Biochemical Correlates of Auto-Aggressive Behavior

Inferences from the Lesch-Nyhan Syndrome
  • Theodore Page
  • William L. Nyhan


The auto-aggressive behavior that characterizes the Lesch-Nyhan syndrome1 is unique among behavioral abnormalities in that the genetic and molecular basis of the disorder has been firmly established.2 The syndrome is a consequence of the deficiency of the enzyme hypoxanthineguanine phosphoribosyl transferase (HPRT; E.C.; the deficiency is inherited in a simple X-linked fully recessive manner. However, the exact etiology of the auto-aggressive behavior, the way in which the abnormality in purine metabolism leads to the behavioral phenotype, remains obscure despite an extensive body of research on the metabolic consequences of HPRT deficiency. It is almost certain that neurotransmitter metabolism is involved. Animal models suggest ways in which early neurotransmitter imbalances may cause autoaggressive behavior. Several mechanisms for an effect of HPRT deficiency on neurotransmitter metabolism seem plausible, including a direct action of the substrates of HPRT on receptors, and the participation of GTP-binding proteins. Experimental approaches to therapy have also contributed to our knowledge of what is— and what is not— involved in auto-aggressive behavior.


Purine Metabolism Purine Nucleotide Purine Nucleoside Phosphorylase Purine Synthesis Central Nervous System Symptom 
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  1. 1.
    Lesch M, Nyhan WL : A familial disorder of uric acid metabolism and central nervous system function. Am J Med 36:561–570, 1964PubMedCrossRefGoogle Scholar
  2. 2.
    Seegmiller JE, Rosenbloom FM, Kelley WN : Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science 155:1682–1684, 1967PubMedCrossRefGoogle Scholar
  3. 3.
    Nyhan WL : The Lesch-Nyhan syndrome. Annu Rev Med 24:41–60, 1973PubMedCrossRefGoogle Scholar
  4. 4.
    Gibbs DA, McFayden IR, Crawford MR, et al : First trimester diagnosis of Lesch-Nyhan syndrome. Lancet 2:1180–1183, 1984PubMedCrossRefGoogle Scholar
  5. 5.
    Kelley WN, Wyngaarden JB : Clinical syndromes associated with hypoxanthine-guanine phosphoribosyl transferase deficiency, in Stanbury JB Wyngaarden JB Fredrickson DS, et al(eds), The Metabolic Basis of Inherited Disease, ed 5. New York, McGraw-Hill, 1983, pp 1115–1143Google Scholar
  6. 6.
    Bakay B, Nissenen E, Sweetman L, et al : Utilization of purines by an HPRT variant in an intelligent nonmutilative patient with features of the Lesch-Nyhan syndrome. Pediatr Res 13:1365–1370, 1979PubMedCrossRefGoogle Scholar
  7. 7.
    Gottlieb RP, Koppell MM, Nyhan WL, et al : Hyperuricemia and choreoathetois in a child without mental retardation or self-mutilation—A new HPRT variant. J Inher Metab Dis 5:183–186, 1982PubMedCrossRefGoogle Scholar
  8. 8.
    Nyhan WL : Behavior in the Lesch-Nyhan syndrome. J Autism Child Schizophr 6:235–251, 1976PubMedCrossRefGoogle Scholar
  9. 9.
    Bassermann R, Gutensohn W, Springmann JS : Pathological and immunological observations in a case of Lesch-Nyhan syndrome. Eur J Pediatr 132:93–104, 1979PubMedCrossRefGoogle Scholar
  10. 10.
    Crussi FG, Robertson DM, Hiscox JL : The pathological condition of the Lesch-Nyhan syndrome. Am J Dis Child 118:501–506, 1969PubMedGoogle Scholar
  11. 11.
    Seegmiller, JE: Summary: Pathology and pathologic physiology. Fed Proc 27:1042–1046, 1968Google Scholar
  12. 12.
    Emmerson BT, Thompson L : The spectrum of hypoxanthine-guanine phosphoribosyltransferase deficiency. Q J Med 166:1423–1440, 1973Google Scholar
  13. 13.
