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Disorders of Nucleic Acid Metabolism

  • Chapter
Biology of Brain Dysfunction

Abstract

The cardinal clinical characteristics of the Lesch-Nyhan syndrome are mental retardation, spastic cerebral palsy, choreoathetosis, and self-mutilative biting behavior. These patients have hyperuricemia and thus may have any of the clinical manifestations of gout, including urinary tract stone disease, nephropathy, arthritis, and tophi. Activity of the enzyme hypoxanthine-guanine phosphoribosyl transferase is virtually absent.

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References

  1. M. Lesch and W. L. Nyhan, A familial disorder of uric acid metabolism and central nervous system function, Am. J. Med. 36:561, 1964.

    Article  Google Scholar 

  2. W. L. Nyhan, W. J. Oliver, and M. Lesch, A familial disorder of uric acid metabolism and central nervous system function. II, J.Pediat. 67:251, 1965.

    Google Scholar 

  3. W. L. Nyhan, A disorder of uric acid metabolism and cerebral function in childhood, Arthritis and Rheumatism 8:659, 1965.

    Article  Google Scholar 

  4. W. L. Nyhan, Introduction—clinical and genetic features, in Seminars on the Lesch-Nyhan Syndrome (J. H. Bland, ed.), Fed. Proc. 27:1027, 1968.

    Google Scholar 

  5. W. M. Michener, Hyperuricemia and mental retardation with athetosis and self-mutilation, Am. J. Dis. Child. 113:195, 1967.

    Google Scholar 

  6. R. S. Howard and M. P. Walzak, A new cause for uric acid stones in childhood, J.Urol. 98:639, 1968.

    Google Scholar 

  7. J. E. Seegmiller, F. M. Rosenbloom, and W. N. Kelley, Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis, Science 155:1682, 1967.

    Article  Google Scholar 

  8. W. L. Nyhan, L. Sweetman, and M. Lesch, Effects of the uricogenic agent, 2-ethylamino-1,3,4,-thiadiazole in hypoxanthine-guanine phosphoribosyl transferase deficiency, Metabolism 17:846, 1968.

    Article  Google Scholar 

  9. L. Sweetman and W. L. Nyhan, Excretion of hypoxanthine and xanthine in a genetic disease of purine metabolism, Nature 215:859, 1967.

    Article  Google Scholar 

  10. M. E. Balis, I. H. Krakoff, P. H. Berman, and J. Dancis, Urinary metabolites in congenital hyperuricosuria, Science 156:1122, 1967.

    Article  Google Scholar 

  11. L. Sweetman, Urinary and cerebrospinal oxypurine levels and allopurinol metabolism in the Lesch-Nyhan syndrome, Fed. Proc. 27:1055, 1968.

    Google Scholar 

  12. L. Sweetman and W. L. Nyhan, Detailed comparison of the urinary excretion of purines in a patient with the Lesch-Nyhan syndrome and a control subject, Biochem. Med. 4:121, 1970.

    Article  Google Scholar 

  13. D. S. Newcombe, The urinary excretion of aminoimidazolecarboxamide in the Lesch-Nyhan syndrome, Pediatrics 46:508, 1970.

    Google Scholar 

  14. W. L. Nyhan, Purine metabolism and abnormal behavior in childhood, in “Brain Chemistry and Mental Disease” (B. T. Ho and W. M. McIsaac, eds.), pp. 281–301, New York, 1971.

    Google Scholar 

  15. B. Bakay, M. A. Telfer, and W. L. Nyhan, Assay of hypoxanthine-guanine and adenine phosphoribosyl transferases. A simple screening test for the Lesch-Nyhan syndrome and related disorders of purine metabolism, Biochem. Med. 3:230, 1969.

    Article  Google Scholar 

  16. P. H. Berman, M. E. Balis, and J. Dancis, Diagnostic test for hyperuricemia with central nervous system dysfunction, J.Lab. Clin. Med. 71:247, 1968.

    Google Scholar 

  17. F. M. Rosenbloom, W. L. Kelley, J. Miller, J. F. Henderson, and J. E. Seegmiller, Inherited disorder of purine metabolism: Correlation between central nervous system dysfunction and biochemical defects, J.A.M.A. 202:175, 1967.

    Article  Google Scholar 

  18. T. A. Krenitsky, R. Papaioannou, and G. B. Elion, Human hypoxanthine phosphoribosyltransferase. I. Purification, properties and specificity, J. Biol. Chem. 244:1263, 1969.

