Skip to main content
SpringerLink
Log in

Inborn errors of purine and pyrimidine metabolism

  • Metabolic Dissertation
  • Published:
Journal of Inherited Metabolic Disease

Summary

Genetic disorders of purine and pyrimidine (PP) metabolism are under-reported and infrequently mentioned in the general literature, as well as in reviews dedicated to other inborn errors of metabolism. Owing to limited awareness, relatively recent recognition, as well as considerable phenotypic variation, these disorders may often be misdiagnosed or remain undiagnosed. Disorders that arise as a result of dysfunction in PP metabolism represent some of the most challenging diagnostic problems in medicine. In addition to their low prevalence rates, they also present with extremely variable signs and symptoms. They may affect any system in a variety of manners, and often mimic other, more recognizable disorders. The diagnostic problem is compounded by the fact that some biochemically affected patients are symptom-free. Rapidly evolving laboratory techniques such as high-performance liquid chromatography coupled to tandem mass spectrometry are now well established as the preferred method for detection for these defects, but currently the most important step in diagnosis consists of suspecting the disorder. Diagnosis is vital because genetic counselling can be provided and, in some cases, specific treatment can be offered that may slow or even reverse clinical symptoms. If undiagnosed, these disorders can be devastating to patients and their families, resulting in early death or institutionalization for the rest of patient’s life. This article describes the current state of knowledge about inborn errors of purine and pyrimidine metabolism, focusing on the varying clinical presentations, the laboratory findings and discusses indications for selective screening for these disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ATP:

adenosine triphosphate

CMHI:

Children’s Memorial Health Institute

DNA:

deoxyribonucleic acid

FU:

fluorouracil

GC-MS:

gas chromatography–mass spectrometry

HPLC:

high-performance liquid chromatography

IEM:

inborn error of metabolism

MS/MS:

mass spectrometry

PCR:

polymerase chain reaction

PP:

purines/pyrimidines

RNA:

ribonucleic acid

TLC:

thin-layer chromatography

References

  • Assmann B, Gohlich G, Baethmann M, etal (2006) Clinical findings and a therapeutic trial in the first patient with beta-ureidopropionase deficiency. Neuropediatrics 37: 20–25. doi:10.1055/s-2006-923933.

    Article  PubMed  CAS  Google Scholar 

  • Bakkeren JA, De Abreu RA, Sengers RC, Gabreels FJ, Maas JM, Renier WO (1984) Elevated urine, blood and cerebrospinal fluid levels of uracil and thymine in a child with dihydropirymidine dehydrogenase deficiency. Clin Chim Acta 140: 247–256. doi:10.1016/0009-8981(84)90206-7.

    Article  PubMed  CAS  Google Scholar 

  • Berg M, Tymoczko JL, Stryer L (2002) Biosynthesis of nucleotides. In: Berg M, Tymoczko JL, Stryer L, eds. Biochemistry. New York: W.H. Freeman and Company, 602–626.

    Google Scholar 

  • Bosch TM, Bakker R, Schellens JH, Cats A, Smits PH, Beijnen JH (2007) Rapid detection of the DPYD IVS14+1G>A mutation for screening patients to prevent fluorouracil-related toxicity. Mol Diagn Ther 11: 105–108.

    PubMed  CAS  Google Scholar 

  • Cameron JS, Moro F, Simmonds HA (1993) Gout, uric acid and purine metabolism in paediatric nephrology. Pediatr Nephrol 7: 105–118. doi:10.1007/BF00861588.

    Article  PubMed  CAS  Google Scholar 

  • Chace DH, DiPierna JC, Naylor EW (1999) Laboratory integration and utilisation of tandem mass spectrometry in neonatal screening: a model for clinical mass spectrometry in the next millennium. Acta Pediatr 88(12 Supplement 432): 45–47. doi:10.1080/080352599750029367.

    Article  CAS  Google Scholar 

  • Cif L, Biolsi B, Gavarini S, etal (2007) Antero-ventral internal pallidum stimulation improves behavioral disorders in Lesch-Nyhan disease. Mov Disord 22: 2126–2129. doi:10.1002/mds.21723.

    Article  PubMed  Google Scholar 

  • Clarke J (2006). Laboratory investigations and Treatment. In: Clarke J, ed. A Clinical Guide to Inherited Metabolic Diseases. Port Chester, NY: Cambridge University Press, 241–321.

