35 Disorders of Purine and Pyrimidine Metabolism Georges van den Berghe, M.- Françoise Vincent, Sandrine Marie 35.1 Inborn Errors of Purine Metabolism – 435 35.1.1 Phosphoribosyl Pyrophosphate Synthetase Superactivity – 435 35.1.2 Adenylosuccinase Deficiency – 436 35.1.3 AICA-Ribosiduria – 437 35.1.4 Muscle AMP Deaminase Deficiency – 437 35.1.5 Adenosine Deaminase Deficiency – 438 35.1.6 Adenosine Deaminase Superactivity – 439 35.1.7 Purine Nucleoside Phosphorylase Deficiency – 440 35.1.8 Xanthine Oxidase Deficiency – 440 35.1.9 Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency – 441 35.1.10 Adenine Phosphoribosyltransferase Deficiency – 442 35.1.11 Deoxyguanosine Kinase Deficiency – 442 35.2 Inborn Errors of Pyrimidine Metabolism – 445 35.2.1 UMP Synthase Deficiency (Hereditary Orotic Aciduria) – 445 35.2.2 Dihydropyrimidine Dehydrogenase Deficiency – 445 35.2.3 Dihydropyrimidinase Deficiency – 446 35.2.4 Ureidopropionase Deficiency – 446 35.2.5 Pyrimidine 5’-Nucleotidase Deficiency – 446 35.2.6 Cytosolic 5’-Nucleotidase Superactivity – 447 35.2.7 Thymidine Phosphorylase Deficiency – 447 35.2.8 Thymidine Kinase Deficiency – 447 References – 447 434 Chapter 35 · Disorders of Purine and Pyrimidine Metabolism Purine Metabolism Purine nucleotides are essential cellular constituents 4 The catabolic pathway starts from GMP, IMP and which intervene in energy transfer, metabolic regula- AMP, and produces uric acid, a poorly soluble tion, and synthesis of DNA and RNA. Purine metabo- compound, which tends to crystallize once its lism can be divided into three pathways: plasma concentration surpasses 6.5–7 mg/dl (0.38– 4 The biosynthetic pathway, often termed de novo, 0.47 mmol/l). starts with the formation of phosphoribosyl pyro- 4 The salvage pathway utilizes the purine bases, gua- phosphate (PRPP) and leads to the synthesis of nine, hypoxanthine and adenine, which are pro- inosine monophosphate (IMP). From IMP, adeno- vided by food intake or the catabolic pathway, and sine monophosphate (AMP) and guanosine mono- reconverts them into, respectively, GMP, IMP and phosphate (GMP) are formed. Further metabolism AMP. Salvage of the purine nucleosides, adenosine (not illustrated) leads to their di- and triphosphates, and guanosine, and their deoxy counterparts, cata- to their corresponding deoxyribonucleotides, and lyzed by kinases, also occurs. to RNA and DNA. VIII . Fig. 35.1. Pathways of purine metabolism. AICAR, aminoimi- 3, AICAR transformylase; 4, IMP cyclohydrolase (3 and 4 form dazolecarboxamide ribotide; AMP, adenosine monophosphate; ATIC); 5, adenylosuccinate synthetase; 6, AMP deaminase; FAICAR, formylaminoimidazolecarboxamide ribotide; GMP, gua- 7, 5c-nucleotidase(s), 8, adenosine deaminase; 9, purine nucleo- nosine monophosphate; IMP, inosine monophosphate; P, phos- side phosphorylase; 10, hypoxanthine-guanine phosphoribosyl- phate; PRPP, phosphoribosyl pyrophosphate, S-Ado, succinylade- transferase; 11, adenine phosphoribosyltransferase; 12, adeno- nosine; SAICAR, succinylaminoimidazolecarboxamide ribotide; sine kinase; 13, guanosine kinase; 14, xanthine oxidase (dehydro- S-AMP, adenylosuccinate, XMP, xanthosine monophosphate. genase). Enzyme defects are indicated by solid bars across the 1, PRPP synthetase; 2, adenylosuccinase (adenylosuccinate lyase); arrows 435 35 35.1 · Inborn Errors of Purine Metabolism the first intermediate of the de novo synthesis of purine Inborn errors exist of the biosynthetic, catabolic, and nucleotides (not shown in full detail in . Fig. 35.1), which salvage pathways of purine and pyrimidine metabo- leads to the formation of inosine monosphosphate (IMP), lism, which are depicted in . Fig. 35.1 and 35.3, respec- from which the other purine compounds are derived. PRPP tively. The major presenting signs and laboratory find- synthetase is highly regulated. Various genetic regulatory ings in these inborn errors are listed in . Table 35.1. and catalytic defects [1, 2] lead to superactivity, resulting in increased generation of PRPP. Because PRPP amidotrans- ferase, the rate-limiting enzyme of the de novo pathway, is physiologically not saturated by PRPP, the synthesis of 35.1 Inborn Errors of Purine purine nucleotides increases, and hence the production of Metabolism uric acid. PRPP synthetase superactivity is one of the few known examples of an hereditary anomaly of an enzyme Inborn errors of purine metabolism comprise errors of: which enhances its activity. The mechanism of the neuro- 4 purine nucleotide synthesis: phosphoribosylpyrophos- logical symptoms is unresolved. phate (PRPP) synthetase superactivity, adenylosuc- cinase (ADSL) deficiency, AICA-ribosiduria caused by Genetics ATIC deficiency; The various forms of PRPP synthetase superactivity are 4 purine catabolism: the