Physiopathology of neurological signs of hypoxanthine-guanine phosphoribosyltransferase deficiency

OBJECTIVE: Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is characterized by an increase in renal uric acid excretion, usually with hyperuricemia and may be associated with more or less important neurological symptoms. Based on a series of 20 patients from 16 Spanish families we propose that HPRT deficiency could be clinically classified in four different groups. In the more severe form (classic Lesch-Nyhan syndrome) HPRT deficiency is characterized by choreoathetosis, spasticity, mental retardation and compulsive self-mutilation behavior. The pathophysiology of the neurological symptoms remains unclear and there is no effective therapy. This review is intended to provide a research strategy for a better knowledge of the neurological pathophysiology of HPRT deficiency. DEVELOPMENT: We have analyzed the knowledge on the neurological symptoms of HPRT deficiency. This knowledge comes from histopathological studies of the brains from Lesch-Nyhan patients, chemical studies of the cerebrospinal fluid, experimental animal models (pharmacologic and lesioning and genetic approaches), and human in vivo studies with positron-emission tomography. CONCLUSIONS: The observed findings suggest that the neurological symptoms of Lesch-Nyhan syndrome could be related with the neonatal neuronal and/or dopaminergic terminations damage. This damage could be due to lost or reorganization of dopaminergic system, and is associated with a reduced dopamine levels and with hypersensitivity of the D1 subclass dopamine receptors.