    Google Scholar 

  19. B. Bakay and W. L. Nyhan, The separation of adenine and hypoxanthine-guanine phosphoribosyl transferase isoenzymes by disc gel electrophoresis, Biochem. Genet. 5:81, 1971.

    Article  Google Scholar 

  20. B. Bakay and W. L. Nyhan, Electrophoretic properties of hypoxanthine-guanine phosphoribosyl transferase in erythrocytes of subjects with the Lesch-Nyhan syndrome, Biochem. Genet., in press.

    Google Scholar 

  21. C. S. Rubin, J. Dancis, L. C. Yip, R. C. Niwinski, and M. E. Balis, Purification of IMP: Pyrophosphate phosphoribosyltransferases, catalytically incompetent enzymes in Lesch-Nyhan syndrome, Proc. Natl. Acad. Sci. 68:1461, 1971.

    Article  Google Scholar 

  22. W. Arnold and W. N. Kelley, Unpublished observations.

    Google Scholar 

  23. B. Bakay, W. L. Nyhan, and P. Svenson, Unpublished observations.

    Google Scholar 

  24. J. A. McDonald and W. N. Kelley, Lesch-Nyhan syndrome. Altered kinetic properties of mutant enzyme, Science 171:689, 1971.

    Article  Google Scholar 

  25. W. N. Kelley and J. C. Meade, Studies on hypoxanthine-guanine phosphoribosyltransferase in fibroblasts from patients with the Lesch-Nyhan syndrome. Evidence for genetic heterogeneity, J. Biol. Chem. 246:2953, 1971.

    Google Scholar 

  26. W. N. Kelley, Hypoxanthine-guanine phosphoribosyltransferase deficiency in the Lesch-Nyhan syndrome and gout, Fed. Proc. 27:1047, 1968.

    Google Scholar 

  27. L. Sweetman and W. L. Nyhan, Clinical and biochemical features of X-linked uric aciduria (Lesch-Nyhan syndrome). V. Further studies of the enzyme composition of mutant cells, Arch. Int. Med., in press.

    Google Scholar 

  28. M. L. Greene, J. A. Boyle, and J. E. Seegmiller, Substrate stabilization: Genetically controlled reciprocal relationship of two human enzymes, Science 167:887, 1970.

    Article  Google Scholar 

  29. I. H. Fox and W. N. Kelley, Phosphoribosyl-pyrophosphate in man: Biochemical and clinical significance, Ann. Int. Med. 74:424, 1971.

    Google Scholar 

  30. C. S. Rubin, M. E. Balis, S. Piomelli, P. H. Berman, and J. Dancis, Elevated AMP pyro-phosphorylase activity in congenital IMP pyrophosphorylase deficiency (Lesch-Nyhan disease), J. Lab. Clin. Med. 74:132, 1969.

    Google Scholar 

  31. B. Bakay and W. L. Nyhan, Unpublished data.

    Google Scholar 

  32. F. M. Rosenbloom, J. F. Henderson, I. C. Caldwell, W. N. Kelley, and J. E. Seegmiller, Biochemical bases of accelerated purine biosynthesis de novo in human fibroblasts lacking hypoxanthine-guanine phosphoribosyltransferase, J.Biol. Chem. 243:1166, 1968.

    Google Scholar 

  33. W. N. Kelley, I. H. Fox, and J. B. Wygaarden, Regulation of purine biosynthesis in cultured human cells. I. Effects of orotic acid, Biochim. Biophys. Acta 215:512, 1970.

    Article  Google Scholar 

  34. W. N. Kelley, M. L. Greene, I. H. Fox, F. M. Rosenbloom, R. I. Levy, and J. E. Seegmiller, Effects of orotic acid on purine and lipoprotein metabolism in man, Metabolism 19:1025, 1970.

    Article  Google Scholar 

  35. W. L. Nyhan, J. Pesek, L. Sweetman, D. G. Carpenter, and C. H. Carter, Genetics of an X-linked disorder of uric acid metabolism and cerebral function, Pediat. Res. 1:5, 1967.

    Article  Google Scholar 

  36. B. R. Migeon, V. M. DerKaloustian, W. L. Nyhan, and W. J. Young, X-linked hypoxan-thine-guanine phosphoribosyl transferase deficiency: Heterozygote has two clonal populations, Science 160:425, 1968.

    Article  Google Scholar 

  37. J. Salzmann, R. DeMars, and P. Benke, Single-allele expression at an X-linked hyperuricemia locus in heterozygous human cells, Proc. Natl. Acad. Sci. 60:545, 1968.

