Martin L. Greene

Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency in Gout

Excerpt INTRODUCTION Sophisticated biochemical studies in recent years have revealed that the regulation of intracellular metabolism is a logical, orderly, and intricate process. Control of enzyme ...

Urine uric acid to creatinine ratio—a screening test for inberited disorders of purine metabolism

The ratio of uric acid to creatinine (UA/C) in morning samples of urine provides a screening test for detection of the syndrome of choreoathetosis, mental retardation, self-mutilation, and hyperuricemia (Lesch-Nyhan syndrome) which is associated with virtually complete absence of activity of the enzyme phosphoribosyltransferase (PRT). This same ratio can be used on 24 hour urine samples from adult patients with gout for detection of patients with partial deficiency of the same enzyme. Data concerning UA/C from over 1,500 subjects are presented. Normal mean UA/C is 1.55 in the first week of life and declines to 0.61 at age 10. Mean for adults on normal diets is 0.49. Thirteen children with Lesch-Nyhan syndrome had a mean UA/C of 3.19, and 8 patients with gout and partial deficiency of PRT had mean UA/C of 1.06. Correlations of the ratio with age, sex, diet, and time of day, and values of UA/C in patients with gout and other disorders of purine metabolism are presented and discussed.

Effects of orotic acid on purine and lipoprotein metabolism in man

Abstract In the present study, it was demonstrated that orotic acid, a normal intermediate in pyrimidine synthesis, inhibits purine biosynthesis de novo in normal man. This was associated with depletion of erythrocyte 5-phosphoribosyl-1-pyrophosphate (PP-ribose-P) content. Orotic acid had no inhibitory effect on purine biosynthesis in patients who exhibited elevated levels of PP-ribose-P due to a deficiency of hypoxanthine-guanine phosphoribosyltransferase. These findings suggest that the inhibitory effect of orotic acid on purine biosynthesis de novo is due to depletion of intracellular PP-ribose-P levels. This provides the first in vivo evidence that the physiologic intracellular concentration of PP-ribose-P is important for the regulation of purine biosynthesis de novo in man. Orotic acid administration also produced a modest though statistically significant decrease in the plasma concentration of cholesterol, triglycerides, and beta and prebeta lipoproteins. The uricosuric effect of orotic acid noted previously after its intravenous administration was confirmed in the present study in which the compound was administered orally.

Substrate stabilization: genetically controlled reciprocal relationship of two human enzymes.

5-Phosphoribosyl-l-pyrophosphate, a substrate shared by adenine phosphoribosyltransferase and hypoxanthine-guanine phosphoribosyltransferase, accumulates in human erythrocytes lacking hypoxanthine-guanine phosphoribosyltransferase. 5-Phosphoribosyl-l-pyrophosphate added to purified adenine phosphoribosyltransferase stabilizes it against heat inactivation. The increased activity of adenine phosphoribosyltransferase seen in erythrocytes deficient in hypoxanthine-guanine phosphoribosyltransferase may result from substrate stabilization of this enzyme in vivo.

Hypouricemia due to isolated renal tubular defect: Dalmatian dog mutation in man

Abstract A twenty-three year old man was found to have low serum urate concentrations (0.9 to 1.8 mg/100 ml) during evaluation for recurrent urinary calcium oxalate stones. His urinary clearance of uric acid was markedly increased (30 to 46 ml/minute), and was only minimally decreased after administration of pyrazinamide, an inhibitor of renal tubular secretion of uric acid. No other renal tubular abnormalities were detected. His sister also was hypouricemic and had an increased renal clearance of uric acid. We suggest that this man had a genetically determined renal abnormality affecting tubular reabsorption of uric acid; a similar defect is present in the Dalmatian coachhound. The association of idiopathic hypercalciuria with the renal uric acid reabsorptive defect in this case is probably fortuitous.

Benign symmetric lipomatosis (Launois-Bensaude adenolipomatosis) with gout and hyperlipoproteinemia.

