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Disorders of Purine and Pyrimidine Metabolism

  • Chapter
Inborn Metabolic Diseases

Abstract

Inborn errors exist of the biosynthetic, catabolic, and salvage pathways of purine and pyrimidine metabolism, which are depicted in Fig. 35.1 and 35.3, respectively. The major presenting signs and laboratory findings in these inborn errors are listed in Table 35.1.

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References

  1. Sperling O, Boer P, Persky-Brosh S et al (1972) Altered kinetic property of erythrocyte phosphoribosylpyrophosphate synthetase in excessive purine production. Rev Eur Etud Clin Biol 17:703–706

    PubMed  CAS  Google Scholar 

  2. Becker MA, Puig JG, Mateos FA et al (1988) Inherited superactivity of phosphoribosylpyrophosphate synthetase: association of uric acid overproduction and sensorineural deafness. Am J Med 85:383–390

    Article  PubMed  CAS  Google Scholar 

  3. Becker MA, Smith PR, Taylor W et al (1995) The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity. J Clin Invest 96:2133–2141

    PubMed  CAS  Google Scholar 

  4. Kranen S, Keough D, Gordon RB, Emmerson BT (1985) Xanthine-containing calculi during allopurinol therapy. J Urol 133:658–659

    PubMed  CAS  Google Scholar 

  5. Jaeken J, Van den Berghe G (1984) An infantile autistic syndrome characterised by the presence of succinylpurines in body fluids. Lancet 2:1058–1061

    PubMed  CAS  Google Scholar 

  6. Jaeken J, Wadman SK, Duran M et al (1988) Adenylosuccinase deficiency: an inborn error of purine nucleotide synthesis. Eur J Pediatr 148:126–131

    Article  PubMed  CAS  Google Scholar 

  7. Valik D, Miner PT, Jones JD (1997) First U.S. case of adenylosuccinate lyase deficiency with severe hypotonia. Pediatr Neurol 16:252–255

    Article  PubMed  CAS  Google Scholar 

  8. Van den Bergh FAJTM, Bosschaart AN, Hageman G et al (1998) Adenylosuccinase deficiency with neonatal onset severe epileptic seizures and sudden death. Neuropediatrics 29:51–53

    PubMed  Google Scholar 

  9. Van den Berghe G, Vincent MF, Jaeken J (1997) Inborn errors of the purine nucleotide cycle: adenylosuccinase deficiency. J Inherit Metab Dis 20:193–202

    Article  PubMed  Google Scholar 

  10. De Volder AG, Jaeken J, Van den Berghe G et al (1988) Regional brain glucose utilization in adenylosuccinase-deficient patients measured by positron emission tomography. Pediatr Res 24:238–242

    PubMed  Google Scholar 

  11. Stone RL, Aimi J, Barshop BA et al (1992) A mutation in adenylosuccinate lyase associated with mental retardation and autistic features. Nat Genet 1:59–63

    Article  PubMed  CAS  Google Scholar 

  12. Marie S, Cuppens H, Heuterspreute M et al (1999) Mutation analysis in adenylosuccinate lyase deficiency. Eight novel mutations in the re-evaluated full ADSL coding sequence. Hum Mutat 13:197–202

    Article  PubMed  CAS  Google Scholar 

  13. Kmoch S, Hartmannova H, Stiburkova B et al (2000) Human adenylosuccinate lyase (ADSL), cloning and characterization of full-length cDNA and its isoform, gene structure and molecular basis for ADSL deficiency in six patients. Hum Mol Genet 9:1501–1513

    Article  PubMed  CAS  Google Scholar 

  14. Marie S, Race V, Nassogne MC et al (2002) Mutation of a nuclear respiratory factor 2 binding site in the 5′untranslated region of the ADSL gene in three patients with adenylosuccinate lyase deficiency. Am J Hum Genet 71:14–21

    Article  PubMed  CAS  Google Scholar 

  15. Laikind PK, Seegmiller JE, Gruber HE (1986) Detection of 5′-phosphoribosyl-4-(N-succinylcarboxamide)-5-aminoimidazole in urine by use of the Bratton-Marshall reaction: identification of patients deficient in adenylosuccinate lyase activity. Anal Biochem 156:81–90

    Article  PubMed  CAS  Google Scholar 

  16. Sebesta I, Shobowale M, Krijt J, Simmonds HA (1995) Screening tests for adenylosuccinase deficiency. Screening 4:117–124

    CAS  Google Scholar 

  17. Marie S, Flipsen JWAM, Duran M et al (2000) Prenatal diagnosis in adenylosuccinate lyase deficiency. Prenat Diagn 20:33–36