    Google Scholar 

  • Cory JG (2005) Purine and pyrimidine nucleotide metabolism. In: Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations. New York: Willey-Liss, 825–859.

    Google Scholar 

  • Dabrowski E, Smathers SA, Ralstrom CS, Nigro MA, Leleszi JP (2005) Botulinum toxin as a novel treatment for self-mutilation in Lesch–Nyhan syndrome. Dev Med Child Neurol 47: 636–639. doi:10.1017/S0012162205001246.

    Article  PubMed  Google Scholar 

  • Dawson PA, Gordon RB, Keuough DT, Emmerson BT (2005) Normal coding region in a male with gout due to HPRT deficiency. Mol Genet Metab 85: 78–80. doi:10.1016/j.ymgme.2005.01.005.

    Article  PubMed  CAS  Google Scholar 

  • Dent CE, Philpot GR (1954) Xanthinuria: An inborn error (or deviation) of metabolism. Lancet 266: 182–185. doi:10.1016/S0140-6736(54)91257-X.

    Article  PubMed  CAS  Google Scholar 

  • Duran M, Rovers P, de Bree PK, etal (1990) Dihydropyrimidinuria. Lancet 336: 817–818. doi:10.1016/0140-6736(90)93288-Z.

    Article  PubMed  CAS  Google Scholar 

  • Duran M, Dorland L, Wadman SK, Berger R (1994) Group tests for selective screening of inborn errors of metabolism. Eur J Pediatr 153(Supplement 1): S27–S32. doi:10.1007/BF02138774.

    Article  PubMed  CAS  Google Scholar 

  • Duran M, Dorland L, Meuleman EE, Allers P, Berger R (1997) Inherited defects of purine and pyrimidine metabolism: laboratory methods for diagnosis. J Inherit Metab Dis 20: 227–236. doi:10.1023/A:1005360907238.

    Article  PubMed  CAS  Google Scholar 

  • Enns GM, Barkovich AJ, Van Kuilenburg AB, etal (2004) Head imaging abnormalities in dihydropyrimidine dehydrogenase deficiency. J Inherit Metab Dis 27: 513–522. doi:10.1023/B:BOLI.0000037350.24142.d5.

    Article  PubMed  CAS  Google Scholar 

  • Fernandez-Salguero PM, Sapone A, Wei X, etal (1997) Lack of correlation between phenotype and genotype for the polymorphically expressed dihydropyrimidine dehydrogenase in a family of Pakistan origin. Pharmacogenetics 7: 161–163 doi:10.1097/00008571-199704000-00012.

    Article  PubMed  CAS  Google Scholar 

  • Garcia MG, Torres RJ, Prior C, Puig JG (2008) Normal HPRT coding region in complete and partial HPRT deficiency. Mol Genet Metab 94: 167–172. doi:10.1016/j.ymgme.2008.01.006.

    Article  PubMed  CAS  Google Scholar 

  • Gross M (1997) Clinical heterogeneity and molecular mechanisms in inborn muscle AMP deaminase deficiency. J Inherit Metab Dis 20: 186–192. doi:10.1023/A:1005352605421.

    Article  PubMed  CAS  Google Scholar 

  • Gutierrez C, Pellene A, Micheli F (2008) Botulinum toxin: treatment of self-mutilation in patients with Lesch–Nyhan syndrome. Clin Neuropharmacol 31: 180–183. doi:10.1097/WNF.0b013e31814a62cc.

    Article  PubMed  CAS  Google Scholar 

  • Henderson MJ, Jones S, Walker P, Duley J, Simmonds HA (1995) Heterogeneity of symptomatology in two male siblings with thymine uraciluria. J Inherit Metab Dis 18: 85–86. doi:10.1007/BF00711383.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Ito T, van Kuilenburg AB, Bootsma AH, etal (2000) Rapid screening of high-risk patients for disorders of purine and pyrimidine metabolism using HPLC-electrospray tandem mass spectrometry of liquid urine or urine-soaked filter paper strips. Clin Chem 46: 445–452.

    PubMed  CAS  Google Scholar 

  • Jaeken J, Van den Berghe G (1984) An infantile autistic syndrome characterized by the presence of succinylpurines in body fluids. Lancet 2(8411): 1058–1061.