    Article  Google Scholar 

  38. W. L. Nyhan, B. Bakay, J. D. Connor, J. F. Marks, and D. K. Keele, Hemizygous expression of glucose-6-phosphate dehydrogenase in erythrocytes of heterozygotes for the Lesch-Nyhan syndrome, Proc. Natl. Acad. Sci. 65:214, 1970.

    Article  Google Scholar 

  39. W. L. Nyhan, Unpublished data.

    Google Scholar 

  40. J. L. Goldstein, J. F. Marks, and S. M. Gartler, Expression of two X-linked genes in human hair follicles of double heterozygotes, Proc. Natl. Acad. Sci. 68:1425, 1971.

    Article  Google Scholar 

  41. P. J. Fialkow, R. Lisker, J. Detter, E. R. Giblett, and C. Zavala, 6-Phosphogluconate dehydrogenase: Hemizygous manifestation in a patient with leukemia, Science 163:194, 1969.

    Article  Google Scholar 

  42. M. L. Greene, W. L. Nyhan, and J. E. Seegmiller, Hypoxanthine-guanine phosphoribosyl transferase deficiency and Xg blood group, Am. J. Hum. Genet. 22:50, 1970.

    Google Scholar 

  43. P. J. Fialkow, R. Lisker, and E. R. Giblett, Xg locus: Failure to detect inactivation in women with chronic myelocytic leukaemia, Nature 226:367, 1971.

    Article  Google Scholar 

  44. P. J. Fialkow, Is lyonization total in man? Lancet 2:315, 1970.

    Google Scholar 

  45. F. M. Rosenbloom, W. N. Kelley, J. F. Henderson, and J. E. Seegmiller, Lyon hypothesis and X-linked disease, Lancet 2:305, 1967.

    Article  Google Scholar 

  46. J. S. Felix and R. DeMars, Detection of females heterozygous for the Lesch-Nyhan mutation by 8-azaguanine-resistant growth of cultured fibroblasts, J.Lab. Clin. Med. 77:596, 1971.

    Google Scholar 

  47. B. R. Migeon, X-linked hypoxanthine-guanine phosphoribosyl transferase deficiency. Detection of heterozygotes by selective medium, Biochem. Genet. 4:377, 1970.

    Article  Google Scholar 

  48. S. M. Gartler, R. C. Scott, J. L. Goldstein, B. Campbell, and R. Sparkes, Lesch-Nyhan syndrome: Rapid detection of heterozygotes by use of hair follicles, Science 172:572, 1971.

    Article  Google Scholar 

  49. R. DeMars, G. Sarto, J. S. Felix, and P. Benke, Lesch-Nyhan mutation: Prenatal detection with amniotic fluid cells, Science 164:1303, 1969.

    Article  Google Scholar 

  50. W. Y. Fujimoto, J. E. Seegmiller, B. W. Uhlendorf, and C. B. Jacobsen, Biochemical diagnosis of an X-linked disease in utero, Lancet 2:511, 1968.

    Article  Google Scholar 

  51. J. A. Boyle, K. O. Raivio, K. H. Astrin, J. D. Schulman, M. L. Graf, J. E. Seegmiller, and C. B. Jacobsen, Lesch-Nyhan syndrome. Preventive control by prenatal diagnosis, Science 169:688, 1970.

    Article  Google Scholar 

  52. J. E. Seegmiller, Personal communication.

    Google Scholar 

  53. A. G. Motulsky, G. R. Frazer, and J. Felsenstein, Public health and long-term genetic implications of intrauterine diagnosis and selective abortion, Birth Defects Orig. Art. Ser., Vol. 7, No. 5, p. 22, April 1971.

    Google Scholar 

  54. J. M. Kaufman, M. L. Greene, and J. E. Seegmiller, Urine uric acid to creatinine ratio— a screening test for inherited disorders of purine metabolism, J. Pediat. 73:583, 1968.

    Article  Google Scholar 

  55. R. DeMars, Genetic studies of HG-PRT deficiency and the Leach-Nyhan syndrome with cultured human cells, Fed. Proc. 30:944, 1971.

    Google Scholar 

  56. R. J. Albertini and R. DeMars, Diploid azaguanine-resistant mutants of cultured human fibroblasts, Science 169:482, 1970.

    Article  Google Scholar 

  57. J. W. Littlefield and S. Goldstein, Some aspects of somatic cell hybridization, In Vitro 6:21, 1970.

    Article  Google Scholar 

  58. A. G. Schwartz, P. R. Cook, and H. Harris, Correction of a genetic defect in a mammalian cell, Nature New Biol. 230:5, 1971.