    Hersh JH, Page T, Hand ME, et al : Clinical correlations in partial hypoxanthine-guanine phosphoribosyltransferase deficiency. Pediatr Neurol 2:302–304, 1986PubMedCrossRefGoogle Scholar
  14. 14.
    Page T, Bakay B, Nissinen E, et al : Hypoxanthine-guanine phosphoribosyltransferase variants: Correlation of clinical phenotype with enzyme activity. J Inher Metab Dis 4:203–206, 1981PubMedCrossRefGoogle Scholar
  15. 15.
    Srivastava SK, Beutler E : Purification and kinetic studies of adenine phosphoribosyltransferase from human erythrocytes. Arch Biochem Biophys 142:426–434, 1971PubMedCrossRefGoogle Scholar
  16. 16.
    Lindberg B, Klenow H, Hansen K : Some properties of partially purified mammalian adenosine kinase. J Biol Chem 242:350–356, 1967PubMedGoogle Scholar
  17. 17.
    Krenitsky TA, Papaioannou R : Human hypoxanthine phosphoribosyltransferase. II. Kinetics and chemical modification. J Biol Chem 244:1271–1277, 1969PubMedGoogle Scholar
  18. 18.
    Henderson JF : Kinetic properties of hypoxanthine-guanine phosphoribosyltransferase. Fed Proc 27:1053–1054, 1968PubMedGoogle Scholar
  19. 19.
    Fox IH, Marchant PJ : Purine metabolism in man: Characterization of microsomal 5’ nucleotidase. Can J Biochem 54:462–469, 1976PubMedCrossRefGoogle Scholar
  20. 20.
    Wiginton DA, Coleman MS, Hutton JJ : Characterization of purine nucleoside phosphorylase from human granulocytes and its metabolism of deoxyribonucleosides. J Biol Chem 255:6663–6669, 1980PubMedGoogle Scholar
  21. 21.
    Carcassi A, Mercolongo R, Marinello E, et al : Liver xanthine oxidase in gouty patients. Arthritis Rheum 12:17–20, 1969PubMedCrossRefGoogle Scholar
  22. 22.
    Hershko A, Rain A, Mager J : Regulation of the synthesis of 5-phosphoribosyl-l-pyrophosphte in intact red blood cells and in cell-free preparations. Biochim Biophys Acta 184:64–76, 1969PubMedCrossRefGoogle Scholar
  23. 23.
    Holmes EW, McDonald JA, McCord JM, et al : Human glutamine phosphoribosylpyrophosphate amidotransferase— Kinetic and regulatory properties. J Biol Chem 248:144–150, 1973PubMedGoogle Scholar
  24. 24.
    Van Der Weyden MB, Kelley WN : Human adenylosuccinic synthetase: Partial purification, kinetic and regulatory properties of the enzyme from placenta. J Biol Chem 249:7242–7281, 1974Google Scholar
  25. 25.
    Holmes EW, Pehlke DM, Kelley WN : The role of human inosinic acid dehydrogenase in the control of purine biosynthesis de novo. Biochim Biophys Acta 364:209–217, 1974PubMedGoogle Scholar
  26. 26.
    Mager J, Magasanik B : Guanosine-5’ -phosphate reductase and its role in the interconversion of purine nucleotides. J Biol Chem 235:1474–1478, 1960PubMedGoogle Scholar
  27. 27.
    Rosenbloom FM, Kelley WN, Miller J, et al : Inherited disorder of purine metabolism: Correlation between central nervous system dysfunction and biochemical defects. JAMA 202:175–177, 1967PubMedCrossRefGoogle Scholar
  28. 28.
    McCollister RJ, Gilbert WR, Ashton DM, et al : Psuedofeedback inhibition of purine synthesis by 6-mercaptopurine and other purine analogs. J Biol Chem 239:1560–1566, 1964PubMedGoogle Scholar
  29. 29.
    Gutensohn W, Guroff G : Hypoxanthine-guanine phosphoribosyltransferase from rat brain (purification, kinetic properties, development and distribution). J Neurochem 19:2139–2150, 1972PubMedCrossRefGoogle Scholar
  30. 30.
