Phosphoribosylpyrophosphate (PRPP) synthetase superactivity is a rare X chromosome-linked disorder of purine metabolism in which excessive Phosphoribosyl Pyrophosphate Synthetase (PRS) activity results in accelerated purine nucleotide and uric acid synthesis. PRS superactivity appears to be a rare disorder, with less than 30 affected kindreds described since 1972. Hyperuricemia and hyperuricosuria are demonstrable in all affected individuals who are thus predisposed to gout with uric acid overproduction and uric acid urolithiasis. In affected men presenting in late adolescence or early adulthood, gouty arthritis and urinary tract stones are usually the sole manifestations of PRS superactivity. Other families show a more severe phenotype in which affected male children display uric acid crystalluria, hyperuricemia, and hyperuricosuria in conjunction with neurodevelopmental impairment, and heterozygous carrier women may show milder metabolic and neurological abnormalities. Genetic heterogeneity underlies the different phenotypic expressions of inherited PRS superactivity. The severe clinical phenotype is usually associated with point mutation in the translated region of the PRPS1 gene that results in defective allosteric control of PRS1 isoform activity. In contrast, the later-onset, less severe disorder is usually associated with selective acceleration of PRPS1 transcription, resulting in increased concentration of normal PRS1 isoform. Treatment of uric acid overproduction with allopurinol successfully reverses or prevents the consequences of hyperuricemia and hyperuricosuria. Success in managing associated neurodevelopmental impairments, however, awaits pathogenetic understanding of these manifestations.
Last update: February 2005