    Google Scholar 

  59. E. H. Szybalski and W. Szybalski, Genetics of human cell lines. IV. DNA-mediated hereditable transferase of a biochemical trait, Proc. Natl. Acad. Sci. 48:2026, 1962.

    Article  Google Scholar 

  60. W. L. Nyhan, Discussion of additional features, in Seminars on the Lesch-Nyhan Syndrome (J. H. Bland, ed.), Fed. J. Proc. 27:1044, 1968.

    Google Scholar 

  61. L. L. Morgan, N. Schneiderman, and W. L. Nyhan, Theophylline: Induction of self-biting in rabbits, Psychon. Sci. 19:37, 1970.

    Google Scholar 

  62. J. S. Felix and R. DeMars, Purine requirement of cells cultured from humans affected by Lesch-Nyhan syndrome (HGPRT deficiency), Proc. Natl. Acad. Sci. 62:536, 1969.

    Article  Google Scholar 

  63. S. P. M. VanDerZee, E. J. P. Lommen, J. M. F. Trijbels, and E. D. A. M. Schretlen, The influence of adenine on the clinical features and purine metabolism in the Lesch-Nyhan syndrome, Acta Paediat. Scand. 59:259, 1970.

    Article  Google Scholar 

  64. W. N. Kelley, F. M. Rosenbloom, J. Miller, and J. E. Seegmiller, An enzymatic basis for variation in response to allopurinol, New Engl. J. Med. 278:286, 1968.

    Article  Google Scholar 

  65. R. Pomales, S. Bieber, R. Friedman, and G. H. Hitchings, Augmentation of the incorporation of hypoxanthine into nucleic acids by the administration of an inhibitor of xanthine oridase, Biochim. Biophys. Acta 72:119, 1963.

    Article  Google Scholar 

  66. D. S. Newcombe, S. L. Shapiro, G. L. Sheppard, and F. E. Dreifuss, Treatment of X-linked primary hyperuricemia with allopurinol, J.A.M.A. 198:315, 1966.

    Article  Google Scholar 

  67. J. F. Marks, J. Baum, D. K. Keele, J. L. Kay, and A. MacFarlen, Lesch-Nyhan syndrome treated from the early neonatal period, Pediatrics 42:357, 1968.

    Google Scholar 

  68. M. L. Greene, W. Y. Fujimoto, and J. E. Seegmiller, Urinary xanthine stones—a rare complication of allopurinol therapy, New Engl. J. Med. 280:426, 1969.

    Article  Google Scholar 

  69. H. Ghadimi, C. K. Bhalla, and D. M. Kirschenbaum, The significance of the deficiency state in Lesch-Nyhan disease, Acta Paediat. Scand. 59:233, 1970.

    Article  Google Scholar 

  70. P. J. Benke and J. Anderson, Use of folic acid, adenine and bicarbonate in newborn twins with Lesch-Nyhan syndrome, Proc. Soc. Pediat. Res. 39:12, 1969.

    Google Scholar 

  71. M. D. Kogut, G. N. Donnell, W. L. Nyhan, and L. Sweetman, Disorder of purine metabolism due to partial deficiency of hypoxanthine-guanine phosphoribosyltransferase, Am. J. Med. 48:148, 1970.

    Article  Google Scholar 

  72. J. F. Henderson, W. N. Kelley, F. M. Rosenbloom, and J. E. Seegmiller, Inheritance of purine phosphoribosyltransferase in man, Am. J. Hum. Genet. 21:61, 1969.

    Google Scholar 

  73. W. N. Kelley, M. L. Greene, F. M. Rosenbloom, J. F. Henderson, and J. E. Seegmiller, Hypoxanthine-guanine phosphoribosyltransferase deficiency in gout, Ann. Int. Med. 70:155, 1969.

    Google Scholar 

  74. B. Bakay, W. L. Nyhan, N. Fawcett, and M. D. Kogut, Isoenzymes of hypoxanthine-guanine phosphoribosyl transferase in a family with partial deficiency of the enzyme, Biochem. Genet. 7:73, 1972.

    Article  Google Scholar 

  75. P. Benke and N. Herrick, Purine analog-resistance as a manifestation of a new hyperuricemia disorder, Abst., p. 199, Society for Pediatric Research, Atlantic City, April 1971.

    Google Scholar 

  76. B. T. Emmerson and J. B. Wyngaarden, Purine metabolism in heterozygous carriers of hypoxanthine-guanine phosphoribosyl transferase deficiency, Science 166:1533, 1969.

    Article  Google Scholar 

  77. W. L. Nyhan, J. A. James, A. J. Teberg, L. Sweetman, and L. G. Nelson, A new disorder of purine metabolism with behavioral manifestations, J.Pediat. 74:20, 1969.