    PubMed  CAS  Google Scholar 

  • Jinnah HA, De Gregorio L, Harris JC (2000) The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and review of 196 previously reported cases. Mutat Res 463: 309–326. doi:10.1016/S1383-5742(00)00052-1.

    Article  PubMed  CAS  Google Scholar 

  • Jinnah HA, Harris JC, Nyhan WL, O’Neill JP (2004) The spectrum of mutations causing HPRT deficiency: an update. Nucleosides Nucleotides Nucleic Acids 23: 1153–1160. doi:10.1081/NCN-200027400.

    Article  PubMed  CAS  Google Scholar 

  • Jurecka A, Zikanova M, Tylki-Szymanska A, etal (2008a) Clinical, biochemical and molecular findings in seven Polish patients with adenylosuccinate lyase deficiency. Mol Genet Metab 94: 435–442. doi:10.1016/j.ymgme.2008.04.013.

    Article  PubMed  CAS  Google Scholar 

  • Jurecka A, Tylki-Szymanska A, Zikanova M, Krijt J, Kmoch S (2008b) d-Ribose treatment in 4 Polish patients with adenylosuccinate lyase deficiency: absence of positive effect. J Inherit Metab Dis [2008 Jul 12 Epub ahead of print]. doi:10.1007/s10545-008-0904-z.

  • Jurecka A, Popowska E, Tylki-Szymanska A, etal (2008c) Hypoxanthine-guanine phosphoribosyltransferase deficiency – the spectrum of Polish mutations. J Inherit Metab Dis [2008 Nov 21 Epub ahead of print]. doi:10.1007/s10545-008-1013-8.

    Google Scholar 

  • Loffler M, Fairbanks LD, Zameitat E, Marinaki AM, Simmonds HA (2005) Pyrimidine pathways in health and disease. Trends Mol Medicine 11: 430–437. doi:10.1016/j.molmed.2005.07.003.

    Article  CAS  Google Scholar 

  • Marie S, Heron B, Bitoun P, Timmerman T, Van den Bergh G, Vincent MF (2004) AICA-Ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC. Am J Hum Genet 74: 1276–1281. doi:10.1086/421475.

    Article  PubMed  CAS  Google Scholar 

  • Moolenaar SH, Gohlich-Ratmann G, Engelke UF, etal (2001) Beta-ureidoprionase deficiency: a novel inborn error of metabolism discovered using NMR spectroscopy on urine. Magn Reson Med 46: 1014–1017. doi:10.1002/mrm.1289.

    Article  PubMed  CAS  Google Scholar 

  • Nyhan WL (2005) Disorders of purine and pyrimidine metabolism. Mol Genet Metab 86: 25–33. doi:10.1016/j.ymgme.2005.07.027.

    Article  PubMed  CAS  Google Scholar 

  • Ochs HD, Yount JE, Giblett ER, Chen SH, Scott CR, Wedgwood RJ (1973) Adenosine-deaminase deficiency and severe combined immunodeficiency syndrome. Lancet 301( 7816) 1393–1394. doi:10.1016/S0140-6736(73)91725-X.

    Article  Google Scholar 

  • Peters GJ, Beijnen JH (1994) Purine and pyrimidine metabolism: still a black box? Pharm World Sci 16: 37–38. doi:10.1007/BF01880654.

    Article  PubMed  CAS  Google Scholar 

  • Peters GJ, Van Kuileburg AB, Abreu RA (2004) Purine and pyrimidine metabolism: new challenges. Nucleosides Nucleotides Nucleic Acids 23: 1077–1079. doi:10.1081/NCN-200027355.

    Article  PubMed  CAS  Google Scholar 

  • Rijksen G, Kuis W, Wadman SK, etal (1987) A new case of purine nucleoside phosphorylase deficiency: enzymologic, clinical, and immunologic characteristics. Pediatr Res 21: 137–141. doi:10.1203/00006450-198702000-00006.

    Article  PubMed  CAS  Google Scholar 

  • Sanderson J, Ansari A, Marinaki T, Duley J (2004) Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem 41(Pt 4): 294–302. doi:10.1258/0004563041201455.

    Article  PubMed  CAS  Google Scholar 

  • Scriver CR, Beaudet AL, Sly WS, Valle D, eds (2001) Purines and pyrimidines. In: The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York, McGraw-Hill, 2512–2702.