    Krenitzky TA : Tissue distribution of purine ribosyl- and phosphoribosyltransferases in the rhesus monkey. Biochim Biophys Acta 179:506–509, 1969Google Scholar
  31. 31.
    Murray AW : Purine phosphoribosyltransferase activities in rat and mouse tissues and in Ehrlich ascitestumor cells. Biochem J 100:664–670, 1966PubMedGoogle Scholar
  32. 32.
    Nyhan WL, Oliver WJ, Lesch M : A familial disorder of uric acid metabolism and central nervous system function. J Pediatr 2:257–263, 1965Google Scholar
  33. 33.
    Newcombe DS, Lapes M, Thomson C : Urinary excretion 4-amino-5-imidazole carboxamide in X-linked primary hyperuricemia. Clin Res 15:45, 1967Google Scholar
  34. 34.
    Pignero A, Giliberti P, Tancredi F : Effect of the treatment of folic acid on urinary excretion pattern of amidoimidazole carboxamide in the Lesch-Nyhan syndrome. Perspect Inher Metab Dis 1:42–47, 1973Google Scholar
  35. 35.
    Beardmore TD, Meade JC, Kelley WN : Increased activity of the enzymes of pyrimidine biosynthesis de novo in erythrocytes from patients with the Lesch-Nyhan syndrome. J Lab Clin Med 81:43–52, 1973PubMedGoogle Scholar
  36. 36.
    Pehlke DM, McDonald JA, Holmes EW, et al : Inosinic acid dehydrogenase activity in the Lesch-Nyhan syndrome. J Clin Invest 51:1398–1404, 1972PubMedCrossRefGoogle Scholar
  37. 37.
    Reem GH : Purine metabolism in murine virus-induced erythroleukemic cells during differentiation in vitro. Proc Natl Acad Sci USA 72:1630–1634, 1975PubMedCrossRefGoogle Scholar
  38. 38.
    Lommen EJP, Bogels GD, Van Der Zee SPM, et al : Concentrations of purine nucleotides in erythrocytes of patients with the Lesch-Nyhan syndrome before and during oral administration of adenine. Acta Paediatr Scand 60:642–646, 1971PubMedCrossRefGoogle Scholar
  39. 39.
    Sidi Y, Mitchell BS : Z-Nucleotide accumulation in erythrocytes from Lesch-Nyhan patients. J Clin Invest 76:2416–2419, 1985PubMedCrossRefGoogle Scholar
  40. 40.
    Rosenbloom FM, Henderson JF, Caldwell IC : Biochemical basis of accelerated purine biosynthesis de novo in human fibroblasts lacking hypoxanthine-guanine phosphoribosyltransferase. J Biol Chem 243:1166–1173, 1968PubMedGoogle Scholar
  41. 41.
    Snyder FF, Cruikshank MK, Seegmiller JE : A comparison of purine metabolism and nucleotide pools in normal and hypoxanthine-guanine phosphoribosyltransferase-deficient neuroblastoma cells. Biochim Biophys Acta 543:556–569, 1978PubMedCrossRefGoogle Scholar
  42. 42.
    Lake CR, Ziegler MG : Lesch-Nyhan syndrome: Low dopamanine (3-hydroxylase activity and diminished sympathetic response to stress and posture. Science 196:905–906, 1977PubMedCrossRefGoogle Scholar
  43. 43.
    Breakfield XO, Castiglione CM, Edelstein SB : Monoamine oxidase activity decreased in cells lacking hypoxanthine phosphoribosyltransferase activity. Science 192:1018–1019, 1976CrossRefGoogle Scholar
  44. 44.
    Singh S, Willers I, Kluss EM, et al : Monoamine oxidase and catechol-o-methyltransferase activity in cultured fibroblasts from patients with maple syrup urine disease, Lesch-Nyhan syndrome and healthy controls. Clin Genet 15:153–159, 1979PubMedCrossRefGoogle Scholar
  45. 45.
    Lloyd KG, Homykiewicz O, Davidson L, et al : Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch-Nyhan syndrome. N Engl J Med 305:1106–1111, 1981PubMedCrossRefGoogle Scholar
  46. 46.
