Abstract
Hypoxanthine guanine phosphoribosyltransferase (E.C.2.4.2.8.; HGPRT) deficiency is associated with a marked clinical heterogeneity [1–3]. All patients with HGPRT deficiency exhibit a common characteristic: increased uric acid production [3]. However, the clinical consequences of this uric acid overproduction may differ markedly from patient to patient. This variability depends not only on the rate of uric acid production but also on the factors that determine urate precipitation, some of which remain to be fully delineated. Among the known factors associated with urate precipitation, effective hypouricemic treatment has dramatically changed the spectrum of the clinical manifestations related to urate deposition in HGPRT deficient patients. In addition, HGPRT deficiency may be associated with a neurological syndrome that in its full expression is characterized by spasticity, hyperreflexia, choreoathetoid movements, mental retardation, and compulsive self-injurious behavior (Fig.1) [4–6].
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Emmerson BT, Thompson L (1973) The spectrum of hypoxanthine-guanine phosphoribosyltransferase deficiency. Q J Med 42: 423–440
de Bruyn CHMM (1976) Hypoxanthine-guanine phosphoribosyl transferase deficiency. Hum Genet 31: 127–150
Stout JT; Caskey CT (1989) Hypoxanthine phosphoribosyltransferase deficiency: the Lesch-Nyhan syndrome and gouty arthritis. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 1007–1028
Lesch M, Nyhan WL (1964) A familial disorder of uric acid metabolism and central nervous system function. Am J Med 36: 561–570
Cristie R, Bay C, Kaufman IA, Bakay B, Borden M, Nyhan WL (1982) Lesch-Nyhan disease: clinical experience with nineteen patients. Develop Med Child Neurol 24: 293–306
Watts RWE, Spellacy E, Gibbs DA, Allsop J, McKeran RO, Slavin GE (1982) Clinical, post-mortem, biochemical and therapeutic observations on the Lesch-Nyhan syndrome with particular reference to the neurological manifestations. Q J Med 51: 43–78
Kelley WN, Greene ML, Rosenbloom FM, Henderson JF, Seegmiller JE (1969) Hypoxanthine-guanine phosphoribosyltransferase deficiency in gout. Ann Intern Med 70: 155–206
Seegmiller JE (1989) Contributions of Lesch-Nyhan syndrome to the understanding of purine metabolism. J Inher Metab Dis 12: 184–196
Nuki G, Lever J, Seegmiller JE (1974) Biochemical characteristics of 8-azaguanine resistant human lymphoblast mutants selected in vitro. Adv Exp Med Biol 41A: 255–267
Seegmiller JE, Rosenbloom FM, Kelley WN (1967) Enzyme defect associated with a sex-linked human neurological disorder and excessive purine synthesis. Science 155: 1682–1684
Sorensen LB (1970) Mechanism of excessive purine biosynthesis in hypoxanthine-guanine phosphoribosyltransferase deficiency. J Clin Invest 49: 968–978
Edwards NL, Recker D, Fox IH (1979) Overproduction of uric acid in hypoxanthine- guanine phosphoribosyltransferase deficiency. Contribution by impaired purine salvage. J Clin Invest 63: 922–930
Puig JG. Jiménez ML, Mateos FA, Fox IH (1989) Adenine nucleotide turnover in hypoxanthine-guanine phosphoribosyl-transferase deficiency: evidence for an increased contribution of purine biosynthesis de novo. Metabolism 38: 410–418
Puig JG, Mateos FA, Jiménez ML, Ramos TH (1988) Renal excretion of hypoxanthine and xanthine in primary gout. Am J Med 85: 533–537
Rosenbloom FM, Henderson JF; Caldwell IC, Kelley WN, Seegmiller JE (1968) Biochemical basis of accelerated purine biosynthesis de novo in human fibroblasts lacking hypoxanthine-guanine phosphoribosyltransferase. J Biol Chem 243: 1166–1173
Itakura M, Sabina RL, Heald PW, Holmes EW (1981) Basis for the control of purine biosynthesis by purine ribosnucleotides. J Clin Invest 67: 994–10002
Zoref-Shani E, Sperling O (1980) Dependence of the metabolic fate of IMP on the rate of total IMP synthesis. Studies in cultured fibroblasts from normal subjects and from purine-overproducing mutant patients. Biochim Biophys Acta 607: 503–511
Vincent MF, van der Berghe G, Hers HG (1986) Effect of fructose on the concentration of phosphoribosyltransferase in isolated hepatocytes. Adv Exp Med Biol 195B: 615–621
