Genetics of an X-Linked Disorder of Uric Acid Metabolism and Cerebral Function

Abstract

Extract: A syndrome of mental retardation, spastic cerebral palsy, choreoathetosis, and self-destructive biting has recently been described in children with elevated concentrations of uric acid in the blood. It is the purpose of this report to describe genetic studies which support an X-linked recessive mode of transmission. Two new pedigrees have been constructed following the study of propositi. Patients D.B. and G.W. were studied at 5 years of age; the concentration of uric acid in the plasma was 9.9 and 11.7 mg% respectively. The excretion of uric acid in the urine of patient D. B. ranged from 546 to 847 mg per 24 hours, with a mean excretion of uric acid of 3.02 mg per mg of creatinine. The specific activity of the uric acid in the urine after administration of glycine-U-C14 was maximal in the first 12 hours and amounted to 118 cpm per mg. Cumulative recovery of radioactivity in uric acid amounted to 1.97 percent in 7 days. The difference between patient and controls is of the order of magnitude of 200 times. Genetic transmission in an X-linked pattern was suggested from study of pedigrees (fig. 4 and fig. 5). Among the relatives of D. B., there were 15 affected individuals, all males. In the family of G.W., the disease was observed exclusively in males and, in each instance, transmission was through a female. In a trait transmitted as an X-linked recessive, one-fourth of the daughters an all sons of carrier females are expected to be affected. In this test of the hypothesis, the observed proportion of affected and unaffected grandsons did not differ significantly from this expectation. The results of testing with Xga antiserum indicated that throughout most of the kindred the X chromosome carrying the pathologic hyperuricemic gene also carried the silent Xg gene. Recombination must be invoked to explain case III-15, who was Xg (a+) and had an Xg (a+) son and an involved son. Neither the concentration of uric acid in the plasma nor the excretion of uric acid in the urine were useful in the detection of the abnormal gene. However, these data suggest that there may be some abnormality in uric acid metabolism in the heterozygote, but that it is not regularly possible to detect the presence of the abnormal gene by measuring the excretion of uric acid in the urine. The adult males were all found to excrete less uric acid than any of the groups of females. The observations recorded provide further confirmation for the concept that the disorder under study is a distinct disease entity. Genetic data accumulating indicate that the disorder is inherited in an X-linked recessive pattern. Speculation: This condition has now been observed to present all the clinical manifestations of gout, including hyperuricemia, urinary tract crystals and calculi, renal failure, arthritis and tophi. It differs in the age of onset and the involvement of the central nervous system. Most gout in adults appears to be renal in origin; some reflects an overproduction of uric acid. The overproduction of uric acid in this condition greatly exceeds that of any form of gout in adults. It appears likely that the mechanism of overproduction will be found likewise to be different. In the presence of X-linked transmission, it should be possible to develop methods which detect the heterozygous carrier.