Chapter 107

## Abstract

1. Inherited deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) causes three overlapping clinical syndromes, depending on the amount of residual enzyme activity. Patients with at least 8 percent of residual enzyme activity demonstrate marked overproduction of uric acid, with associated hyperuricemia, nephrolithiasis, and gout. Patients with 1.5 to 8 percent of residual activity demonstrate uric acid overproduction with neurologic disability that varies from minor clumsiness to debilitating extrapyramidal and pyramidal motor dysfunction. Patients with less than 1.5 percent of residual activity demonstrate overproduction of uric acid, debilitating neurologic disability, varying degrees of cognitive disability, and behavioral abnormalities that include impulsive and self-injurious behaviors. This latter and most severe form of the disease is known as Lesch-Nyhan disease (LND).

2. HPRT deficiency is inherited as an X-linked recessive condition, and the HPRT gene has been mapped to Xq26-q27. The entire HPRT gene has been cloned and sequenced and more than 200 mutations responsible for disease have been characterized. These advances at the molecular genetic level have allowed for the development of rapid and convenient methods for diagnosis, carrier identification, and prenatal testing.

3. The metabolic basis for the overproduction of uric acid in HPRT deficiency has been determined to result from changes in the regulation of purine synthesis and degradation. The overproduction of uric acid can be blocked by the administration of allopurinol, providing an effective means to reduce the risk of nephrolithiasis and gout in affected patients. Unfortunately, allopurinol has no efficacy against the neurobehavioral features.

4. The pathogenesis of the neurologic and behavioral features remains incompletely understood, although growing evidence suggests that these features result from dysfunction of the dopamine transmitter systems of the basal ganglia. Treatments for the neurobehavioral features are limited to protective physical devices and behavior therapy.

5. Current research efforts are focused on prevention, elucidating the basis for the central nervous system dysfunction, and developing more effective treatment strategies for the neurobehavioral features.

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