorders of Sphingolipid Metabolism and Neuronal Ceroid-Lipofuscinoses Marie T. Vanicr, Catherine Caillaud	555
39.1	Gaucher Disease	557
39.1.1	Clinical Presentation	557
39.1.2	Metabolic Derangement	558
39.1.3	Genetics	558
39.1.4	Diagnostic Tests	558
39.1.5	Treatment and Prognosis	558
39.2	Acid Sphingomyelinase-deficient Niemann-Pick Disease (Type A, Type B and Intermediate Forms)	559
39.2.1	Clinical Presentation	559
39.2.2	Metabolic Derangement	560
39.2.3	Genetics	560
39.2.4	Diagnostic Tests	560
39.2.5	Treatment and Prognosis	560
39.3	GM1 Gangliosidosis	561
39.3.1	Clinical Presentation	561
39.3.2	Metabolic Derangement	561
39.3.3	Genetics	562
39.3.4	Diagnostic Tests	562
39.3.5	Treatment and Prognosis	562
39.4	GM2 Gangliosidoses	562
39.4.1	Clinical Presentation	562
39.4.2	Metabolic Derangement	562
39.4.3	Genetics	563
39.4.4	Diagnostic Tests	563
39.4.5	Treatment	563
39.5	Krabbe Disease	563
39.5.1	Clinical Presentation	563
39.5.2	Metabolic Derangement	564
39.5.3	Genetics	564
39.5.4	Diagnostic Tests	564
39.5.5	Treatment	565
39.6	Metachromatic Leukodystrophy	565
39.6.1	Clinical Presentation	565
39.6.2	Metabolic Derangement	565
39.6.3	Genetics	565
39.6.4	Diagnostic Tests	565
39.6.5	Treatment and Prognosis	566
39.7	Fabry Disease	566
39.7.1	Clinical Presentation	566
39.7.2	Metabolic Derangement	567
39.7.3	Genetics	567
39.7.4	Diagnostic Tests	567
39.7.5	Treatment and Prognosis	567
39.8	Farber Disease	568
39.8.1	Clinical Presentation	568
39.8.2	Metabolic Derangement and Genetics	568
39.8.3	Diagnostic Tests	568
39.8.4	Treatment and Prognosis	568
39.9	Prosaposin Deficiency	568
39.9.1	Clinical Presentation	568
39.9.2	Metabolic Derangement and Genetics	568
39.9.3	Diagnostic Tests	568
39.10	Niemann-Pick Disease Type C	569
39.10.1	Clinical Presentation	569
39.10.2	Metabolic Derangement	569
39.10.3	Genetics	570
39.10.4	Diagnostic Tests	570
39.10.5	Treatment and Prognosis	570
39.11	Disorders of Sphingolipid Synthesis	571
39.12	Neuronal Ceroid Lipofuscinoses	571
39.12.1	Clinical Presentation	571
39.12.2	Metabolic Derangement	572
39.12.3	Genetics	572
39.12.4	Diagnostic Tests	572
39.12.5	Treatment and Prognosis	573
	References	574
40	Mucopolysaccharidoses and Oligosaccharidoses J. Ed Wraith	579
40.1	Clinical Presentation	581
40.1.1	Mucopolysaccharidoses	581
40.1.2	Oligosaccharidoses	587
40.2	Metabolic Derangements	588
40.3	Genetics	588
40.4	Diagnostic Tests	588
40.5	Treatment and Prognosis	589
	References	589
41	Peroxisomal Disorders Bwee Tien Poll-The, Patrick Aubourg, Ronald J.A. Wanders	591
41.1	Clinical Presentation	593
41.1.1	The Neonatal Period	594
41.1.2	The First 6 Months of Life	595
41.1.3	Between 6 Months and 4 Years	595
41.1.4	Beyond 4 Years of Age	596
41.2	Metabolic Derangements	597
41.2.1	Defects of Peroxisome Biogenesis	599
41.2.2	Deficiencies of Single Peroxisomal Enzymes	599
41.3	Genetics	601
41.4	Diagnostic Tests	601
41.4.1	Diagnostic Group 1	601
41.4.2	Diagnostic Group 2	602
41.4.3	Diagnostic Group 3	602
41.4.4	Diagnostic Group 4	602
41.4.5	Histological Detection	602
41.4.6	Prenatal Diagnosis	603
41.5	Treatment and Prognosis	603
	References	603
42	Congenital Disorders of Glycosylation Jaak Jaeken	607
42.1	Introduction	608
42.2	Congenital Disorders of Protein N-Glycosylation	612
42.2.1	Phosphomannomutase-2 Deficiency (PMM2-CDG)	612
42.2.2	Phosphomannose-lsomerase Deficiency (MPI-CDG)	613
42.2.3	Glucosyltransferase I Deficiency (ALG6-CDG)	613
42.3	Congenital Disorders of Protein O-Glycosylation	614
42.3.1	Hereditary Multiple Exostoses (EXT1/EXT2-CDG)	614
42.3.2	Walker-Warburg Syndrome (POMT1/POMT2-CDG)	614
42.3.3	Muscle-eye-brain Disease (POMGNT1-CDG)	615
42.4	Defects in Lipid Glycosylation	615
42.4.1	GM3 Synthase Deficiency (ST3GAL5-CDG)	615
42.5	Defects in Multiple Glycosylation Pathways and in Other Pathways	615
42.5.1	Hereditary Inclusion Body Myopathy (GNE-CDG)	615
42.5.2	COG7 Deficiency	615
42.5.3	ATP6V0A2 (Autosomal Recessive Cutis Laxa Type 2)	615
	References	616
43	Cystinosis Michel Broyer, Patrick Niaudet	617
43.1	Infantile Cystinosis	618
43.1.1	Clinical Presentation	618
43.1.2	Metabolic Derangement	620
43.1.3	Genetics	620
43.1.4	Diagnostic Tests	621
43.1.5	Treatment	621
43.2	Intermediate Cystinosis	622
43.3	Ocular Cystinosis	622
	References	622
Appendix A	Medications Used in the Treatment of Inborn Errors JH Walter and JE Wraith	625
	Subject Index	633