Azaguanine-resistance as a manifestation of a new form of metabolic overproduction of uric acid

A young man is described with overproduction of uric acid and several features of the Lesch-Nyhan (L-N) syndrome, including borderline normal intelligence, mild spasticity and an episode of self-mutilation. Enzymatic analyses of the activity of hypoxanthine-guanine phosphoribosyltransferase (H-G PRT), the defective enzyme in the L-N syndrome, in red cells and fibroblasts from the patient gave normal results, as did studies of heat stability and starch gel electrophoresis of this enzyme from red cell hemolysates. Red cell adenine phosphoribosyltransferase (A-PRT) activity in the patient was increased, as in patients with the L-N syndrome. Several features of purine metabolism in fibroblasts were similar to those in cell lines with H-G PRT deficiency. Both cell lines showed growth resistance to 8-azaguanine compared to cell lines from normal subjects. When the accelerated purine synthesis was measured by formate-1-C¹⁴ incorporation into formylglycinamide ribonucleotide (FGAR) during azaserine block, both cell lines showed further stimulation of purine synthesis by hypoxanthine, whereas control cell lines showed expected feedback inhibition. Fibroblasts from the patient were more sensitive to inhibition of de novo purine synthesis by adenine than those from a normal control subject in a manner previously shown for H-G PRT deficient cell lines. A distinguishing feature was that fibroblasts from patients with H-G PRT deficiency could not grow in culture media with the folic acid antagonist aminopterin, whereas cell lines from the patient and normal control subjects could use hypoxanthine from the media for growth. We suggest that accelerated purine synthesis and clinical and biochemical similarities to the L-N syndrome, but apparently normal H-G PRT activity, constitute a distinct form of primary gout.