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

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.