lesch nyhan syndrome

Summary

Summary: An inherited disorder transmitted as a sex-linked trait and caused by a deficiency of an enzyme of purine metabolism; HYPOXANTHINE PHOSPHORIBOSYLTRANSFERASE. Affected individuals are normal in the first year of life and then develop psychomotor retardation, extrapyramidal movement disorders, progressive spasticity, and seizures. Self-destructive behaviors such as biting of fingers and lips are seen frequently. Intellectual impairment may also occur but is typically not severe. Elevation of uric acid in the serum leads to the development of renal calculi and gouty arthritis. (Menkes, Textbook of Child Neurology, 5th ed, pp127)

Top Publications

  1. Nyhan W, Vuong L, Broock R. Prenatal diagnosis of Lesch-Nyhan disease. Prenat Diagn. 2003;23:807-9 pubmed
  2. Ogasawara N, Stout J, Goto H, Sonta S, Matsumoto A, Caskey C. Molecular analysis of a female Lesch-Nyhan patient. J Clin Invest. 1989;84:1024-7 pubmed
  3. Jinnah H, De Gregorio L, Harris J, Nyhan W, O Neill J. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res. 2000;463:309-26 pubmed
  4. Nyhan W. Dopamine function in Lesch-Nyhan disease. Environ Health Perspect. 2000;108 Suppl 3:409-11 pubmed
    ..There are decreased quantities and activities of a number of dopaminergic functions. Positron emission tomography scanning has indicated deficiency in the dopamine transporter...
  5. Yang T, Patel P, Chinault A, Stout J, Jackson L, Hildebrand B, et al. Molecular evidence for new mutation at the hprt locus in Lesch-Nyhan patients. Nature. 1984;310:412-4 pubmed
    ..Further molecular analysis of the origin of new mutations at the hprt locus should aid in resolving the issue of an apparent difference in the frequency of hprt mutations in males and females...
  6. Jinnah H, Langlais P, Friedmann T. Functional analysis of brain dopamine systems in a genetic mouse model of Lesch-Nyhan syndrome. J Pharmacol Exp Ther. 1992;263:596-607 pubmed
    ..These results indicate the existence of an inherent abnormality in the dopamine systems in the brains of HPRT- mice, despite their apparently normal spontaneous behavior...
  7. Prior C, Torres R, Puig J. Hypoxanthine decreases equilibrative type of adenosine transport in lymphocytes from Lesch-Nyhan patients. Eur J Clin Invest. 2007;37:905-11 pubmed
    ..The aim of this study was to determine adenosine transporter subtypes affected by HPRT deficiency and by the associated hypoxanthine excess...
  8. Torres R, Prior C, Puig J. Efficacy and safety of allopurinol in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency. Metabolism. 2007;56:1179-86 pubmed
    ..Xanthine lithiasis, developing as a consequence of allopurinol therapy, should be preventable by adjustment of allopurinol dose...
  9. Bavaresco C, Chiarani F, Wannmacher C, Netto C, Wyse A. Intrastriatal hypoxanthine reduces Na(+),K (+)-ATPase activity and induces oxidative stress in the rats. Metab Brain Dis. 2007;22:1-11 pubmed
    ..We suggest that hypoxanthine induces oxidative stress in all cerebral structures studied (striatum, hippocampus and cerebral cortex) and that the reduction of Na(+),K(+)-ATPase activity was probably mediated by reactive oxygen species...

More Information

Publications62

  1. Pinto C, Jinnah H, Shirley T, Nyhan W, Seifert R. Altered membrane NTPase activity in Lesch-Nyhan disease fibroblasts: comparison with HPRT knockout mice and HPRT-deficient cell lines. J Neurochem. 2005;93:1579-86 pubmed
    ..Thus, future studies on biochemical changes in LND should be conducted in parallel in several HPRT-deficient systems...
