Purine metabolism in female heterozygotes for hypoxanthine-guanine phosphoribosyltransferase deficiency

Background Female carriers of the X-linked recessive disorder hypoxanthine- guanine phosphoribosyltransferase (HPRT) deficiency show somatic cell mosai cism, and this may cause an increased synthesis of purines. We have examine d whether urinary oxypurines could be useful for carrier diagnosis; Methods Carrier testing was performed in 35 women belonging to 16 unrelated Spanish families with at least one subject affected by the Lesch-Nyhan syn drome (11 families, 14 patients) or the Kelley-Seegmiller syndrome (five fa milies, six patients) by means of HPRT and adenine phosphoribosyltransferas e activities in hair follicles and/or molecular studies. Plasma and 24-h ur inary concentrations of hypoxanthine, xanthine and uric acid were measured while subjects were on a purine-restricted diet. Results Mean plasma urate concentrations and 24-h urinary hypoxanthine, xan thine and uric acid excretion rates were significantly higher in 22 heteroz ygotes than in 13 non-carriers (P < 0.02). Daily urinary oxypurine excretio n rates were also significantly higher in heterozygotes than in 12 normal w omen (P=0.0011). Cumulative 5-day radioactivity excretion after [8-C-14]-ad enine infusion was markedly increased in 10 carrier women compared with fiv e normal women (P = 0.0369). The sensitivity of 24-h urinary hypoxanthine a nd xanthine excretion rates was 86% and 77%, respectively, and the specific ity 100% for both tests. Conclusion Female heterozygotes for HPRT deficiency show an enhanced purine nucleotide degradation and purine overproduction. An elevated hypoxanthine and/or xanthine excretion rate differentiated most heterozygotes for HPRT deficiency from non-carrier women and thus could be useful for carrier diag nosis.