A specific enzyme defect in gout associated with overproduction of uric acid.

Gout is classed among the inborn errors of metabolism,1 but unlike the majority of such disorders no single specific metabolic defect has yet been found to account for the hyperuricemia characteristic of this disease.2 Although impaired renal excretion of uric acid is responsible for the hyperuricemia of some patients, an increased rate of purine biosynthesis de novo contributes to the hyperuricemia in the majority of gouty patients.' In affected members of certain families excessive production of purines is the sole cause of their hyperuricemia.4 Accelerated purine synthesis also occurs in other distinctive metabolic disorders.5' 6 The increased rate of purine synthesis in patients with glycogen-storage disease (Type I) is attributed to the deficiency of glucose-6-phosphatase, which is the basis for this disorder.' We have recently demonstrated the complete absence (<0.05 % of normal) of an enzyme of purine metabolism, hypoxanthine-guanine phosphoribosyltransferase (HGPRT),' in four unrelated patients who have an Xlinked familial neurological and behavioral disorder associated with excessive production of uric acid.6' 8, 9 Although no specific biochemical defect had been demonstrated to account for excessive uric acid production in typical gouty arthritis, a derangement in some aspect of the regulation of purine synthesis had been proposed.10"1 In this study we show that a partial loss of HGPRT activity is associated with excessive purine synthesis in some of these gouty patients. Materials and Methods.-The rate of purine synthesis was evaluated in three ways. One method was to measure the uric acid excreted in a 24-hour urine after a patient had been maintained for at least five days on a diet essentially free of purines, containing 2600 calories, 70 grams of protein, 350 grams of carbohydrate, and 100 grams of fat. No drugs known to affect uric acid excretion or synthesis were administered. The average uric acid excretion over a three-day period for normal male subjects is 426 mg/24 hr (SD i 81),3 and excretion of quantities greater than 600 mg/24 hr was taken as evidence of excessive purine biosynthesis. Uric acid was determined in serum and urine by a specific method using uricase.'2 Urinary creatinine was determined"3 to assess the completeness of urine collections. Purine synthesis was also evaluated in some patients by determining the pool size and turnover of uric acid by the use of isotopically labeled uric acid administered intravenously'4' 15 and by determining the extent of incorporation of isotopically labeled glycine into urinary uric acid.'6 3 Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (EC 2.4.2.8) and adenine phosphoribosyltransferase (APRT) (EC 2.4.2.7) activities were assayed by a radiochemical method. The reactions catalyzed by HGPRT and APRT are as follows: