Inherited enzyme abnormalities in the urate biosynthesis pathway that can cause urate overproduction
- • Overactivity of phosphoribosylpyrophosphate (PRPP) synthetase.
- • Partial deficiency of hypoxanthine–guanine phosphoribosyltransferase (HGPRT) (Kelley-Seegmiller syndrome).
These enzyme abnormalities, which cause urate overproduction, are inherited as X-linked traits. Men with these abnormalities often present with early-onset gout (<25 years of age) and a high incidence of uric acid nephrolithiasis. Complete HGPRT deficiency results in Lesch-Nyhan syndrome (mental retardation, spasticity, choreoathetosis, and self-mutilation). Furthermore, patients with glucose-6-phosphatase deficiency (von Gierke’s disease) also exhibit urate overproduction due to an accelerated ATP breakdown during hypoglycemia-induced glycogen degradation. Inhibition of renal tubular urate secretion can also occur in this disease as a result of competitive anions from lactic acidosis. Finally, patients with hereditary fructose intolerance caused by fructose-1-phosphate aldolase deficiency can develop hyperuricemia in part because of accelerated ATP catabolism