  2. Jinnah H, Lewis R, Visser J, Eddey G, Barabas G, Harris J. Ocular motor dysfunction in Lesch-Nyhan disease. Pediatr Neurol. 2001;24:200-4 pubmed
    ..These disturbances of ocular motility are consistent with dysfunction of the basal ganglia or its connections with ocular motor centers in the prefrontal cortex or midbrain...
  3. Engle S, Womer D, Davies P, Boivin G, Sahota A, Simmonds H, et al. HPRT-APRT-deficient mice are not a model for lesch-nyhan syndrome. Hum Mol Genet. 1996;5:1607-10 pubmed
    ..Thus, APRT-HPRT-deficient mice, which are devoid of any purine salvage pathways, show no novel phenotype and are not a model for the behavioral abnormalities associated with the Lesch-Nyhan syndrome as previously suggested...
  4. Criswell H, Mueller R, Breese G. Assessment of purine-dopamine interactions in 6-hydroxydopamine-lesioned rats: evidence for pre- and postsynaptic influences by adenosine. J Pharmacol Exp Ther. 1988;244:493-500 pubmed
    ..Relative potencies of the adenosine agonists for A1 and A2-adenosine receptors suggested involvement of an A2-adenosine receptor in this action.(ABSTRACT TRUNCATED AT 250 WORDS)..
  5. Torres R, Deantonio I, Prior C, Puig J. Adenosine transport in peripheral blood lymphocytes from Lesch-Nyhan patients. Biochem J. 2004;377:733-9 pubmed
    ..This indicates that hypoxanthine affects adenosine transport in control and hypoxanthine-guanine phosphoribosyltransferase-deficient cells by different mechanisms...
  6. Rinat C, Zoref Shani E, Ben Neriah Z, Bromberg Y, Becker Cohen R, Feinstein S, et al. Molecular, biochemical, and genetic characterization of a female patient with Lesch-Nyhan disease. Mol Genet Metab. 2006;87:249-52 pubmed
    ..Cultured fibroblasts from this patient exhibited the biochemical alterations in purine nucleotide metabolism characteristic of male LND fibroblasts...
  7. Pinto C, Seifert R. Decreased GTP-stimulated adenylyl cyclase activity in HPRT-deficient human and mouse fibroblast and rat B103 neuroblastoma cell membranes. J Neurochem. 2006;96:454-9 pubmed
    ..We discuss several possibilities to explain the abnormalities in AC regulation in HPRT deficiency that encompass various species and cell types...
  8. De Gregorio L, Jinnah H, Harris J, Nyhan W, Schretlen D, Trombley L, et al. Lesch-Nyhan disease in a female with a clinically normal monozygotic twin. Mol Genet Metab. 2005;85:70-7 pubmed
    ..As in many other reported cases of X-linked diseases, the discordant phenotype of the two monozygous twin sisters suggests that the process responsible for monozygotic twinning can trigger skewed X inactivation...
  9. García M, Torres R, Prior C, Puig J. Normal HPRT coding region in complete and partial HPRT deficiency. Mol Genet Metab. 2008;94:167-72 pubmed publisher
    ..This is the first report of a patient with Lesch-Nyhan syndrome due to a defect in HPRT gene expression regulation...
  10. Sege Peterson K, Chambers J, Page T, Jones O, Nyhan W. Characterization of mutations in phenotypic variants of hypoxanthine phosphoribosyltransferase deficiency. Hum Mol Genet. 1992;1:427-32 pubmed
  11. Jinnah H, Harris J, Nyhan W, O Neill J. The spectrum of mutations causing HPRT deficiency: an update. Nucleosides Nucleotides Nucleic Acids. 2004;23:1153-60 pubmed
    ..The reasons for some apparent exceptions to this proposal are addressed...
  12. Yang T, Stout J, Konecki D, Patel P, Alford R, Caskey C. Spontaneous reversion of novel Lesch-Nyhan mutation by HPRT gene rearrangement. Somat Cell Mol Genet. 1988;14:293-303 pubmed
    ..The original mutation therefore has the potential for spontaneous somatic reversion. This may explain the relatively mild symptoms of the Lesch-Nyhan syndrome exhibited by this patient...
