The LESCH-NYHAN Syndrome-Clinical and Therapeutic Features

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The Lesch-Nyhan syndrome was first recognized by Catel and Schmidt in 1959. In 1964, Lesch and Nyhan for the first time described the biochemical features, i. e. increasing rate of purine de novo synthesized. Since then, this syndrome has been called the Lesch-Nyhan syndrome. This is an inborn error of purine metabolism with X-linked recessive inheritance, in which hyperuricemia is associated with self-mutilation, mental retardation and choreo-athetosis. In Japan, Wada and we first reported this syndrome in 1967. We are provided now with information on a total of about 15 cases in Japan, including 5 cases of our own. As shown in TABLE I, the clinical symptoms are stereotypical as in Nyhan's report. The pre- and perinatal histories of these cases have nothing to be remarked. The parents had been aware of their delayed development and involuntary movements in the first year of life. At first, they were usually diagnosed as cerebral palsy. Some careful parents have found out the diapers stained in orange color. At the age of 2-3 years, the patients began to bite forcibly their own lip, fingers and tongue. This phenomenon is so-called self-mutilation. Their pain sense seemed to be evidently normal. Hyperuricemia was found in all the cases. Mental retardation was invariably present. In 5 cases, uric acid and oxypurine were studied in urine, plasma and CSF. A purine-free diet were given to all the cases at least for one week before the study. Uric acid was assayed by the method of Liddle et al., oxypurine by that of Jørgensen et al., and urinary xanthine and hypoxanthine by a modified one of Weissmann et al. The activity of hypoxanthine-guanine phosphoribosyltransferase (HG-PRTase) of erythrocyte hemolyzate was assayed by the method of Seegmiller et al. Uric acid levels of plasma, urine and CSF are 2 to 3 times as high as those in normal children. Oxypurine, i. e. xanthine and hypoxanthine, is about 10 times as much as in control children (TABLE II) The patients excrete more hypoxanthine than xanthine in their urine. The ratio of hypoxanthine to xanthine is 10 times as high as in control children (TABLE III) In order to reduce overproduction of uric acid, we have used allopurinol, a xanthine oxidase inhibitor, in 5 cases in the dosage of 50-150mg daily for 13-360 days. Plasma and urinary uric acid decreased and oxypurine concentration increased. We have observed urinary xanthine stones in case 4 after 6 months' treatment by allopurinol. Uricosuric drugs, e. g. probenecid and anturan, once lowered plasma uric acid level, but raised it afterwards. Imuran or azathioprine is the inhibitor of amidotransferase, which was used in 2 cases in the dosage of 100mg daily for one week. Uric acid and oxypurine levels in plasma and urine did not change in the patients. Benzbromarone was used in 3 cases in the dosage of 100-150mg daily for 5 to 360 days. This is a kind of uricosuric agents and seems to have an inhibitory action of xanthine oxidase. Plasma uric acid decreased whereas uric acid in urine increased. Plasma oxypurine did not change but slightly decreased in urine. Total oxypurine, i. e. uric acid, hypoxanthine and xanthine, in the urine showed a decrease by 0.61-0.67 times when benzbromarone was administered (TABLE IV). The ratio of urinary uric acid to creatinine did not change in 2 of the 3 cases when benzbromarone was given (Fig. 1). The ratio of urinary hypoxanthine to xanthine ratio decreased to nearly 1.0 and xanthine level increased when allopurinol was given. However, the ratio increased when benzbromarone was taken, as xanthine level were not raised. Treatment of self-mutilation is now almost hopeless. Mouthpiece or extraction of teeth is ineffective, and we fixed the patients' elbow joints with corsets and gave them diazepam in order to alleviate their dystonic movement.
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The LESCH-NYHAN Syndrome-Clinical and Therapeutic Features

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