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BACKGROUND Lesch-Nyhan (LN) syndrome is associated with deficient hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity, but the connection between the aberrant purine metabolism and the neurological symptoms remains largely unknown. The aim of this study was to determine adenosine transporter subtypes affected by HPRT deficiency and by the associated hypoxanthine excess. MATERIALS AND METHODS Nucleoside transporter types (depending on their sodium dependence and 10 microm nitrobenzylthioinosine, NBTI, sensitivity) involved in adenosine transport were compared between peripheral blood lymphocytes (PBL) obtained from nine LN patients, PBL(LN) (2-21 years) and from nine controls, PBL(C) (2-23 years) under basal conditions and after 25 microm hypoxanthine incubation. RESULTS We found four types of adenosine transporters in PBL: equilibrative and concentrative transporters that are either sensitive (ENT1 or cs) or insensitive (ENT2 or ci) to NBTI. Adenosine ENT1 uptake was the predominant transporter in both PBL(C) (55%) and PBL(LN) (46%). Under basal conditions no significant differences were found in adenosine transport between PBL(C) and PBL(LN). Incubation of PBL with 25 microm hypoxanthine markedly decreased total adenosine transport in both cell types. Hypoxanthine affected equilibrative transport (mainly ENT2 type) in PBL(LN) and PBL(C). Only in PBL(C) was concentrative transport affected by hypoxanthine. Expressions of human (h) ENT1 and hENT2 mRNA were not significantly modified by hypoxanthine incubation in PBL(C). CONCLUSIONS This study contributes to further knowledge of the defective adenosine transport found in PBL(LN). Increased hypoxanthine levels, similar to those reported in HPRT deficient patients, reduced adenosine uptake by 32% in PBL(LN) as compared to normal transport.

Background Female carriers of the X-linked recessive disorder hypoxanthine‐guanine phosphoribosyltransferase (HPRT) deficiency show somatic cell mosaicism, and this may cause an increased synthesis of purines. We have examined 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 syndrome (11 families, 14 patients) or the Kelley‐Seegmiller syndrome (five families, six patients) by means of HPRT and adenine phosphoribosyltransferase activities in hair follicles and/or molecular studies. Plasma and 24-h urinary 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, xanthine and uric acid excretion rates were significantly higher in 22 heterozygotes than in 13 non-carriers (P < 0·02). Daily urinary oxypurine excretion rates were also significantly higher in heterozygotes than in 12 normal women (P o 0·0011). Cumulative 5-day radioactivity excretion after [8- 14 C]-adenine infusion was markedly increased in 10 carrier women compared with five normal women (P o 0·0369). The sensitivity of 24-h urinary hypoxanthine and xanthine excretion rates was 86% and 77%, respectively, and the specificity 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 diagnosis.