deficiencies of muscle AMP inherited as X-linked traits. In the families in which the deaminase (AMP-DA, also termed myoadenylate de- anomaly is associated with sensorineural deafness, hetero- aminase), adenosine deaminase (ADA), purine nuc- zygous females have also been found with gout and/or leoside phosphorylase (PNP) and xanthine oxidase; hearing impairment [2]. Studies of the gene in six families 4 purine salvage: the deficiencies of hypoxanthine-gua- revealed a different single base change in each of them [3]. nine phosphoribosyltransferase (HGPRT) and adenine phosphoribosyltransferase (APRT). The deficiency of Diagnostic Tests deoxyguanosine kinase causes mitochondrial DNA Diagnosis requires extensive kinetic studies of the enzyme, depletion (7 also Chap. 15). which are performed on erythrocytes and cultured fibro- blasts in a few laboratories in the world. The disorder should With the exception of muscle AMP-DA deficiency, all these be differentiated from partial HGPRT deficiency, which enzyme defects are very rare. gives similar clinical signs. Treatment and Prognosis 35.1.1 Phosphoribosyl Pyrophosphate Patients should be treated with allopurinol, which inhibits Synthetase Superactivity xanthine oxidase, the last enzyme of purine catabolism (. Fig. 35.1). This results in a decrease of the production of Clinical Presentation uric acid and in its replacement by hypoxanthine, which is The disorder is mostly manifested by the appearance, about 10-fold more soluble, and xanthine, which is slightly in young adult males, of gouty arthritis and/or uric acid more soluble than uric acid. Initial dosage of allopurinol is lithiasis, potentially leading to renal insufficiency [1, 2]. 10–20 mg/kg per day in children and 2–10 mg/kg per day Uricemia can be very high, reaching 10–15 mg/dl (0.60– in adults. It should be adjusted to the minimum required to 0.90 mmol/l) [normal adult values: 2.9–5.5 mg/dl (0.17– maintain normal uric acid levels in plasma, and reduced 0.32 mmol/l)]. The urinary excretion of uric acid is also in subjects with renal insufficiency. In rare patients with a increased, reaching up to 2400 mg (14 mmol)/24 h, or considerable increase in de novo synthesis, xanthine calculi 2.5 mmol/mmol creatinine [normal adult values: 500– can be formed during allopurinol therapy [4]. Consequently, 800 mg (3-4.7 mmol)/24 h, or 02–0.3 mmol/mmol creati- additional measures to prevent cristallization are recom- nine]. mended. These include a low purine diet (free of organ A few patients have been reported in which clinical meats, fishes such as anchovy, herring, mackerel, salmon, signs of uric acid overproduction already appeared in in- sardines and tuna, dried beans and peas), high fluid intake fancy and were accompanied by neurologic abnormalities, and, since uric acid and xanthine are more soluble at alka- mainly sensorineural deafness, particularly for high tones, line than at acid pH, administration of sodium bicarbonate, but also hypotonia, locomotor delay, ataxia and autistic potassium citrate or citrate mixtures to bring urinary pH to features [2]. 6.0-6.5. Adequate control of the uricemia prevents gouty arthritis and urate nephropathy, but does not correct the Metabolic Derangement neurological symptoms. The enzyme forms phosphoribosyl pyrophosphate (PRPP) from ribose-5-phosphate and ATP (. Fig. 35.1). PRPP is 436 Chapter 35 · Disorders of Purine and Pyrimidine Metabolism . Table 35.1. Main presenting clinical signs and laboratory data in inborn errors of purine and pyrimidine metabolism Clinical signs Diagnostic possibilities Clinical signs Diagnostic possibilities Arthritis PRPP synthetase superactivity Muscle cramps Muscle AMP deaminase deficiency HGPRT deficiency (partial) Muscle wasting Adenylosuccinase deficiency Ataxia PNP deficiency Psychomotor delay PRPP synthetase superactivity HGPRT deficiency (complete) Adenylosuccinase deficiency Cytosolic 5’-nucleotidase superactivity AICA-ribosiduria (ATIC deficiency) Autistic features PRPP synthetase superactivity Combined xanthine and sulfite oxidase Adenylosuccinase deficiency deficiency Dihydropyrimidine dehydrogenase HGPRT deficiency (complete) deficiency UMP synthase deficiency Cytosolic 5’-nucleotidase superactivity Dihydropyrimidine dehydrogenase Congenital blindness AICA-ribosiduria (ATIC deficiency) deficiency Convulsions Adenylosuccinase deficiency Dihydropyrimidinase deficiency Combined xanthine and sulfite Ureidopropionase deficiency oxidase deficiency Cytosolic 5’-nucleotidase superactivity Dihydropyrimidine dehydrogenase Recurrent infections ADA deficiency deficiency PNP deficiency Dihydropyrimidinase deficiency Cytosolic 5’-nucleotidase superactivity Cytosolic 5’-nucleotidase superactivity Renal insufficiency PRPP synthetase superactivity Deafness