In fibroblasts from an 8 year-old male (VRG) with tophaceous gout, uric acid overproduction, and sensorineural deafness, and from his gouty mother, superactivity of PS due to purine nucleotide inhibitor-resistance was found. Compared with normal cells, VRG fibroblasts showed increases in the following: PRPP concentration (3-fold) and generation (2-fold); purine synthesis de novo (2.5-fold); purine base salvage (2.6-fold); ATP and GTP concentrations (1.4-fold); and excretion of newly synthesized purines (5-fold). Derangements in PS and in PRPP and purine synthesis were attenuated in cells from the mother, suggesting that VRG is a hemizygote for an X chromosome-linked defect and his mother is a heterozygote. Comparison was made of affected males in 8 families with PS superactivity. VRG was intermediate in range of expression of PS superactivity and in severity of the enzyme defect as measured by the degree of aberration of PRPP and purine nucleotide synthesis in fibroblasts. Metabolic abnormalities were more severe in VRG than in most patients (in whom expression is limited to early adult-onset gout with uric acid overproduction), but less severe than in 2 patients with more complex defects in PS associated with uric acid over-production and neurodevelopmental abnormalities, including deafness in hemizygous male children and heterozygous women. Within the spectrum of defects resulting in PS superactivity, certain derangements may be causally related to neurological impairment, most commonly sensorineural deafness.
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