Journal of Inherited Metabolic Disease

, Volume 20, Issue 2, pp 171–178 | Cite as

The recognition of Lesch-Nyhan syndrome as an inborn error of purine metabolism

  • W. L. Nyhan


Lesch-Nyhan syndrome was first described over thirty years ago. The original patient was a 4-year-old boy with neurological abnormalities as well as haematuria. Crystals in his urine were identified and confirmed to be uric acid. The massive excretion of this purine led to metabolic studies using isotopically labelled uric acid to study turnover rates. Clues to the site of the enzyme defect resulted from studies with the immunosuppressive agent azathioprine, which normally causes uric acid concentrations to fall in blood and urine but was without effect in a Lesch-Nyhan patient. A deficiency of hypoxanthine phosphoribosyltransferase (HPRT) activity explained this observation in Lesch-Nyhan patients. Subsequent studies have indicated that the degree of HPRT deficiency appears to determine the severity of the disease. Molecular studies have shown that most families carry a unique mutation. Attempts are being made to correlate the type and site of a specific mutation with a particular phenotype.


Uric Acid Purine Immunosuppressive Agent Hypoxanthine Agent Azathioprine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bakay B, Nissinen E, Sweetman L, Francke U, Nyhan WL (1979) Utilization of purines by an HPRT variant in an intelligent, nonmutilative patient with features of the Lesch-Nyhan syndrome. Pediatr Res 13: 1365–1370.Google Scholar
  2. Catel VW, Schmidt J (1959) Uber familiar gichtische Diathese in Verbindung mit zerebralen und renalen Symptomen bei einem Kleinkind. Dtsch Med Wochenschr 84: 2145–2147.Google Scholar
  3. Davidson BL, Tarle SA, Antwerp MV, et al (1991) Identification of 17 independent mutations responsible for human hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Am J Hum Genet 48: 951–958.Google Scholar
  4. Ehrlich M, Wang RY-H (1981) 5-Methylcytosine in eukaryotic DNA. Science 212: 1350–1370.Google Scholar
  5. Jolly DJ, Okayama H, Berg P, Esty AC, Filpula D, Bohlen GG, et al (1983) Isolation and characterization of a full length, expressible cDNA for human hypoxanthine guanine phosphoribosyl transferase. Proc Natl Acad Sci USA 80 477–481.Google Scholar
  6. Lesch M, Nyhan WL (1964) A familial disorder of uric acid metabolism and central nervous system function. Am J Med 36: 561–570.Google Scholar
  7. Nieto LH, Nyhan WL, Page T, et al (1985) Sindrome de Lesch-Nyhan: neuva variante con actividad de hipoxantina-guanina fosforribosil transferasa (HPRT) superior a la de la enfermedad clasica y deteccion del rasgo heterocigoto en los hematies de la portadora. Medicina Clinica (Barc) 84: 68–71.Google Scholar
  8. Nyhan WL, Pesek J, Sweetman L, Carpenter DG, Carter CH (1967) Genetics of an X-linked disorder of uric acid metabolism and cerebral function. Pediatr Res 1: 5–13.Google Scholar
  9. Nyhan WL, Sweetman, Carpenter DG, Carter CH, Hoefnagel D (1968) Effects of azathioprine in a disorder of uric acid metabolism and cerebral function. J Pediatr 72: 111–118.Google Scholar
  10. Page T, Nyhan WL (1989) The spectrum of HPRT deficiency: an update. In Mikanagi K, Nishioka K, Kelley WN, eds. Purine and Pyrimidine Metabolism in Man — VI, Part A. New York: Plenum 1989, 129–133.Google Scholar
  11. 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.Google Scholar
  12. Sege-Peterson K, Chambers J, Page T, Jones OW, Nyhan WL (1992a) Characterization of mutations in phenotypic variants in hypoxanthine phosphoribosyltransferase deficiency. Hum Mol Genet 1: 427–432.Google Scholar
  13. Sege-Peterson K, Nyhan WL, Page T (1992b) Lesch-Nyhan disease and HPRT deficiency. In Rosenberg RN, Prusiner SB, DiMauro S, Barchi RL, Kunkel LM, eds. The Molecular and Genetic Basis of Neurological Disease. Stoneham, MA: Butterworth-Heineman, 241–259.Google Scholar
  14. Shear CS, Nyhan WL, Kirman BH, Stern J (1971) Self-mutilative behavior as a feature of the De Lange syndrome. J Pediatr 78: 506–509.Google Scholar
  15. Sweetman L, Nyhan WL (1974) Incorporation of glycine-13C into uric acid. In Mamer OA, Mitchell WK, Scriver CR, eds. Application of Gas Chromatography —Mass Spectrometry to the Investigation of Human Disease, Proceedings of a Workshop. Montreal: McGill University, Montreal Children's Hospital Research Institute, 179–180.Google Scholar
  16. Yang TP, Patel PI, Stout JT, Jackson LG, Hildebrand BM, Caskey CT (1984) Molecular evidence for new mutations in the HPRT locus in Lesch-Nyhan patients. Nature 310: 412–414.Google Scholar

Copyright information

© Kluwer Academic Publishers 1997

Authors and Affiliations

  • W. L. Nyhan
    • 1
  1. 1.Division of Biochemical Genetics, Department of PediatricsUniversity of California, San DiegoLa JollaUSA

Personalised recommendations