    Article  Google Scholar 

  78. C. Hooft, C. Van Nevel, and A. F. DeSchaepdryver, Hyperuricosuria encephalopathy without hyperuricaemia, Arch. Dis. Child. 43:734, 1968.

    Article  Google Scholar 

  79. E. Orowan, The origin of man, Nature 175:683, 1955.

    Article  Google Scholar 

  80. D. Stetten, Jr., and J. Z. Hearon, Intellectual level measured by Army classification battery and serum uric acid concentration, Science 129:1737, 1959.

    Article  Google Scholar 

  81. G. W. Brooks and E. Mueller, Serum urate concentrations among university professors, J.A.M.A. 195:415, 1966.

    Article  Google Scholar 

  82. S. V. Kasl, G. W. Brooks, and S. Cobb, Serum urate concentrations in male high-school students, J.A.M.A. 198:713, 1966.

    Article  Google Scholar 

  83. C. E. Dent and G. R. Philpot, Xanthinuria, an inborn error (or deviation) of metabolism, Lancet 1:182, 1954.

    Article  Google Scholar 

  84. J. H. Ayvazian, Xanthinuria and hemochromatosis, New Engl. J. Med. 270:18, 1964.

    Article  Google Scholar 

  85. K. Engelman, R. W. E. Watts, J. R. Klinenberg, A. Sjoerdsma, and J. E. Seegmiller, Clinical, physiological and biochemical studies of a patient with xanthinuria and pheo-chromocytoma, Am. J. Med. 37:839, 1964.

    Article  Google Scholar 

  86. O. Sperling, U. A. Liberman, M. Frank, and A. DeVries, Xanthinuria: An additional case with demonstration of xanthine oxidase deficiency, Am. J. Clin. Pathol. 55:351, 1971.

    Google Scholar 

  87. R. W. E. Watts, K. Engelman, J. R. Klinenberg, J. E. Seegmiiler, and A. Sjoerdsma, Enzyme defect in a case of xanthinuria, Nature 201:395, 1964.

    Article  Google Scholar 

  88. M. J. Bradford, I. H. Krakoff, R. Leeper, and M. E. Balis, Study of purine metabolism in a xanthinuric female, J.Clin. Invest. 47:1325, 1968.

    Article  Google Scholar 

  89. C. M. Huguley, Jr., J. A. Bain, S. L. Rivers, and R. B. Scoggins, Refractory megaloblastic anemia associated with excretion of orotic acid, Blood 14:615, 1959.

    Google Scholar 

  90. H. J. Fallon, L. H. Smith, J. B. Graham, and C. H. Burnett, A genetic study of hereditary orotic aciduria, New Engl. J. Med. 270:878, 1964.

    Article  Google Scholar 

  91. L. H. Smith, M. Sullivan, and C. M. Huguley, Jr., Pyrimidine metabolism in man. IV. The enzymatic defect of orotic acidurea, J.Clin. Invest. 40:656, 1961.

    Article  Google Scholar 

  92. M. Lotz, H. J. Fallon, and L. H. Smith, Jr., Excretion of orotic acid and orotidine in heterozygotes of congenital orotic aciduria, Nature 197:194, 1963.

    Article  Google Scholar 

  93. K.-D. Wuu and R. S. Krooth, Dihydroorotic acid dehydrogenase activity of human diploid cell strains, Science 160:539, 1968.

    Article  Google Scholar 

  94. L. Pinsky and R. S. Krooth, Studies on the control of pyrimidine biosynthesis in human diploid cell strains. I. Effect of 6-azauridine on cellular phenotype, Proc. Natl. Acad. Sci. 57:925, 1967.

    Article  Google Scholar 

  95. L. Pinsky and R. S. Krooth, Studies on the control of pyrimidine biosynthesis in human diploid cell strains. II. Effects of 6-azaorotic acid, barbituric acid, and pyrimidine precursors on cellular prototype, Proc. Natl. Acad. Sci. 57:1267, 1967.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California, USA

    William L. Nyhan

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Editors and Affiliations

  1. New York State Institute for Basic Research in Mental Retardation, Staten Island, New York, USA

    Gerald E. Gaull

  2. Mt. Sinai School of Medicine of the City University of New York, New York, New York, USA

    Gerald E. Gaull

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Nyhan, W.L. (1973). Disorders of Nucleic Acid Metabolism. In: Gaull, G.E. (eds) Biology of Brain Dysfunction. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-2667-0_7

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  • DOI: https://doi.org/10.1007/978-1-4684-2667-0_7

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