    Sweetman L, Borden M, Kulovich S, et al : Altered excretion of 5-hydroxyindoleacetic acid and glycine in patients with the Lesch-Nyhan syndrome, in Muller MM Kaiser E Seegmiller JE(eds), Purine Metabolism in Man, Vol. II: Regulation of Pathways and Enzyme Defects. New York, Plenum, 1977, pp 398–404Google Scholar
  47. 47.
    Castells S, Chakrabarti C, Winsberg, et al : Effects of L-5-hydroxytryptophan on monoamine and amino acid turnover in the Lesch-Nyhan syndrome. J Autism Devel is 9:95–103, 1979CrossRefGoogle Scholar
  48. 48.
    Silverstein FS, Johnston MV, Hutchinson RJ, et al : Lesch-Nyhan syndrome: CSF neurotransmitter abnormalities. Neurology (NY) 35:907–911, 1985Google Scholar
  49. 49.
    Sweetman L : Urinary and cerebrospinal fluid oxypurine levels and allopurinol metabolism in the Lesch-Nyhan syndrome. Fed Proc 27:1055–1059, 1967Google Scholar
  50. 50.
    Marks JF, Baum J, Keele DK, et al : Lesch-Nyhan syndrome treated from the early neonatal period. Pediatrics 42:357–359, 1968PubMedGoogle Scholar
  51. 51.
    Kelley WN, Greene ML, Rosenbloom FM, et al : Hypoxanthine-guanine phosphoribosyltransferase in gout. Ann Intern Med 70:155–206, 1967Google Scholar
  52. 52.
    Skolnick P, Marangos PJ, Goodwin FK, et al : Identification of inosine and hypoxanthine as endogenous inhibitors of [3H]diazepam binding in the central nervous system. Life Sci 23:1473–1480, 1978PubMedCrossRefGoogle Scholar
  53. 53.
    Skaper SD, Seegmiller JE : Increased concentrations of glycine in hypoxanthine-guanine phosphoribosyltransferase-deficient neuroblastoma cells. J Neurochem 26:689–694, 1976PubMedCrossRefGoogle Scholar
  54. 54.
    Benke PJ, Herrick N, Smiten L, et al : Adenine and folic acid in the Lesch-Nyhan syndrome. Pediatr Res 7:729–738, 1973PubMedCrossRefGoogle Scholar
  55. 55.
    Wood MH, Fox RM, Vincent L, et al : The Lesch-Nyhan syndrome: Report of three cases. Aust NZ J Med 2:57–64, 1972CrossRefGoogle Scholar
  56. 56.
    Seegmiller JE, Laster L, Stetten D : Incorporation of 4-amino-5-imidazole carboxamide-4-C13 into uric acid in the normal human. J Biol Chem 216:653–662, 1955PubMedGoogle Scholar
  57. 57.
    Howard WJ, Kerson LA, Appel SH : Synthesis de novo of purines in slices of rat brain and liver. J Neurochem 17:121–123, 1970PubMedCrossRefGoogle Scholar
  58. 58.
    Simmonds HA, Fairbanks LD, Morris GS, et al : Erythrocyte GTP depletion in PNP deficiency presenting with hemolytic anemia and hypouricemia, in Nyhan WL Thompson LF Watts RWE(eds), Purine and Pyrimidine Metabolism in Man. Vol V: Clinical Aspects Including Molecular Genetics. New York, Plenum, 1986, pp 197–204Google Scholar
  59. 59.
    Miwa S, Watanabe Y, Hayaishi O : 6-R-L-Erythro-5,6,7,8-tetrahydrobiopterin as a regulator of dopamine and serotonin biosynthesis in the rat brain. Arch Biochem Biophys 239:234–241, 1985PubMedCrossRefGoogle Scholar
  60. 60.
    Niederweiser A, Blau N, Wang M, et al : GTP cyclohydrolase I deficiency, a new enzyme defect causing hyperphenylalaninemia with neopterin, biopterin, dopamine, and serotonin deficiencies and muscular hypotonia. Eur J Pediatr 141:208–214, 1984CrossRefGoogle Scholar
  61. 61.