  13. Jinnah H, Visser J, Harris J, Verdu A, Larovere L, Ceballos Picot I, et al. Delineation of the motor disorder of Lesch-Nyhan disease. Brain. 2006;129:1201-17 pubmed
    ..Explanations for the differing observations available in the literature are provided, along with a summary of how the motor disorder of LND relates to current understanding of its pathophysiology involving the basal ganglia...
  14. O Neill J. Mutation carrier testing in Lesch-Nyhan syndrome families: HPRT mutant frequency and mutation analysis with peripheral blood T lymphocytes. Genet Test. 2004;8:51-64 pubmed
    ..This approach provides a rapid assay that yields information on carrier status within 10 days of sample receipt...
  15. Shirley T, Lewers J, Egami K, Majumdar A, Kelly M, Ceballos Picot I, et al. A human neuronal tissue culture model for Lesch-Nyhan disease. J Neurochem. 2007;101:841-53 pubmed
    ..These cells combine the analytical power of multiple lines and a human, neuronal origin to provide an important tool to investigate the pathophysiology of HPRT deficiency...
  16. Schroeder S, Oster Granite M, Berkson G, Bodfish J, Breese G, Cataldo M, et al. Self-injurious behavior: gene-brain-behavior relationships. Ment Retard Dev Disabil Res Rev. 2001;7:3-12 pubmed
    ..SIB is a rapidly growing area of scientific interest to both basic and applied researchers. In many respects it is a model for the study of gene-brain-behavior relationships in developmental disabilities...
  17. Ceballos Picot I, Mockel L, Potier M, Dauphinot L, Shirley T, Torero Ibad R, et al. Hypoxanthine-guanine phosphoribosyl transferase regulates early developmental programming of dopamine neurons: implications for Lesch-Nyhan disease pathogenesis. Hum Mol Genet. 2009;18:2317-27 pubmed publisher
    ..These results provide novel evidence that HPRT deficiency may affect dopaminergic neurons by influencing early developmental mechanisms...
  18. Yeh J, Zheng S, Howard B. Impaired differentiation of HPRT-deficient dopaminergic neurons: a possible mechanism underlying neuronal dysfunction in Lesch-Nyhan syndrome. J Neurosci Res. 1998;53:78-85 pubmed
  19. Dabrowski E, Smathers S, Ralstrom C, Nigro M, Leleszi J. Botulinum toxin as a novel treatment for self-mutilation in Lesch-Nyhan syndrome. Dev Med Child Neurol. 2005;47:636-9 pubmed
    ..Our findings suggest that treatment with BTX-A affects both the central and peripheral nervous systems, resulting in reduced self-abusive behavior in this patient...
  20. Ea H, Bardin T, Jinnah H, Aral B, Lioté F, Ceballos Picot I. Severe gouty arthritis and mild neurologic symptoms due to F199C, a newly identified variant of the hypoxanthine guanine phosphoribosyltransferase. Arthritis Rheum. 2009;60:2201-4 pubmed publisher
    ..Careful neurologic examination is warranted in juvenile and middle-aged patients with gout, in order to detect mild symptoms that may lead to a diagnosis of HPRT deficiency...
  21. Cossu A, Orru S, Jacomelli G, Carcassi C, Contu L, Sestini S, et al. HPRTSardinia: a new point mutation causing HPRT deficiency without Lesch-Nyhan disease. Biochim Biophys Acta. 2006;1762:29-33 pubmed
    ..A multicentre survey gathering patients with variant neurological forms could contribute to understand the pathophysiology of the neurobehavioral symptoms of HPRT deficiency...