    Google Scholar 

  • Simmonds HA (1994) When and how does one search for inborn errors of purine and pyrimidine metabolism? Pharm World Sci 16(2): 139–148. doi:10.1007/BF01880664.

    Article  PubMed  CAS  Google Scholar 

  • Simmonds HA, van Gennip AH (2003) Purine and pyrimidine disorders. In: Blau N, Duran M, Blaskovics M, Gibron KM, eds. Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases. Berlin, Heidelberg: Springer-Verlag, 445–465.

    Google Scholar 

  • Simmonds HA, Duley JA, Davies PM (1991) Analysis of purines and pyrimidines in blood, urine and other physiological fluids. In: Hommes F, ed. Techniques in Diagnostic Human Biochemical Genetics: A Laboratory Manual. New York: Wiley-Liss, 397–425.

    Google Scholar 

  • Simmonds HA, Duley JA, Fairbanks LD, McBride MB (1997) When to investigate for purine and pyrimidine disorders. Introduction and review of clinical and laboratory indications. J Inherit Metab Dis 20: 214–226. doi:10.1023/A:1005308923168.

    Article  PubMed  CAS  Google Scholar 

  • Simoni RE, Gomes LN, Scalco FB, Oliveira CP, Aquino Neto FR, de Oliveira ML (2007) Uric acid changes in urine and plasma: an effective tool in screening for purine inborn errors of metabolism and other pathological conditions. J Inherit Metab Dis 30: 295–309. doi:10.1007/s10545-007-0455-8.

    Article  PubMed  CAS  Google Scholar 

  • Sokolic R, Kesserwan C, Candotti F (2008) Recent advances in gene therapy for severe congenital immunodeficiency diseases. Curr Opin Hematol 15: 375–380. doi:10.1097/MOH.0b013e328302c807.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Valik D, Jones J (1997) Hereditary disorders of purine and pyrimidine metabolism: identification of their biochemical phenotypes in the clinical laboratory. Mayo Clin Proc 72: 719–725.

    Article  PubMed  CAS  Google Scholar 

  • Van Gennip AH (1999) Defects in metabolism of purines and pyrimidines. Ned Tijdsch Klin Chem 24: 171–175.

    Google Scholar 

  • Van Gennip AH, Busch S, Elzinga L, etal (1993) Application of simple chromatographic methods for the diagnosis of defects in pyrimidine degradation. Clin Chem 39: 380–385.

    PubMed  Google Scholar 

  • Van Gennip AH, Abeling NG, Vreken P, van Kuilenburg AB (1997) Inborn errors of pyrimidine degradation: clinical, biochemical and molecular aspects. J Inherit Metab Dis 20: 203–213. doi:10.1023/A:1005356806329.

    Article  PubMed  Google Scholar 

  • Van Gennip AH, Van Kuilenburg ABP (2000) Defects of pyrimidine degradation: clinical, molecular and diagnostic aspects. Adv Exp Med Biol 486: 233–241. doi:10.1007/0-306-46843-3_46.

    Article  PubMed  Google Scholar 

  • Van Gennip AH, Bierau J, Nyhan WL (2006) Inborn errors of purine and pyrimidine metabolism. In: Blau N, Hoffman G, Leonard J, eds. Physician’s Guide to the Treatment and Follow-up of Metabolic Diseases. Berlin, Heidelberg: Springer-Verlag, 245–255.

    Chapter  Google Scholar 

  • Van Kuilenburg AB, Vreken P, Abeling NG, etal (1999) Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency. Hum Genet 104: 1–9. doi:10.1007/PL00008711.

    Article  PubMed  Google Scholar 

  • Van Kuilenburg AB, Meinsma R, Zoetekouw L, Van Gennip AH (2002) High prevalence of the IVS14+1G>A mutation in the dihydropirymidine dehydrogenase gene of patients with severe 5-fluorouracil-associated toxicity. Pharmacogenetics 12: 555–558. doi:10.1097/00008571-200210000-00007.

    Article  PubMed  Google Scholar 

  • Van Kuilenburg AB, Meinsma R, Van Gennip AH (2004a) Pyrimidine degradation defects and severe 5-fluorouracil toxicity. Nucleosides Nucleotides Nucleic Acids 23: 1371–1375. doi:10.1081/NCN-200027624.

