Inborn Metabolic Diseases (eBook)

Preface 5
Contents 7
List of Contributors 19
I Diagnosis and Treatment: General Principles 24
1 A Clinical Approach to Inherited Metabolic Diseases 26
2 Newborn Screening for Inborn Errors of Metabolism 72
3 Diagnostic Procedures: Function Tests and Postmortem Protocol 81
4 Emergency Treatments 93
5 Treatment: Present Status and New Trends 103
II Disorders of Carbohydrate Metabolism 121
6 The Glycogen Storage Diseases and Related Disorders 123
7 Disorders of Galactose Metabolism 143
8 Disorders of the Pentose Phosphate Pathway 153
Disorders of Fructose Metabolism 157
10 Persistent Hyperinsulinemic Hypoglycemia 165
11 Disorders of Glucose Transport 173
III Disorders of Mitochondrial Energy Metabolism 181
12 Disorders of Pyruvate Metabolism and the Tricarboxylic Acid Cycle 183
13 Disorders of Mitochondrial Fatty Acid Oxidation and Related Metabolic Pathways 197
14 Disorders of Ketogenesis and Ketolysis 213
15 Defects of the Respiratory Chain 219
16 Creatine Deficiency Syndromes 233
IV Disorders of Amino Acid Metabolism and Transport 241
17 Hyperphenylalaninaemia 243
18 Disorders of Tyrosine Metabolism 255
19 Branched- Chain Organic Acidurias/ Acidemias 267
20 Disorders of the Urea Cycle and Related Enzymes 285
21 Disorders of Sulfur Amino Acid Metabolism 295
22 Disorders of Ornithine Metabolism 305
23 Cerebral Organic Acid Disorders and Other Disorders of Lysine Catabolism 315
24 Nonketotic Hyperglycinemia (Glycine Encephalopathy) 329
25 Disorders of Proline and Serine Metabolism 337
26 Transport Defects of Amino Acids at the Cell Membrane: Cystinuria, Lysinuric Protein Intolerance and Hartnup Disorder 343
V Vitamin-Responsive Disorders 352
27 Biotin-Responsive Disorders 353
28 Disorders of Cobalamin and Folate Transport and Metabolism 363
VI Neurotransmitter and Small Peptide Disorders 379
29 Disorders of Neurotransmission 381
30 Disorders in the Metabolism of Glutathione and Imidazole Dipeptides 395
31 Trimethylaminuria and Dimethyl glycine Dehydrogenase Deficiency 403
VII Disorders of Lipid and Bile Acid Metabolism 409
32 Dyslipidemias 411
33 Disorders of Cholesterol Synthesis 433
34 Disorders of Bile Acid Synthesis 443
VIII Disorders of Nucleic Acid and Heme Metabolism 454
35 Disorders of Purine and Pyrimidine Metabolism 455
36 Disorders of Heme Biosynthesis 473
37 Disorders in the Transport of Copper, Zinc and Magnesium 489
X Organelle-Related Disorders: Lysosomes, Peroxisomes, and Golgi and Pre- Golgi Systems 500
38 Disorders of Sphingolipid Metabolism 501
39 Mucopolysaccharidoses and Oligosaccharidoses 517
40 Peroxisomal Disorders 531
41 Congenital Disorders of Glycosylation 545
42 Cystinosis 553
43 Primary Hyperoxalurias 561
Subject Index 569

35.1 Inborn Errors of Purine (P. 435)

Metabolism

Inborn errors of purine metabolism comprise errors of: 4 purine nucleotide synthesis: phosphoribosylpyrophosphate (PRPP) synthetase superactivity, adenylosuccinase (ADSL) deficiency, AICA-ribosiduria caused by ATIC deficiency,

4 purine catabolism: the deficiencies of muscle AMP deaminase (AMP-DA, also termed myoadenylate deaminase), adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP) and xanthine oxidase, 4 purine salvage: the deficiencies of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and adenine phosphoribosyltransferase (APRT).

The deficiency of deoxyguanosine kinase causes mitochondrial DNA depletion (7 also Chap. 15). With the exception of muscle AMP-DA deficiency, all these enzyme defects are very rare.

35.1.1 Phosphoribosyl Pyrophosphate Synthetase Superactivity

Clinical Presentation

The disorder is mostly manifested by the appearance, in young adult males, of gouty arthritis and/or uric acid lithiasis, potentially leading to renal insufficiency [1, 2]. Uricemia can be very high, reaching 10–15 mg/dl (0.60– 0.90 mmol/l) [normal adult values: 2.9–5.5 mg/dl (0.17– 0.32 mmol/l)]. The urinary excretion of uric acid is also increased, reaching up to 2400 mg (14 mmol)/24 h, or 2.5 mmol/mmol creatinine [normal adult values: 500– 800 mg (3-4.7 mmol)/24 h, or 02–0.3 mmol/mmol creatinine].

A few patients have been reported in which clinical signs of uric acid overproduction already appeared in infancy and were accompanied by neurologic abnormalities, mainly sensorineural deafness, particularly for high tones, but also hypotonia, locomotor delay, ataxia and autistic features [2].

Metabolic Derangement

The enzyme forms phosphoribosyl pyrophosphate (PRPP) from ribose-5-phosphate and ATP (. Fig. 35.1). PRPP is the first intermediate of the de novo synthesis of purine nucleotides (not shown in full detail in . Fig. 35.1), which leads to the formation of inosine monosphosphate (IMP), from which the other purine compounds are derived.

PRPP synthetase is highly regulated. Various genetic regulatory and catalytic defects [1, 2] lead to superactivity, resulting in increased generation of PRPP. Because PRPP amidotransferase, the rate-limiting enzyme of the de novo pathway, is physiologically not saturated by PRPP, the synthesis of purine nucleotides increases, and hence the production of uric acid.

PRPP synthetase superactivity is one of the few known examples of an hereditary anomaly of an enzyme which enhances its activity. The mechanism of the neurological symptoms is unresolved.

Genetics

The various forms of PRPP synthetase superactivity are inherited as X-linked traits. In the families in which the anomaly is associated with sensorineural deafness, heterozygous females have also been found with gout and/or hearing impairment [2]. Studies of the gene in six families revealed a different single base change in each of them [3].