LESCH-NYHAN Syndrome and Disorder of Purine Metabolism

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Recently, deficiency of an enzyme participating in purine metabolism, hypoxanthine-guanine phosphoribosyltransferase (HGPRT), has been demonstrated in children with cerebral dysfunction and hyperuricemia (Lesch-Nyhan syndrome). This study was performed to clarify the biochemical features of the syndrome, effects of allopurinol and benziodaron (Amplivix) on uric acid metabolism in the patients, and changes in activity of HGPRT during pre- and postnatal development. Material and Methods: Serum uric acid, urinary uric acid/creatinine ratio, and specific activity of urinary uric acid after intravenous administration of glycine-14C (U) were determined in 4 Lesch-Nyhan syndrome patients aged 1-6 years. The major symptoms were choreatic and ballistic movement, abnormal postural reflex and mild mental deficiency. Activity of HGPRT in erythrocytes were determined by a modified method of Seegmiller et al. using hypoxanthine-14C. HGPRT activity in various organs from a fetus, an autopsied infant and an adult control was also determined by the method. Results: 1) Serum uric acid levels in the patients showed daily fluctuations and ranged from 5.80 to 11.40mg/dl with an average of 8.68±1.20. 2) Uric acid/creatinine ratio in a single urine sample from the patients was higher than 2.80 with an average of 3.35, and daily urinary uric acid excretion was more than 20mg/kg/day.(Fig. 1) 3) Specific activity of urinary uric acid after intravenous administration of glycine-14C, 2μc/kg, in the patients was ranged 0.64 to 1.69% (control: 0.008%).(Fig. 2) 4) Activity of HGPRT in erythrocytes of the patients was remarkably lower as compared with those of the control.(TABLE I) 5) By administration of allopurinol, 100mg per day, both the serum and urinary uric acid levels were decreased remarkably. Uric acid/creatinine ratio in the patients became lower than those of the control. After administration of Amplivix, 100mg to 150mg per day, the normal serum uric acid levels were obtained invariably in all the patients, while decrease in urinary excretion of uric acid was not remarkable. By administration of allopurinol, a remarkable increase of xanthine-hypoxanthine fraction in the urine was observed. On the other hand, during the Amplivix treatment, increase of the fraction was not observed, which appeared to indicate that Amplivix showed an uricosuria in during action and inhibition of oxypurine production. In spite of the normal serum uric acid levels for several months during Amplivix treatment, a marked improvement in neurological symptoms was not obtained.(Fig. 3, 4) 6) HGPRT Activity was observed, although low, even in the organs of an embryo of 4 weeks. In comparison with the activity in the brain and liver of an infant of 2 years, the activity of the organs of a fetus of 8 months as well as of an adult tended to be lower.(TABLE II) Discussion and Conclusion: Although the precise mechanism of neurological dysfunction in patients with Lesch-Nyhan syndrome are not known, enzyme deficiency in the brain might play an important role in the development of the extrapyramidal symptoms. Overproduction of uric acid through de novo purine synthesis was comfirmed by detecting hyperuricemia, increased urinary uric acid excretion and increased incorporation of isotopically labeled glycine into uric acid. As to the cause of cerebral dysfunction, hyperuricemia does not appear to play a predominant role, while the significance of increased hypoxanthine is to be determined. Based on the experience concerning allopurinol and Amplivix treatment, a better effect of the latter on the neurological symptoms has been expected because Amplivix treatment did not result in accumulation of xanthine and hypoxanthine.
Japan Society of Clinical Chemistryの論文

LESCH-NYHAN Syndrome and Disorder of Purine Metabolism

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