    Article  PubMed  CAS  Google Scholar 

  • Van Kuilenburg AB, Meinsma R, Beke E, etal (2004b) Beta-ureidopropionase deficiency: an inborn error of pyrimidine degradation with neurological abnormalities. Hum Mol Genet 13: 2793–2801. doi:10.1093/hmg/ddh303.

    Article  PubMed  Google Scholar 

  • Wadman SK, de Bree PK, van Gennip AH, etal (1977) Urinary purines in a patients with severely defective T cell immunity and purine nucleoside phosphorylase deficiency. Adv Exp Med Biol 76A: 471–476.

    PubMed  CAS  Google Scholar 

  • Wadman SK, Duran M, Beemer FA, etal (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(Supplement 1): 78–83. doi:10.1007/BF01811328.

    Article  PubMed  Google Scholar 

  • Wadman SK, Beemer FA, de Bree PK, etal (1984) New defects of pyrimidine metabolism. Adv Exp Med Biol 165: 109–114.

    PubMed  Google Scholar 

  • Yaplito-Lee J, Pitt J, Mejier J, Zoetekouw L, Meinsma R, van Kuilenburg AB (2008) β-Uredidopropionase deficiency presenting with congenital anomalies of the urogenital and colorectal systems. Mol Genet Metab 93: 190–194. doi:10.1016/j.ymgme.2007.09.009.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

My thesis ‘Prevalence of inborn errors of purine and pyrimidine metabolism in Poland’ could not have been written without the encouragement and help of my mentor Professor Ewa Pronicka to whom I am very grateful. I would also like to thank Professor Anna Tylki-Szymanska for her support and inspiration. I am indebted to all the colleagues from both the Polish and international laboratories who helped me perform my research. Particularly, I would like to thank Dr Wanda Gradowska (Department of Laboratory Diagnostics CMHI), Dr Ryszard Smolenski and Dr Ewa Slominska (Department of Biochemistry, Medical University of Gdansk), Dr Anne Simmonds, Dr Anthony Marinaki and Dr Lynette Fairbanks (Purine Research Unit, St Thomas’s Hospital, London, UK), Dr Stan Kmoch, Dr Jakub Krijt, Dr Marie Zikanova and Dr Blanka Stiburkova (Institute for Inherited Metabolic Disorders, Prague, Czech Republic) and Dr Louis Elsas and Dr Carla Cuthbert (Department of Genetics, University of Miami, Florida, USA) for sharing their vast knowledge about inborn errors of purine and pyrimidine metabolism, high-performance liquid chromatography and mass spectrometry, as well as providing excellent technical support.

I wish to thank Dr Anne Simmonds, Dr Anthony Marinaki and Professor Anna Tylki-Szymanska for critical reading of the manuscript.

Collaboration with other laboratories was made possible by the EU Programme ‘PERFECT’, a Postgraduate School of Molecular Medicine (Warsaw, Poland) scholarship and a grant supported by the Polish Scientific Research Commitee no. PB 1121/P01/2007/32.

Author information

Authors and Affiliations

  1. Department of Metabolic Diseases, Endocrinology and Diabetology, The Children’s Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland

    A. Jurecka

Authors
  1. A. Jurecka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Jurecka.

Additional information

Communicating editor: Georg Hoffmann

Competing interests: None declared

References to electronic databases: Adenosine deaminase deficiency: OMIM 102700. Adenosine deaminase: EC 3.5.4.4. Adenylosuccinate lyase deficiency: OMIM 103050. Adenylosuccinate lyase: EC 4.3.2.2. Dihydropirymidine dehydrogenase deficiency: OMIM 222748. Dihydropirymidinase: EC 3.5.2.2. Dihydropirymidine dehydrogenase deficiency: 274270. Dihydropirymidine dehydrogenase: EC 1.3.1.2. Hypoxanthine-guanine phosphoribosyltransferase: OMIM 308000. Hypoxanthine-guanine phosphoribosyltransferase: EC 2.4.2.8. Xanthine dehydrogenase deficiency: OMIM 278300. Xanthine dehydrogenase: EC 1.2.1.37.

This article is based on a PhD thesis accepted by the Children’s Memorial Health Institute, Warsaw, Poland. Promotor: Professor Dr. E. Pronicka.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jurecka, A. Inborn errors of purine and pyrimidine metabolism. J Inherit Metab Dis 32, 247–263 (2009). https://doi.org/10.1007/s10545-009-1094-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-009-1094-z

Keywords

Search

Navigation