    Article  PubMed  CAS  Google Scholar 

  18. Salerno C, D’Eufemia P, Finocchiaro R et al (1999) Effect of D-ribose on purine synthesis and neurological symptoms in a patient with adenylosuccinase deficiency. Biochim Biophys Acta 1453:135–140

    PubMed  CAS  Google Scholar 

  19. Salerno C, Crifo C, Curatolo P, Ciardo F (2000) Effect of uridine administration to a patient with adenylosuccinate lyase deficiency. Adv Exp Biol Med 486:75–78

    CAS  Google Scholar 

  20. Marie S, Heron B, Bitoun P et al (2004) AICA-Ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC. Am J Hum Genet 74:1276–1281

    Article  PubMed  CAS  Google Scholar 

  21. Fishbein WN, Armbrustmacher VW, Griffin JL (1978) Myoadenylate deaminase deficiency: a new disease of muscle. Science 200:545–548

    Article  PubMed  CAS  Google Scholar 

  22. Shumate JB, Katnik R, Ruiz M et al (1979) Myoadenylate deaminase deficiency. Muscle Nerve 2:213–216

    Article  PubMed  CAS  Google Scholar 

  23. Mercelis R, Martin JJ, de Barsy T, Van den Berghe G (1987) Myoadenylate deaminase deficiency: absence of correlation with exercise intolerance in 452 muscle biopsies. J Neurol 234:385–389

    Article  PubMed  CAS  Google Scholar 

  24. Van den Berghe G, Bontemps F, Vincent MF, Van den Bergh F (1992) The purine nucleotide cycle and its molecular defects. Progr Neurobiol 39:547–561

    Article  PubMed  Google Scholar 

  25. Hers HG, Van den Berghe G (1979) Enzyme defect in primary gout. Lancet 1:585–586

    Article  PubMed  CAS  Google Scholar 

  26. Ogasawara N, Goto H, Yamada Y et al (1987) Deficiency of AMP deaminase in erythrocytes. Hum Genet 75:15–18

    PubMed  CAS  Google Scholar 

  27. Morisaki T, Gross M, Morisaki H et al (1992) Molecular basis of AMP deaminase deficiency in skeletal muscle. Proc Natl Acad Sci USA 89:6457–6461

    Article  PubMed  CAS  Google Scholar 

  28. Loh E, Rebbeck TR, Mahoney PD et al (1999) Common variant in AMPD1 gene predicts improved outcome in patients with heart failure. Circulation 23:1422–1425

    Google Scholar 

  29. Sabina RL, Fishbein WN, Pezeshkpour G et al (1992) Molecular analysis of the myoadenylate deaminase deficiencies. Neurology 42:170–179

    PubMed  CAS  Google Scholar 

  30. Zöllner N, Reiter S, Gross M et al (1986) Myoadenylate deaminase deficiency: successful symptomatic therapy by high dose oral administration of ribose. Klin Wochenschr 64:1281–1290

    Article  PubMed  Google Scholar 

  31. Giblett ER, Anderson JE, Cohen F et al (1972) Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet 2:1067–1069

    Article  PubMed  CAS  Google Scholar 

  32. Hershfield MS, Arredondo-Vega FX, Santisteban I (1997) Clinical expression, genetics and therapy of adenosine deaminase (ADA) deficiency. J Inherit Metab Dis 20:179–185

    Article  PubMed  CAS  Google Scholar 

  33. Bollinger ME, Arredondo-Vega FX, Santisteban I et al (1996) Brief report: hepatic dysfunction as a complication of adenosine deaminase deficiency. N Engl J Med 334:1367–1371

    Article  PubMed  Google Scholar 

  34. Thompson LF, Vaughn JG, Laurent AB et al (2003) Mechanisms of apoptosis in developing thymocytes as revealed by adenosine deaminase-deficient fetal thymic organ cultures. Biochem Pharmacol 66:1595–1599

    Article  PubMed  CAS  Google Scholar 

  35. Hirschhorn R, Yang DR, Puck JM et al (1996). Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency. Nat Genet 13:290–295

    Article  PubMed  CAS  Google Scholar 

  36. Markert ML, Hershfield MS, Schiff RI, Buckley RH (1987) Adenosine deaminase and purine nucleoside phosphorylase deficiencies: evaluation of therapeutic interventions in eight patients. J Clin Immunol 7:389–399

    Article  PubMed  CAS  Google Scholar 

  37. Hershfield MS (1995) PEG-ADA replacement therapy for adenosine deaminase deficiency: an update after 8.5 years. Clin Immunol Immunopathol 76:S228–S232