Abstract A thirty year old woman with Launois-Bensaude adenolipomatosis, a disease characterized by diffuse symmetric deposits of adipose tissue on the neck, back and upper trunk, has been studied. Gouty arthritis developed at age seventeen, and oligomenorrhea and muscle cramps were prominent symptoms. Pes cavus and extensor plantar reflexes were present. Metabolic studies with the patient on a purine-free diet demonstrated hyperuricemia, a marked increase in the whole body miscible pool and daily turnover of uric acid, augmented extrarenal disposal of uric acid and excessive incorporation of glycine-1- 14 C into urinary uric acid. Azathioprine therapy resulted in moderate suppression of purine synthesis; this suppression was not as marked as that observed in gouty patients studied previously. Glucose tolerance in this patient was abnormal, and immunoreactive insulin response during an oral glucose tolerance test was exaggerated. Plasma triglyceride levels were elevated, and a type IV lipoprotein pattern was present. The patients sister had a similar symmetric lipomatosis, elevated uric acid to creatinine ratio in the urine, hypertriglyceridemia and type IV lipoprotein pattern on electrophoresis.

Cockayne's syndrome: report of a case with hyperlipoproteinemia, hyperinsulinemia, renal disease, and normal growth hormone.

Summary A 9-year-old girl with Cockaynes syndrome had, in addition to the usual clinical features of the disorder, type II hyperlipo-proteinemia, fasting hyperinsulinemia, and renal insufficiency with acidosis. The normal growth hormone response to an intravenous infusion of arginine indicates that the dwarfism in this disorder is not due to inability to elaborate growth hormone.

Adenine Therapy for Lesch-Nyhan Syndrome

Extract: A child with the Lcsch-Nyhan syndrome was identified at birth by demonstrating a gross deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) in cord blood. Therapy with adenine, begun during the 1st month of life, failed to prevent the development of the severe neurological damage characteristic of this disease.Speculation: Since this work was completed, Dr. Grant Bartlett of San Diego has found (unpublished work) a very poor uptake of intravenously administered adenine-14C in the brain of rabbits. This raises a possible reason for the failure of adenine to prevent the neurological dysfunction in this disease. A purine compound that is more readily taken up by brain tissue might, therefore, offer a more reasonable approach to treatment.

Evaluation of Adenine Therapy for Lesch-Nyhan Syndrome

The use of oral adenine to prevent the devastating neurologic consequences of the Lesch-Nyhan syndrome has a sound theoretical basis, and has been proposed for management of this aspect of the disease. We have attempted therapy of two patients with adenine begun in one patient, during the first month of life. Preliminary experiments in rats explored the toxicity of adenine; pretreatment with allopurinol (10 mg/kg) reduced the nephrotoxic effects of the insoluble adenine metabolite, 2,8-dioxyadenine, at adenine doses of 70 mg/kg. Two patients, a 13-year-old male with established neurologic disease and self-mutilation, and a normal-appearing one-month-old boy with documented hypoxanthine-guanine phophoribosyltransferase (PRT) deficiency, were given adenine in doses up to 65 mg/kg/day. Toxicity was monitored by daily estimations of dioxyadenine content of urinary sediment and close attention ot parameters of renal functon; in both patients toxicity necessitated reduction in dose or addition of allopurinol. Erythrocyte 5-phosphori-bosyl-l-pyrophosphate which was normally elevated (40–70 mμmol/ml) as a consequence of PRT deficiency in these patients, was reduced to 5–15 mμmol/ml during adenine treatment, but not to within the normal range (1–5 mμmol/ml). The high uric acid excretion in both was unchanged. Despite treatment of the younger child for seven months, he developed spasticity, motor retardation and early self-mutilation. The older child alos showed no improvement in neurologic dysfunction. We conclude that adenine is of no therapeutic benefit, and is potentially toxic, in treatment of patients with the Lesch-Nyhan Syndrome.