Nuki G, Astria K, Brenton DP, Cruikshank MK, Lever J, Seegmiller JE (1977) Purine and pyrimidine concentration in cells with decreased hypoxanthine-guanine phosphoribosyltransferase activity. Adv Exp Med Biol 76A: 326–339
Brenton DP, Astria K, Cruikshank MK, Seegmiller JE (1977) Measurement of free nucleotides in cultured human lymphoid cells using high pressure liquid chromatography. Biochem Med 17: 271–274
Lommen EJP, Vogels GD, van der Zee SPM, Trijbels JMF, Schretlen EDAM (1971) Concentrations of purine nucleotides in erythrocytes of patients with the Lesch-Nyhan syndrome before and during oral administration of adenine. Acta Pediat Scand 60: 642–646
Rivard GE, Izadi P, Lazerson J, McLaren JD, Parker C, Fish CH (1975) Functional and metabolic studies of platelets from patients with Lesch-Nyhan syndrome. Br J Hematol 31: 245–253
Wood AW, Becker MA, Seegmiller JE (1973) Purine nucleotide synthesis in lymphoblasts cultured from normal subjects and a patient with Lesch-Nyhan syndrome. Biochem Genet 9: 261–274
Holmes EW, Wyngaarden JB, Kelley WN (1973) Human glutamine phosphoribosyl- pyrophosphate amidotransferase: two molecular forms interconvertible by purine ribonucleotides and phosphoribosylpyrophosphate. J Biol Chem 248: 6035–6040
Green ML, Boyle JA, Seegmiller JE (1970) Substrate stabilization: genetically controlled reciprocal relationship of two human enzymes. Science 167: 887–889
Rubin CS, Balis ME, Pionelli S, Berman PH, Dancis J (1969) Elevated AMP pyrophosphorilase activity in congenital IMP pyrophosphorilase deficiency ( Lesch-Nyhan syndrome ). J Lab Clin Med 74: 732–741
Gordon RB, Thompson L, Emmerson BT (1974) Erythrocyte phosphoribosylpyro-phosphate concentrations in heterozygotes for hypoxanthine-guanine phosphoribosyl- transferase deficiency. Metabolism 23: 921–927
Emmerson BT, Gordon RB (1986) HGPRT deficiency with normal erythrocyte PRPP and APRT activity. Adv Exp Med Biol 195A: 163–165
Watts RWE, Watts JEM, Seegmiller JE (1965) Xanthine oxidase activity in human tissues and its inhibition by allopurinol. J Lab Clin Med 66: 688–697
Jarasch E-D, Grund C, Bruder G, Heid HW, KeenanTW, Franke WW(1981) Localization of xanthine oxidase in mammary-gland epithelium and capillary endothelium. Cell 25: 67–82
Wilson JM, Young AB, Kelley WN (1983) Hypoxanthine-guanine phosphoribosyltransferase deficiency. The molecular basis of the clinical syndromes. N Eng J Med 309: 900–910
Sass JK, Itabashi HH, Dexter RA (1965) Juvenile gout with brain involvement. Arch Neurol 13: 639–655
Crussi FG, Robertson DM, Hiscox JL (1969) The paradoxical condition of the Lesch-Nyhan syndrome: report of two cases. Am J Dis Child 118: 501–506
Mizuno T, Endoh H, Konishi Y, Miyachi Y, Akaoka I (1976) An autopsy case of the Lesch-Nyhan syndrome: normal HGPRT activity in liver and xanthine calculi in various tissues. Neuropaediatrie 76: 351–355
Allsop J, Watts RWE (1980) Activities of amido phosphoribosyltransferase and purine phosphoribosyltransferase in developing rat brain. Adv Exp Med Biol 122A: 361–366
Rosenbloom FM, Kelley WN, Miller J, Henderson JF, Seegmiller JE (1967) Inherited disorder of purine metabolism: correlation between central nervous system dysfunction and biochemical defects. JAMA 202: 175–177
Lloyd KG, Hornykiewicz O, Davidson L, Shannak K, Farley I, Goldstein M, Shibuya M, Kelley WN, Fox IH (1981) Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch-Nyhan syndrome. N Eng J Med 305: 1106–1011
Rijksen G, Staal GEJ, van der Vlist MJM (1981) Partial hypoxanthine-guanine phosphoribosyltransferase deficiency with full expression of the Lesch-Nyhan syndrome. Hum Genet 57: 39–47
PageT, Bakay B, Nisinen E, NyhanWL (1981) Hypoxanthine-guanine phosphoribosyltransferase variants: correlation of clinical phenotype with enzyme activity. J Inherit Metab Dis 4: 203–206
Al-Khalidi USA, Chaglassian TH (1965) The species distribution of xanthine oxidase. Biochem J 97: 316–320
Sweetman L (1968) Urinary and cerebrospinal fluid oxypurine levels and allopurinol metabolism in the Lesch-Nyhan syndrome. Fed Proc 27: 1055–1059
Hoefnagel D 81967) Clinical features of the Lesch-Nyhan syndrome: pathology and pathologic physiology. Fred Proc 27: 1042–1046