    Article  PubMed  CAS  Google Scholar 

  38. Blaese RM, Culver KW, Miller AD et al (1995) T-lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 270:475–480

    PubMed  CAS  Google Scholar 

  39. Muul LM, Tuschong LM, Soenen SL et al (2003) Persistence and expression of the adenosine deaminase gene for 12 years and immune reaction to gene transfer components: long-term results of the first clinical gene therapy trial. Blood 101:2563–2569

    Article  PubMed  CAS  Google Scholar 

  40. Aiuti A, Slavin S, Aker M et al (2002) Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning Science 296:2410–2413

    Article  PubMed  CAS  Google Scholar 

  41. Cavazzana-Calvo M, Lagresle C, Hacein-Bey-Abina S, Fisher A (2005) Gene therapy for severe combined immunodeficiency. Annu Rev Med 56:585–602

    Article  PubMed  CAS  Google Scholar 

  42. Valentine WN, Paglia DE, Tartaglia AP, Gilsanz F (1977) Hereditary hemolytic anemia with increased red cell adenosine deaminase (45-to 70-fold) and decreased adenosine triphosphate. Science 195:783–785

    Article  PubMed  CAS  Google Scholar 

  43. Giblett ER, Ammann AJ, Wara DW et al (1975) Nucleoside phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity. Lancet 1:1010–1013

    Article  PubMed  CAS  Google Scholar 

  44. Markert ML (1991) Purine nucleoside phosphorylase deficiency. Immunodefic Rev 3:45–81

    PubMed  CAS  Google Scholar 

  45. Markert ML, Finkel BD, McLaughlin TM et al (1997) Mutations in purine nucleoside phosphorylase deficiency. Hum Mutat 9:118–121

    Article  PubMed  CAS  Google Scholar 

  46. Carpenter PA, Ziegler JB, Vowels MR (1996) Late diagnosis and correction of purine nucleoside phosphorylase deficiency with allogeneic bone marrow transplantation. Bone Marrow Transplant 17:121–124

    PubMed  CAS  Google Scholar 

  47. Dent CE, Philpot GR (1954) Xanthinuria, an inborn error (or deviation) of metabolism. Lancet 1:182–185

    Article  Google Scholar 

  48. Wadman SK, Duran M, Beemer FA et al (1983) Absence of hepatic molybdenum cofactor: an inborn error of metabolism leading to a combined deficiency of sulphite oxidase and xanthine dehydrogenase. J Inherit Metab Dis 6[Suppl 1]:78–83

    Article  PubMed  Google Scholar 

  49. Shih VE, Abroms IF, Johnson JL et al (1977) Sulfite oxidase deficiency. Biochemical and clinical investigations of a hereditary metabolic disorder in sulfur metabolism. N Engl J Med 297:1022–1028

    Article  PubMed  CAS  Google Scholar 

  50. Ichida K, Amaya Y, Kamatani N et al (1997) Identification of two mutations in human xanthine dehydrogenase gene responsible for classical type I xanthinuria. J Clin Invest 99:2391–2397

    PubMed  CAS  Google Scholar 

  51. Yamamoto T, Moriwaki Y, Takahashi S et al (2003) Identification of a new point mutation in the human molybdenum cofactor sulferase gene that is responsible for xanthinuria type II. Metabolism 52:1501–1504

    Article  PubMed  CAS  Google Scholar 

  52. Reiss J, Johnson JL (2003) Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH. Hum Mutat 21:569–576

    Article  PubMed  CAS  Google Scholar 

  53. Lesch M, Nyhan WL (1964) A familial disorder of uric acid metabolism and central nervous system dysfuntion. Am J Med 36:561–570

    Article  PubMed  CAS  Google Scholar 

  54. Kelley WN, Greene ML, Rosenbloom FM et al (1969) Hypoxanthineguanine phosphoribosyltransferase deficiency in gout. Ann Intern Med 70:155–206

    PubMed  CAS  Google Scholar 

  55. Ernst M, Zametkin AJ, Matochik JA et al (1996) Presynaptic dopaminergic deficits in Lesch-Nyhan disease. N Engl J Med 334: 1568–1572

    Article  PubMed  CAS  Google Scholar 

  56. Jinnah HA, De Gregorio L, Harris JC et al (2000) The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res 463:309–326

    Article  PubMed  CAS  Google Scholar 

  57. Alford RL, Redman JB, O’Brien WE, Caskey CT (1995) Lesch-Nyhan syndrome: carrier and prenatal diagnosis. Prenat Diagn 15:329–338

