The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases

In humans, mutations in the gene encoding the purine salvage enzyme hypoxan thine-guanine phosphoribosyltransferase (HPRT) are associated with a spectr um of disease that ranges from hyperuricemia alone to hyperuricemia with pr ofound neurological and behavioral dysfunction. Previous attempts to correl ate different types or locations of mutations with different elements of th e disease phenotype have been limited by the relatively small numbers of av ailable cases. The current article describes the molecular genetic basis fo r 75 new cases of HPRT deficiency, reviews 196 previously reported cases, a nd summarizes four main conclusions that may be derived from the entire dat abase of 271 mutations. First, the mutations associated with human disease appear dispersed throughout the hprt gene, with some sites appearing to rep resent relative mutational hot spots. Second, genotype-phenotype correlatio ns provide no indication that specific disease features associate with spec ific mutation locations. Third, cases with less severe clinical manifestati ons typically have mutations that are predicted to permit some degree of re sidual enzyme function. Fourth, the nature of the mutation provides only a rough guide for predicting phenotypic severity. Though mutation analysis do es not provide precise information for predicting disease severity, it cont inues to provide a valuable tool for genetic counseling in terms of confirm ation of diagnoses, for identifying potential carriers, and for prenatal di agnosis. (C) 2000 Elsevier Science B.V. All rights reserved.