  22. Schretlen D, Ward J, Meyer S, Yun J, Puig J, Nyhan W, et al. Behavioral aspects of Lesch-Nyhan disease and its variants. Dev Med Child Neurol. 2005;47:673-7 pubmed
    ..Although patients with LNV typically do not self-injure or display severe aggression, attention problems are common and a few patients demonstrate other behavioral anomalies...
  23. Pralong E, Pollo C, Coubes P, Bloch J, Roulet E, Tétreault M, et al. Electrophysiological characteristics of limbic and motor globus pallidus internus (GPI) neurons in two cases of Lesch-Nyhan syndrome. Neurophysiol Clin. 2005;35:168-73 pubmed
    ..In order to shed light on the pathophysiology of dystonia, we report the pallidal electrophysiological activity recorded in two patients during deep brain stimulation surgery (DBS)...
  24. Neychev V, Jinnah H. Sudden death in Lesch-Nyhan disease. Dev Med Child Neurol. 2006;48:923-6 pubmed
    ..Better recognition of these processes will help to guide appropriate workup and management that could include chest imaging, endoscopy of the airways, polysomnography, electroencephalogram, and brain and/or spine imaging...
  25. Breese G, Criswell H, Duncan G, Mueller R. A dopamine deficiency model of Lesch-Nyhan disease--the neonatal-6-OHDA-lesioned rat. Brain Res Bull. 1990;25:477-84 pubmed
  26. Puig J, Torres R, Mateos F, Ramos T, Arcas J, Buno A, et al. The spectrum of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Clinical experience based on 22 patients from 18 Spanish families. Medicine (Baltimore). 2001;80:102-12 pubmed
  27. Jinnah H, Jones M, Wojcik B, Rothstein J, Hess E, Friedmann T, et al. Influence of age and strain on striatal dopamine loss in a genetic mouse model of Lesch-Nyhan disease. J Neurochem. 1999;72:225-9 pubmed
    ..The magnitude of dopamine loss measurable is dependent on the genetic background of the mouse strain used, the basal ganglia subregion examined, and the age of the animals at assessment...
  28. Puig J, Mateos F, Torres R, Buno A. Purine metabolism in female heterozygotes for hypoxanthine-guanine phosphoribosyltransferase deficiency. Eur J Clin Invest. 1998;28:950-7 pubmed
    ..We have examined whether urinary oxypurines could be useful for carrier diagnosis...
  29. Harris J, Lee R, Jinnah H, Wong D, Yaster M, Bryan R. Craniocerebral magnetic resonance imaging measurement and findings in Lesch-Nyhan syndrome. Arch Neurol. 1998;55:547-53 pubmed
    ..To provide the first comprehensive magnetic resonance imaging (MRI) assessment of brain in a series of patients with Lesch-Nyhan syndrome (LNS), with emphasis on basal ganglia measurements...
  30. Bertelli M, Cecchin S, Lapucci C, Jacomelli G, Jinnah H, Pandolfo M, et al. Study of the adenosinergic system in the brain of HPRT knockout mouse (Lesch-Nyhan disease). Clin Chim Acta. 2006;373:104-7 pubmed
    ..Altered adenosine transport across the membrane of HPRT-deficient lymphocytes has been reported, suggesting adenosine involvement in LND...
  31. Laróvere L, O Neill J, Randall M, Fairbanks L, Guelbert N, Czornyj L, et al. Hypoxanthine-guanine phosphoribosyltransferase deficiency: biochemical and molecular findings in six Argentine patients. Nucleosides Nucleotides Nucleic Acids. 2007;26:255-8 pubmed
    ..209G >A (G70E), in the other. In the HRND patients a novel transversion mutation, c.584 A >C (Y195S), was found in three related patients and an inherited transition mutation, c.143G >A (R48H), in the fourth subject...
  32. Jinnah H, Wojcik B, Hunt M, Narang N, Lee K, Goldstein M, et al. Dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease. J Neurosci. 1994;14:1164-75 pubmed
    ..These results indicate that HPRT deficiency is associated with a relatively specific deficit in basal ganglia dopamine systems that emerges during the first 2 months of postnatal development...