    PubMed  CAS  Google Scholar 

  58. Kaufman JM, Greene ML, Seegmiller JE (1968) Urine uric acid to creatinine ratio-a screening test for inherited disorders of purine metabolism. Phosphoribosyltransferase (PRT) deficiency in Xlinked cerebral palsy and in a variant of gout. J Pediatr 73:583–592

    Article  PubMed  CAS  Google Scholar 

  59. Seegmiller JE, Rosenbloom FM, Kelley WN (1967) Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science 155:1682–1684

    Article  PubMed  CAS  Google Scholar 

  60. Page T, Bakay B, Nissinen E, Nyhan WL (1981) Hypoxanthine-guanine phosphoribosyltransferase variants: correlation of clinical phenotype with enzyme activity. J Inherit Metab Dis 4:203–206

    Article  PubMed  CAS  Google Scholar 

  61. Watts RWE, McKeran RO, Brown E et al (1974) Clinical and biochemical studies on treatment of Lesch-Nyhan syndrome. Arch Dis Child 49:693–702

    Article  PubMed  CAS  Google Scholar 

  62. Nyhan WL, Parkman R, Page T et al (1986) Bone marrow transplantation in Lesch-Nyhan disease. Adv Exp Med Biol 195A:167–170

    Google Scholar 

  63. Taira T, Kobayashi T, Hori T (2003) Disappearance of self-mutilating behavior in a patient with Lesch-Nyhan syndrome after bilateral chronic stimulation of the globus pallidus internus. Case report. J Neurosurg 98:414–416

    Article  PubMed  Google Scholar 

  64. Cartier P, Hamet M (1974) Une nouvelle maladie métabolique: le déficit complet en adénine-phosphoribosyltransférase avec lithiase de 2,8-dihydroxyadénine. C R Acad Sci Paris 279 [série D]:883–886

    CAS  Google Scholar 

  65. Van Acker KJ, Simmonds HA, Potter C, Cameron JS (1977) Complete deficiency of adenine phosphoribosyltransferase. Report of a family. N Engl J Med 297:127–132

    Article  PubMed  Google Scholar 

  66. Greenwood MC, Dillon MJ, Simmonds HA et al (1982) Renal failure due to 2,8-dihydroxyadenine urolithiasis. Eur J Pediatr 138:346–349

    Article  PubMed  CAS  Google Scholar 

  67. Hidaka Y, Tarlé SA, Fujimori S et al (1988) Human adenine phosphoribosyltransferase deficiency. Demonstration of a single mutant allele common to the Japanese. J Clin Invest 81:945–950

    PubMed  CAS  Google Scholar 

  68. Sahota A, Chen J, Stambrook PJ, Tischfield JA (1991) Mutational basis of adenine phosphoribosyltransferase deficiency. Adv Exp Med Biol 309B:73–76

    PubMed  CAS  Google Scholar 

  69. Eller P, Rosenkranz AR, Mark W et al (2004) Four consecutive renal transplantations in a patient with adenine phosphoribosyltransferase deficiency. Clin Nephrol 61:217–221

    PubMed  CAS  Google Scholar 

  70. Mandel H, Szargel R, Labay V et al (2001) The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nat Genet 29:337–341

    Article  PubMed  CAS  Google Scholar 

  71. Huguley CM, Bain JA, Rivers SL, Scoggins RB (1959) Refractory megaloblastic anemia associated with excretion of orotic acid. Blood 14:615–634

    PubMed  Google Scholar 

  72. Smith LH (1973) Pyrimidine metabolism in man. N Engl J Med 288:764–771

    Article  PubMed  CAS  Google Scholar 

  73. Perry ME, Jones ME (1989) Orotic aciduria fibroblasts express a labile form of UMP synthase. J Biol Chem 264:15522–15528

    PubMed  CAS  Google Scholar 

  74. Suchi M, Mizuno H, Kawai Y et al (1997) Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families. Am J Hum Genet 60:525–539

    PubMed  CAS  Google Scholar 

  75. Berger R, Stoker-de Vries SA, Wadman SK et al (1984) Dihydropyrimidine dehydrogenase deficiency leading to thymine-uraciluria. An inborn error of pyrimidine metabolism. Clin Chim Acta 141:227–234

    Article  PubMed  CAS  Google Scholar 

  76. Van Gennip AH, Abeling NGGM, Vreken P, van Kuilenburg ABP (1997) Inborn errors of pyrimidine degradation: clinical, biochemical and molecular aspects. J Inherit Metab Dis 20:203–213

    Article  PubMed  Google Scholar 

  77. Tuchman M, Stoeckeler JS, Kiang DT et al (1985) Familial pyrimidinemia and pyrimidinuria associated with severe fluorouracil toxicity. N Engl J Med 313:245–249