Jiménez ML, Puig JG, Antón FM, Hernández TR, Castroviejo IP, Vázquez JO (1989) Transporte de purinas a través de la barrera hematoencefálica en la deficiencia de hipoxantina fosforribosiltransferasa. Med Clin (Bare) 92: 167–170
J. G. PUIG and F. A. MATEOS, The Biochemical Basis of HGPRT Deficiency Howard WJ, Kerson LA, Appel SH (1970) Synthesis de novo of purines in slices of rat brain and liver. J Neurochem 17: 121–128
Sidi Y, Mitchell BS (1985) Z-nucleotide accumulation in erythrocytes from Lesch- Nyhan patients. J Clin Invest 76: 2416–2419
Greene I, Urdin IB, Synder SH (1979) Dopamine receptor binding regulated by guanine nucleotides. Mol Pharmacol 16: 69–76
Goldstein M, Anderson LT, Reuben R, Dancis J (1985) Self-mutilation in Lesch- Nyhan disease is caused by dopaminergic denervation [letter]. Lancet 1: 338–339
Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxydopamine induced degeneration of the nigrostriatal dopamine system. Acta Physiol Scand Suppl 361: 69–91
Goldstein M, Kuga S (1984) Dopamine agonist induced compulsive biting behavior in monkeys. Animal model for Lesch-Nyhan syndrome [abstract]. Soc Neurosci 239
Goldstein M, Kuga S (1984) Possible involvement of central dopamine receptors in compulsive self-mutilative behavior [abstract]. Am Neurol Assoc P 39
Goldstein M, Anderson LT, Reuben R, Dancis J (1985) Self-mutilation in Lesch- Nyhan disease is caused by dopaminergic denervation [letter]. Lancet 1: 338
Simmonds HA, Fairbanks LD, Morris GS, Webster DR, Harley EH (1988) Altered erythrocyte nucleotide patterns are characteristic of inherited disorders of purine or pyrimidine metabolism. Clin Chim Acta 171: 197–210
Mateos FA, Puig JG, Jiménez ML, Fox IH (1987) Hereditary xanthinuria. Evidence for enhanced hypoxanthine salvage. J Clin Invest 79: 847–52
Simmonds HA, Webster DR, Wilson J, Potter CF, Fairbanks LD (1984) Evidence of a new syndrome involving hereditary uric acid overproduction, neurological complications and deafness. Adv Exp Med Biol 165A: 97–102
Rockson S, Stone R, van der Weyden M, Kelley WN (1974) Lesch-Nyhan syndrome: evidence for abnormal adrenergic function. Science 186: 934–935
Lake CR, Ziegler MG (1977) Lesch-Nyhan syndrome: low dopamine-3-hydroxylase activity and diminished sympathetic response to stress and posture. Science 196: 905–906
Castells S, Chakrabarti C, Winsberg BG, Hurwic M, Perel JM, Nyhan WL (1979) Effects of L-5-hydroxytryptophan on monoamine and amino acids turnover in the Lesch-Nyhan syndrome. J Autism Dev Disord 9: 95–103
Anders TF, Cann HM, Ciaranello RD, Barchas JD, Berger PA (1978) Further observations on the use of 5-hydroxytryptophan in a child with Lesch-Nyhan syndrome. Neuropediatrie 9: 157–166
Rassin DK, Lloyd KG, Kelley WN, Fox IH (1982) Decreased amino acids in various brain areas of patients with Lesch-Nyhan syndrome. 13: 130–134
HatanakaT, Higashino H, Woo M, Yasuhara A, Sugimoto T, Kobayashi Y(1990) Lesch- Nyhan syndrome with delayed onset of self-mutilation: hyperactivity of interneurons at the brainstem and blink reflex. Acta Neurol Scand 81: 184–187
Skolnick P, Paul SM, Marangos PJ (1980) purines as endogenous ligands of the benzodiazepine receptor. Fed Proc 39: 3050–3055
Phillis JW (1979) Diazepam potentiation of purinergic depression of central neurons. Can J Physiol Pharmacol 57: 432–435
Daly JW; Burns RF, Snyder SH (1981) Adenosine receptors in the central nervous system: relationship to the central actions of methylxanthines. Life Sci 28: 1083–2097
Mizuno T (1986) Long-term follow-up of ten patients with Lesch-Nyhan syndrome. Neuropediatrics 17: 158–161
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1993 Springer Verlag, Berlin Heidelberg
About this paper
Cite this paper
Puig, J.G., Mateos, F.A. (1993). The Biochemical Basis of HGPRT Deficiency. In: Gresser, U. (eds) Molecular Genetics, Biochemistry and Clinical Aspects of Inherited Disorders of Purine and Pyrimidine Metabolism. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-84962-6_3
Download citation
DOI: https://doi.org/10.1007/978-3-642-84962-6_3
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-84964-0
Online ISBN: 978-3-642-84962-6
eBook Packages: Springer Book Archive