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Inborn errors of pyrimidine metabolism: clinical update and therapy

  • ICIEM Symposium 2013
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Inborn errors involving enzymes essential for pyrimidine nucleotide metabolism have provided new insights into their fundamental physiological roles as vital constituents of nucleic acids as well as substrates of lipid and carbohydrate metabolism and in oxidative phosphorylation. Genetic aberrations of pyrimidine pathways lead to diverse clinical manifestations including neurological, immunological, haematological, renal impairments, adverse reactions to analogue therapy and association with malignancies. Maintenance of cellular nucleotides depends on the three aspects of metabolism of pyrimidines: de novo synthesis, catabolism and recycling of these metabolites. Of the ten recognised disorders of pyrimidine metabolism treatment is currently restricted to only two disorders: hereditary orotic aciduria (oral uridine therapy) and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE; allogeneic hematopoetic stem cell transplant and enzyme replacement). The ubiquitous role that pyrimidine metabolism plays in human life highlights the importance of improving diagnostic evaluation in suggestive clinical settings, which will contribute to the elucidation of new defects, future development of novel drugs and therapeutic strategies. Limited awareness of the expanding phenotypic spectrum, with relatively recent descriptions of newer disorders, compounded by considerable genetic heterogeneity has often contributed to the delays in the diagnosis of this group of disorders. The lack of an easily recognisable, easily measurable end product, akin to uric acid in purine metabolism, has contributed to the under-recognition of these disorders.This review describes the currently known inborn errors of pyrimidine metabolism, their variable phenotypic presentations, established diagnostic methodology and recognised treatment options.

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Compliance with ethics guidelines

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5).

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Authors and Affiliations

  1. Metabolic Unit, Princess Margaret Hospital, Roberts Road, Subiaco, Perth, WA, 6008, Australia

    Shanti Balasubramaniam

  2. School of Paediatrics and Child Health, The University of Western Australia, Perth, WA, 6009, Australia

    Shanti Balasubramaniam

  3. School of Pharmacy and the Mater Research Institute, The University of Queensland, Brisbane, QLD 4102, Australia

    John A. Duley

  4. Western Sydney Genetics Program, Children’s Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW, 2145, Australia

    John Christodoulou

  5. Disciplines of Paediatrics and Child Health and Genetic Medicine, University of Sydney, Sydney, NSW, 2006, Australia

    John Christodoulou

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  1. Shanti Balasubramaniam
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  2. John A. Duley
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  3. John Christodoulou
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Correspondence to John Christodoulou.

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Communicated by: Ron A. Wevers

Presented at the 12th International Congress of Inborn Errors of Metabolism, Barcelona, Spain, September 3-6, 2013

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Balasubramaniam, S., Duley, J.A. & Christodoulou, J. Inborn errors of pyrimidine metabolism: clinical update and therapy. J Inherit Metab Dis 37, 687–698 (2014). https://doi.org/10.1007/s10545-014-9742-3

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  • DOI: https://doi.org/10.1007/s10545-014-9742-3

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