The enzyme hypoxanthine phosphoribosyltransferase (HPRT), expressed at low levels in non-neuronal tissues and higher levels in the brain, catalyzes the cellular salvage of the purine bases hypoxanthine and guanine. A complete deficiency of HPRT results in Lesch-Nyhan syndrome (LNS). LNS is characterized by movement deficits, including chorea, dystonia, and ataxia, as well as hyperuricemia, nephrolithiasis, and mental retardation. The most striking feature of LNS is a compulsion toward self-mutilation, most often manifested as biting of the lips, buccal cavity, and fingers. Since its discovery in 1964, investigators have gained greater understanding of the molecular and pharmacologic basis of some of the cardinal symptoms of LNS. The rodent and human HPRT genes have been isolated and characterized. Mutations underlying LNS have been shown t o range from entire gene deletion t o single base changes. Sequence elements important for expression of the gene, particularly in neurons, have been identified. Studies have indicated a role of dopamine (DA) fibers, particularly in the area of the basal ganglia, in the motor dysfunctions associated with LNS. DA activity in the basal ganglia in LNS patients has been reported to be as low as 10% of normal levels: however, manipulation of DA levels in LNS patients has produced inconsistent results.
Attempts t o produce an LNS-like syndrome in experimental animals, by either pharmacologic manipulation or lesioning of DA pathways, has proven mostly unsuccessful. However, the production of gene "knock-out" mice that are HPRT deficient, albeit apparently normal in phenotype, has allowed researchers t o study both the effects of alterations in the purine metabolism pathway and the underlying genetic basis for LNS. Continued study of the regulation of the HPRT gene, elucidation of the neuronal populations affected by HPRT deficiency, and development of effective gene delivery vectors may provide for a better understanding of the pathophysiology of LNS and enable better therapeutic regimens.