    Hoganson G, Berlow S, Kaufman S, et al : Biopterin synthesis defects: Problems in diagnosis. Pediatrics 74:1004–1011, 1984PubMedGoogle Scholar
  62. 62.
    Nyhan WL, Sakati NA : Hyperphenylalaninemia and defective metabolism of tetrahydrobiopterin, in Diagnostic Recognition of Genetic Disease. Philadelphia, Lea & Febiger, 1987, pp 107–112Google Scholar
  63. 63.
    Gilman AG : G Proteins: Transducers of receptor-generated signals. Annu Rev Biochem 56:615–649, 1987PubMedCrossRefGoogle Scholar
  64. 64.
    Rodbell M : The role of hormone receptors and GTP-regulatory proteins in membrane transduction. Nature (Lond) 284:17–22, 1980CrossRefGoogle Scholar
  65. 65.
    Roufogalis BD, Thornton M, Wade DN : Nucleotide requirement of dopamine sensitive adenylate cyclase in the synaptosomal membranes from the striatum of rat brain. J Neurochem 27:1533–1535, 1976PubMedCrossRefGoogle Scholar
  66. 66.
    Creese I, Usdin TB, Snyder SH : Dopamine receptor binding regulated by guanine nucleotides. Mol Pharmacol 16:69–76, 1979PubMedGoogle Scholar
  67. 67.
    MacDermot J, Higashida H, Wilson SP, et al : Adenylate cyclase and acetylcholine release regulated by separate receptors of somatic cell hybrids. Proc Natl Acad Sci USA 76:1135–11439, 1979PubMedCrossRefGoogle Scholar
  68. 68.
    Nyhan WL, Johnson AG, Kaufman I, et al : Serotonergic approaches to the modification of behavior in the Lesch-Nyhan syndrome. Appl Res Ment Retard 1:25–40, 1980PubMedCrossRefGoogle Scholar
  69. 69.
    Fredholm BB, Hedqvist P : Modulation of neurotransmission by purine nucleotides and nucleosides. Biochem Pharmacol 29:1635–1643, 1980PubMedCrossRefGoogle Scholar
  70. 70.
    Sweetman L, Nyhan WL : Detailed comparison of the urinary excretion of purines in a patient with the Lesch-Nyhan syndrome and a control subject. Biochem Med 4:121–134, 1970CrossRefGoogle Scholar
  71. 71.
    Simmonds HA, Van Acker KJ : Adenine phosphoribosyltransferase deficiency, in Stanbury JB Wyngaarden JB Fredrickson DS, et al(eds), The Metabolic Basis of Inherited Disease, ed 5. New York, McGraw-Hill, 1983, pp 1144–1156Google Scholar
  72. 72.
    Breese GR, Baumeister AA, McCown TJ, et al : Neonatal-6-hydroxydopamine treatment: Mode of susceptibility for self-mutilation in the Lesch-Nyhan syndrome. Pharmacol Biochem Behav 21:459–1461, 1984PubMedCrossRefGoogle Scholar
  73. 73.
    Goldstein M, Shegeki K, Kusano N, et al : Dopamine agonist induced self-mutilative biting behavior in monkeys with unilateral ventromedial tegmental lesions of the brainstem: Possible pharmacological model for Lesch-Nyhan syndrome. Brain Res 367:114–120, 1986PubMedCrossRefGoogle Scholar
  74. 74.
    Breese GR, Baumeister A, Napier TC, et al : Evidence that D-l dopamine receptors contribute to the supersensitive behavioral response induced by L-dihydroxyphenylalanine in rats treated neonatally with 6-hydroxydopamine. J Pharmacol Exp Ther 235:287–295, 1985PubMedGoogle Scholar
  75. 75.
    Mizuno T, Yugari Y : Prophylactic effect of l -5-hydroxytryptophan on self-mutilation in the Lesch-Nyhan syndrome. Neuropadiatrie 6:13– 23, 1975CrossRefGoogle Scholar
  76. 76.
    Goldstein M, Anderson LT, Reuben R, et al : Self-mutilation in Lesch-Nyhan disease is caused by dopaminergic denervtion. Lancet 1:338–339, 1985PubMedCrossRefGoogle Scholar
  77. 77.