  33. Wong D, Harris J, Naidu S, Yokoi F, Marenco S, Dannals R, et al. Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo. Proc Natl Acad Sci U S A. 1996;93:5539-43 pubmed
    ..To our knowledge, these findings provide the first in vivo documentation of a dopaminergic reduction in LND and illustrate the role of positron emission tomography imaging in investigating neurodevelopmental disorders...
  34. Taira T, Kobayashi T, Hori T. Disappearance of self-mutilating behavior in a patient with lesch-nyhan syndrome after bilateral chronic stimulation of the globus pallidus internus. Case report. J Neurosurg. 2003;98:414-6 pubmed
    ..The findings indicate that neurobehavioral features of this syndrome are either mediated in the basal ganglia pathways or secondary to the dystonia...
  35. Gibbs R, Nguyen P, Edwards A, Civitello A, Caskey C. Multiplex DNA deletion detection and exon sequencing of the hypoxanthine phosphoribosyltransferase gene in Lesch-Nyhan families. Genomics. 1990;7:235-44 pubmed
    ..LN heterozygotes can be diagnosed without reference to the affected male. In addition, these procedures will be useful for somatic mutagenesis studies...
  36. Schretlen D, Harris J, Park K, Jinnah H, del Pozo N. Neurocognitive functioning in Lesch-Nyhan disease and partial hypoxanthine-guanine phosphoribosyltransferase deficiency. J Int Neuropsychol Soc. 2001;7:805-12 pubmed
    ..The variants produced scores that were intermediate between those of patients with LND and normal participants on nearly every cognitive measure. We discuss these findings in terms of what is known about the neuropathology of LND...
  37. Kuehn M, Bradley A, Robertson E, Evans M. A potential animal model for Lesch-Nyhan syndrome through introduction of HPRT mutations into mice. Nature. 1987;326:295-8 pubmed
    ..Male mice carrying the mutant alleles are viable and analysis of their cells shows a total lack of HPRT activity...
  38. Jinnah H, Ceballos Picot I, Torres R, Visser J, Schretlen D, Verdu A, et al. Attenuated variants of Lesch-Nyhan disease. Brain. 2010;133:671-89 pubmed publisher
    ..Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine-guanine phosphoribosyltransferase deficiency...
  39. Sebesta I, Stiburkova B, Dvorakova L, Hrebicek M, Minks J, Stolnaja L, et al. Unusual presentation of Kelley-Seegmiller syndrome. Nucleosides Nucleotides Nucleic Acids. 2008;27:648-55 pubmed publisher
    ..215A > G (p.Tyr72Cys). Assessment of X-inactivation ratio has shown that > 75% of the active X-chromosome bears the mutant allele and could explain these unusual, previously undescribed findings...
  40. Ray P, Harper J, Ao A, Taylor D, Winston R, Hughes M, et al. Successful preimplantation genetic diagnosis for sex Link Lesch--Nyhan Syndrome using specific diagnosis. Prenat Diagn. 1999;19:1237-41 pubmed
    ..Three PGD cycles were performed using this specific diagnostic test before a successful pregnancy was achieved resulting in the birth of a healthy unaffected baby girl...
  41. Ishida Y, Ishimaru A, Tauchi H, Yamaguchi A, Yokoyama M, Hiroi K, et al. Partial hypoxanthine-guanine phosphoribosyltransferase deficiency due to a newly recognized mutation presenting with renal failure in a one-year-old boy. Eur J Pediatr. 2008;167:957-9 pubmed
    ..The misssense mutation Asp185Gly (554A>G) was identified in exon 8 of his HPRT gene, and this mutation was inherited from the mother...
