Cytosolic 5 '-nucleotidase hyperactivity in erythrocytes of Lesch-Nyhan syndrome patients

Lesch-Nyhan syndrome is a metabolic-neurological syndrome caused by the X-l inked deficiency of the purine salvage enzyme hypoxanthine-guanine phosphor ibosyltransferase (HGPRT). Metabolic consequences of HGPRT deficiency have been clarified, but the connection with the neurological manifestations is still unknown. Much effort has been directed to finding other alterations i n purine nucleotides in different cells of Lesch-Nyhan patients. A peculiar finding was the measure of appreciable amount of Z-nucleotides in red cell s. We found significantly higher IMP-GMP-specific 5'-nucleotidase activity in the erythrocytes of seven patients with Lesch-Nyhan syndrome than in hea lthy controls. The same alteration was found in one individual with partial HGPRT deficiency displaying a severe neurological syndrome, and in two sli ghtly hyperuricemic patients with a psychomotor delay. Since ZMP was a good substrate of 5'-nucleotidase producing Z-riboside, we incubated murine and human cultured neuronal cells with this nucleoside and found that it is to xic for our models, promoting apoptosis. This finding suggests an involveme nt of the toxicity of the Z-riboside in the pathogenesis of neurological di sorders in Lesch-Nyhan syndrome and possibly in other pediatric neurologica l syndromes of uncertain origin. NeuroReport 11:1827-1831 (C) 2000 Lippinco tt Williams & Wilkins.