    Boyd EM, Dolman M, Knight LM, et al : The chronic oral toxicity of caffeine. Can J Physiol Pharmacol 43:995–1007, 1965CrossRefGoogle Scholar
  78. 78.
    Sakata T, Fuchimoto H : Stereotyped and aggressive behavior induced by sustained high doses of theophylline in rats. Jpn J Pharmacol 23:781–785, 1973PubMedCrossRefGoogle Scholar
  79. 79.
    Rosenberg D, Monnet P, Mamelle JL, et al : Encephalopathie avec troubles du metabolisme des purines. Presse Med 76:2333–2336, 1968Google Scholar
  80. 80.
    Berman PH, Balis ME, Dancis J : Congenital hyperuricemia, an inborn error of purine metabolism associated with psychomotor retardation, athetosis, and self-mutilation. Arch Neurol 20:44–53, 1969PubMedCrossRefGoogle Scholar
  81. 81.
    Watts RWE, McKeran RO, Brown E, et al : Clinical and biochemical studies on treatment of Lesch-Nyhan syndrome. Arch Dis Child 49:653–702, 1974CrossRefGoogle Scholar
  82. 82.
    Lowenstein JM : Ammonia production in muscle and other tissues: The purine nucleotide cycle. Physiol Rev 52:382–414, 1972Google Scholar
  83. 83.
    Manzke H, Gustman H, Koke HG, et al: Hypoxanthine and tetrahydrobiopterin treatment of a patient with features of the Lesch-Nyhan syndrome, in Nyhan WL Thompson LF Watts RWE(eds), Purine and Pyrimidine Metabolism in Man. Vol V: Clinical Aspects Including Molecular Genetics. New York, Plenum, 1986, pp 197–204Google Scholar
  84. 84.
    Edwards NL, Jeryc W, Lieberman C, et al : Enzyme replacement in the Lesch-Nyhan syndrome. Clin Res 28:139A, 1980Google Scholar
  85. 85.
    Nyhan WL, Parkman R, Page T, et al : Bone marrow transplantation in Lesch-Nyhan disease, in Nyhan WL Thompson LF Watts RWE(eds), Purine and Pyrimidine Metabolism in Man. Vol V: Clinical Aspects Including Molecular Genetics. New York, Plenum, 1986, pp 167–170Google Scholar
  86. 86.
    Mizuno T, Yugari Y : Self-mutilation in Lesch-Nyhan syndrome. Lancet 1:761, 1974PubMedCrossRefGoogle Scholar
  87. 87.
    Kuehn MR, Bradley A, Robertson EJ, et al : A potential animal model for Lesch-Nyhan syndrome through induction of HPRT mutation into mice. Nature (Lond) 326:295–301, 1987CrossRefGoogle Scholar
  88. 88.
    Jolly DJ, Okayama H, Berg P, et al : Isolation and characterization of a full length expressible cDNA for human hypoxanthine phosphoribosyltransferase. Proc Natl Acad Sci USA 80:477–481, 1983PubMedCrossRefGoogle Scholar
  89. 89.
    Willis RC, Jolly DJ, Miller AD, et al : Partial phenotypic correction of a human Lesch-Nyhan (hypoxanthine-guanine phosphoribosyltransferase-deficient) lymphoblast line with a transmissible retroviral vector. J Biol Chem 259:7842–7849, 1984PubMedGoogle Scholar
  90. 90.
    Gruber HE, Finley KD, Luchtman LA, et al : Insertion of hypoxanthine phosphoribosyltransferase cDNA into human bone marrow by a retrovirus, in Nyhan WL Thompson LF Watts RWE(eds), Purine and Pyrimidine Metabolism in Man. Vol V: Clinical Aspects Including Molecular Genetics. New York, Plenum, 1986, pp 171–175Google Scholar

Copyright information

© Plenum Publishing Corporation 1990

Authors and Affiliations

  • Theodore Page
    • 1
  • William L. Nyhan
    • 1
  1. 1.Department of PediatricsUniversity of California-San DiegoLa JollaUSA

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