title: Inherited superactivity of phosphoribosylpyrophosphate synthetase: association of uric acid overproduction and sensorineural deafness.
abstract: OBJECTIVE
  Superactivity of 5-phosphoribosyl 1-pyrophosphate (PP-Rib-P) synthetase, inherited as an X chromosome-linked trait, has been reported in nearly 20 families in which overproduction of uric acid is invariably present in hemizygous affected males. Clinical manifestations of PP-Rib-P synthetase superactivity are mainly limited to gout in early adulthood. Neurologic deficits, including sensorineural deafness, have rarely been described. We herein document the association of PP-Rib-P synthetase superactivity, gout with excessive uric acid synthesis, and sensorineural deafness in an additional family.
  
  
  METHODS
  Two members of a Spanish family were studied: an eight-year-old boy (Patient 1) with tophaceous gout, purine nucleotide and uric acid overproduction, and sensorineural deafness, and his 27-year-old mother (Patient 2), who had gout. Fibroblast cultures were initiated from skin biopsy specimens, and measurements of PP-Rib-P and purine nucleotide metabolism in the fibroblasts were performed.
  
  
  RESULTS
  A labile but superactive PP-Rib-P synthetase was demonstrated in the fibroblasts cultured from both Patients 1 and 2. The kinetic basis of PP-Rib-P synthetase superactivity in this family was resistance to purine nucleotide inhibition of enzyme activity. More severe derangements in the enzyme and in PP-Rib-P and purine synthesis in Patient 1's cells than in Patient 2's cells suggest that Patient 1 is hemizygous and Patient 2 is heterozygous for an X chromosome-linked genetic defect. Limited pedigree data support this view. Compared with affected members of seven other families with PP-Rib-P synthetase superactivity, these patients are intermediate in the range of clinical expression and in the severity of the enzyme defect as measured by the degree of aberration of PP-Rib-P and purine nucleotide synthesis in fibroblasts. Metabolic abnormalities were more severe in Patient 1's cells than in the cells of most male patients (in whom clinical expression is limited to early adult-onset gout) but were less severe than in the cells of two patients in whom more complex enzyme defects were associated with uric acid overproduction and neurodevelopmental abnormalities (including deafness) in male children and adult women.
  
  
  CONCLUSIONS
  Certain defects resulting in PP-Rib-P synthetase superactivity may be causally related to neurologic impairment, most commonly sensorineural deafness.
authors.affiliation: Department of Medicine, University of Chicago Pritzker School of Medicine, Illinois.
authors.forename: M A
authors.initials: MA
authors.lastname: Becker
authors.forename: J G
authors.initials: JG
authors.lastname: Puig
authors.forename: F A
authors.initials: FA
authors.lastname: Mateos
authors.forename: M L
authors.initials: ML
authors.lastname: Jimenez
authors.forename: M
authors.initials: M
authors.lastname: Kim
authors.forename: H A
authors.initials: HA
authors.lastname: Simmonds
mesh_terms: D000328:Adult; D002648:Child; D003638:Deafness / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D006073:Gout / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D010770:Phosphotransferases / Q000378:metabolism*; D011685:Purine Nucleotides / Q000378:metabolism; D012268:Ribose-Phosphate Pyrophosphokinase / Q000378:metabolism*; D014527:Uric Acid / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D011685:Purine Nucleotides; D014527:Uric Acid; D010770:Phosphotransferases; D012268:Ribose-Phosphate Pyrophosphokinase