Neurological disorders of purine and pyrimidine metabolism

Curr Top Med Chem. 2011;11(8):923-47. doi: 10.2174/156802611795347645.


Purines and pyrimidines, regarded for a long time only as building blocks for nucleic acid synthesis and intermediates in the transfer of metabolic energy, gained increasing attention since genetically determined aberrations in their metabolism were associated clinically with various degrees of mental retardation and/or unexpected and often devastating neurological dysfunction. In most instances the molecular mechanisms underlying neurological symptoms remain undefined. This suggests that nucleotides and nucleosides play fundamental but still unknown roles in the development and function of several organs, in particular central nervous system. Alterations of purine and pyrimidine metabolism affecting brain function are spread along both synthesis (PRPS, ADSL, ATIC, HPRT, UMPS, dGK, TK), and breakdown pathways (5NT, ADA, PNP, GCH, DPD, DHPA, TP, UP), sometimes also involving pyridine metabolism. Explanations for the pathogenesis of disorders may include both cellular and mitochondrial damage: e.g. deficiency of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase and deoxyguanosine kinase are associated to the most severe pathologies, the former due to an unexplained adverse effect exerted on the development and/or differentiation of dopaminergic neurons, the latter due to impairment of mitochondrial functions. This review gathers the presently known inborn errors of purine and pyrimidine metabolism that manifest neurological syndromes, reporting and commenting on the available hypothesis on the possible link between specific enzymatic alterations and brain damage. Such connection is often not obvious, and though investigated for many years, the molecular basis of most dysfunctions of central nervous system associated to purine and pyrimidine metabolism disorders are still unexplained.

Publication types

  • Review

MeSH terms

  • Adenosine Deaminase / deficiency
  • Adenosine Deaminase / metabolism
  • Adenylosuccinate Lyase / deficiency
  • Adenylosuccinate Lyase / metabolism
  • Agammaglobulinemia / metabolism
  • Animals
  • Autistic Disorder
  • Central Nervous System / metabolism
  • Central Nervous System / physiopathology
  • Female
  • Humans
  • Hypoxanthine Phosphoribosyltransferase / deficiency
  • Male
  • Mice
  • Nervous System Diseases / metabolism*
  • Nervous System Diseases / physiopathology
  • Neurons / metabolism*
  • Neurons / pathology
  • Phosphotransferases (Alcohol Group Acceptor) / deficiency
  • Purine-Nucleoside Phosphorylase / deficiency
  • Purine-Pyrimidine Metabolism, Inborn Errors / metabolism
  • Purines / metabolism*
  • Pyrimidines / metabolism*
  • Rats
  • Ribose-Phosphate Pyrophosphokinase / deficiency
  • Ribose-Phosphate Pyrophosphokinase / metabolism
  • Severe Combined Immunodeficiency / metabolism


  • Purines
  • Pyrimidines
  • Purine-Nucleoside Phosphorylase
  • Hypoxanthine Phosphoribosyltransferase
  • Phosphotransferases (Alcohol Group Acceptor)
  • deoxyguanosine kinase
  • Ribose-Phosphate Pyrophosphokinase
  • Adenosine Deaminase
  • Adenylosuccinate Lyase

Supplementary concepts

  • Adenylosuccinate lyase deficiency
  • Phosphoribosylpyrophosphate synthetase deficiency
  • Severe combined immunodeficiency due to adenosine deaminase deficiency