    Article  PubMed  CAS  Google Scholar 

  78. Van Kuilenburg ABP (2004) Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer 40:939–950

    Article  PubMed  CAS  Google Scholar 

  79. Van Kuilenburg AB, Vreken P, Abeling NG et al (1999) Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum Genet 104:1–9

    Article  PubMed  Google Scholar 

  80. Van Gennip AH, Driedijk PC, Elzinga A, Abeling NGGM (1992) Screening for defects of dihydropyrimidine degradation by analysis of amino acids in urine before and after acid hydrolysis. J Inherit Metab Dis 15:413–415

    Article  PubMed  Google Scholar 

  81. Duran M, Rovers P, de Bree PK et al (1991) Dihydropyrimidinuria: a new inborn error of pyrimidine metabolism. J Inherit Metab Dis 14:367–370

    Article  PubMed  CAS  Google Scholar 

  82. Van Kuilenburg AB, Meinsma R, Zonnenberg BA et al (2003) Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity. Clin Cancer Res 9:4363–4367

    PubMed  Google Scholar 

  83. Hamajima N, Kouwaki M, Vreken P et al (1998) Dihydropyrimidinase deficiency: structural organization, chromosomal localization, and mutation analysis of the human dihydropyrimidinase gene. Am J Hum Genet 63:717–726

    Article  PubMed  CAS  Google Scholar 

  84. Putman CW, Rotteveel JJ, Wevers RA et al (1997) Dihydropyrimidinase deficiency: a progressive neurological disorder? Neuropediatrics 28:106–110

    PubMed  CAS  Google Scholar 

  85. Assmann B, Göhlich-Ratmann G, Bräutigam C et al (1998) Presumptive ureidopropionase deficiency as a new defect in pyrimidine catabolism found with in vitro H-NMR spectroscopy. J Inherit Metab Dis 21[Suppl 2]:1

    Google Scholar 

  86. Van Kuilenburg AB, Meinsma R, Beke E et al (2004) Beta-ureidopropionase deficiency: an inborn error or pyrimidine degradation associated with neurological abnormalities. Hum Mol Genet 13:2793–2801

    Article  PubMed  Google Scholar 

  87. Valentine WN, Fink K, Paglia DE et al (1974) Hereditary hemolytic anemia with human erythrocyte pyrimidine 5′-nucleotidase deficiency. J Clin Invest 54:866–879

    Article  PubMed  CAS  Google Scholar 

  88. Page T, Yu A, Fontanesi J, Nyhan WL (1997) Developmental disorder associated with increased cellular nucleotidase activity. Proc Natl Acad Sci USA 94:11601–11606

    Article  PubMed  CAS  Google Scholar 

  89. Nishino I, Spinazzola A, Papadimitriou A et al (2000) MNGIE: an autosomal recessive disorder due to thymidine phosphorylase mutations. Ann Neurol 47:792–800

    Article  PubMed  CAS  Google Scholar 

  90. Saada A, Shaag A, Mandel H et al (2001) Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat Genet 29:342–344

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Metabolic Research Group, Christian de Duve Institute of Cellular Pathology, University of Louvain Medical School, Avenue Hippocrate 75-39, 1200, Brussels, Belgium

    Georges van den Berghe

  2. Laboratory for Inherited Metabolic Diseases, Saint-Luc University Hospital, University of Louvain Medical School, Avenue Hippocrate 10, 1200, Brussels, Belgium

    M.-Françoise Vincent & Sandrine Marie

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  1. Georges van den Berghe
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  2. M.-Françoise Vincent
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  3. Sandrine Marie
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Editors and Affiliations

  1. Department of Pediatrics, University Hospital Groningen, Burgemeester Weertslaan 31, 8162 DP, Epe, The Netherlands

    John Fernandes

  2. Unité de Métabolisme, Département de Pédiatrie, Hôpital Necker Enfants Malades, 149 Rue de Sèvres, 75043, Paris Cedex 15, France

    Jean-Marie Saudubray

  3. Metabolic Research Group, Christian de Duve Institute of Cellular Pathology, University of Louvain Medical School, Avenue Hippocrate 75-39, 1200, Brussels, Belgium

    Georges van den Berghe

  4. Willink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Hospital Road, Pendlebury, Manchester, M27 4HA, UK

    John H. Walter

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van den Berghe, G., Vincent, MF., Marie, S. (2006). Disorders of Purine and Pyrimidine Metabolism. In: Fernandes, J., Saudubray, JM., van den Berghe, G., Walter, J.H. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg . https://doi.org/10.1007/978-3-540-28785-8_35

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