  42. Torres R, Prior C, Puig J. Efficacy and safety of allopurinol in patients with the Lesch-Nyhan syndrome and partial hypoxanthine- phosphoribosyltransferase deficiency: a follow-up study of 18 Spanish patients. Nucleosides Nucleotides Nucleic Acids. 2006;25:1077-82 pubmed
    ..Allopurinol is a very efficacy and fairly safety drug for the treatment of uric acid overproduction in patients with complete and partial HPRT deficiency. Allopurinol was associated with xanthine lithiasis...
  43. Kasim S, Jinnah H. Pharmacologic thresholds for self-injurious behavior in a genetic mouse model of Lesch-Nyhan disease. Pharmacol Biochem Behav. 2002;73:583-92 pubmed
    ..Finally, there was no evidence that the HPRT-deficient mice were more susceptible to SIB when it occurred (clonidine, Bay K 8644)...
  44. Yamada Y, Nomura N, Yamada K, Wakamatsu N. Molecular analysis of HPRT deficiencies: an update of the spectrum of Asian mutations with novel mutations. Mol Genet Metab. 2007;90:70-6 pubmed
    ..Including these nine mutations, 42 HPRT1 mutations have been identified among 47 Asian families with deficiency of HPRT...
  45. Garcia Gil M, Pesi R, Perna S, Allegrini S, Giannecchini M, Camici M, et al. 5'-aminoimidazole-4-carboxamide riboside induces apoptosis in human neuroblastoma cells. Neuroscience. 2003;117:811-20 pubmed
    ..Our results raise the intriguing clue that the neurotoxic effect of AICA riboside on the developing brain might contribute to the neurological manifestations of syndromes related to purine dismetabolisms...
  46. Cram D, Song B, Trounson A. Preimplantation diagnosis of Lesch-Nyhan using mini-sequencing primer extension. Reprod Biomed Online. 2003;7:342-5 pubmed
  47. Hooper M, Hardy K, Handyside A, Hunter S, Monk M. HPRT-deficient (Lesch-Nyhan) mouse embryos derived from germline colonization by cultured cells. Nature. 1987;326:292-5 pubmed
    ..In human males, HPRT deficiency causes Lesch-Nyhan syndrome, which is characterized by mental retardation and self-mutilation...
  48. Davidson B, Tarle S, Van Antwerp M, Gibbs D, Watts R, Kelley W, et al. Identification of 17 independent mutations responsible for human hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency. Am J Hum Genet. 1991;48:951-8 pubmed
    ..In addition, experiments were done to determine enzyme activity and electrophoretic mobility, and predictive paradigms were used to study the impact of these amino acid substitutions on secondary structure...
  49. Allen S, Davis W. Relationship of dopamine to serotonin in the neonatal 6-OHDA rat model of Lesch-Nyhan syndrome. Behav Pharmacol. 1999;10:467-74 pubmed
    ..These data provide evidence of a serial relationship between the D1 and 5-HT2C receptor systems in the neostriatum of animals receiving neonatal 6-OHDA lesions...
  50. Yamada Y. [Complete and partial deficiencies of hypoxanthine guanine phosphoribosyltransferase (HPRT)]. Nihon Rinsho. 2003;61 Suppl 1:288-93 pubmed
  51. Jinnah H. Lesch-Nyhan disease: from mechanism to model and back again. Dis Model Mech. 2009;2:116-21 pubmed publisher
    ..Instead, the modeling efforts have suggested a more fruitful approach that involves developing specific models, each tailored for addressing specific experimental questions...
  52. Micheli V, Sestini S, Rocchigiani M, Jacomelli G, Manzoni F, Peruzzi L, et al. Hypoxanthine-guanine phosphoribosyltransferase deficiency and erythrocyte synthesis of pyridine coenzymes. Life Sci. 1999;64:2479-87 pubmed
    ..These findings suggest that raised NAD concentrations in HPRT- erythrocytes are due to enhanced synthesis as a result of increased enzyme activities...
  53. Torres Jiménez R, Garcia Puig J. [Rare diseases: Lesch-Nyhan syndrome]. Med Clin (Barc). 2004;122:358-9 pubmed