Phosphoribosylpyrophosphate synthetase overactivity as a cause of uric acid overproduction in a young woman.

Overactivity of phosphoribosylpyrophosphate synthetase (PRS) is an X chromosome-linked disorder of purine metabolism that is characterized by gout with uric acid overproduction and, in some families, neurodevelopmental impairment. We present the case of a 24-year-old Spanish woman with renal colic and hyperuricemia, which first manifested at age 11 years. Results of enzymatic and genetic studies supported the view that accelerated purine nucleotide and uric acid production in this woman resulted from defective allosteric regulation of PRS activity, which is, in turn, a consequence of a mutation in one of the patient's PRPS1 genes: an A-to-T substitution at nucleotide 578, encoding leucine for histidine at amino acid residue 192 of the mature PRS1 isoform. A previous example of disordered regulation of PRS1 activity in a family with a different substitution at the same amino acid residue strengthens this proposed mechanism. This is the first reported instance of PRS overactivity in which the propositus and sole affected family member is a woman.