Lesch–Nyhan Disease


Lesch–Nyhan disease (LND) is an X‐linked, inherited neurodevelopmental disease caused by a mutation in the gene encoding the purine salvage enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT). Virtual absence of HPRT is associated with hyperuricemia and specific neurobehavioural features: a hyperkinetic movement disorder dominated by dystonia, cognitive impairment with attentional and executive deficits, and behavioural disturbances including self‐injurious behaviour. Partial HPRT deficiencies result in incomplete phenotypes characterised by hyperuricemia with or without neurological dysfunction, but without self‐injury. HPRT deficiency leads to a deficiency of the neurotransmitter dopamine, and the subsequent dysfunction of the basal ganglia is thought to play an important role in the pathogenesis of the neurobehavioural phenotype. Administering allopurinol reduces the risk of hyperuricemia‐associated urological and articular complications, but there is currently no effective treatment for the neurobehavioural features of LND. Self‐injurious behaviour is managed by restraints and soft padding of the environment, and sometimes neuroleptics, anxiolytics or sedatives.

Key Concepts:

  • Lesch–Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT).

  • LND is characterised by developmental delay, hyperuricemia, dystonia, attentional and executive deficits and behavioural disturbances including self‐injurious behaviour.

  • The severity of the clinical phenotype in LND depends on the amount of residual HPRT enzyme activity.

  • Dysfunction of the basal ganglia dopamine systems are thought to play an important role in the pathogenesis of the neurobehavioural phenotype.

  • LND patients are not globally retarded, but rather have impairments in specific cognitive domains, including attentiveness and mental flexibility.

  • Compulsive self‐injurious behaviour is considered a hallmark of the disease, and emerges usually within the first few years of life.

  • HPRT enzyme activity testing or HPRT gene mutation analysis confirms the diagnosis.

  • As effective treatment for LND is currently lacking, prevention through carrier testing, genetic counselling and prenatal diagnosis is of utmost importance.

Keywords: Lesch–Nyhan disease; hypoxanthine guanine phosphoribosyltransferase; self‐injurious behaviour; purine metabolism; basal ganglia; dystonia; Kelley–Seegmiller syndrome

Figure 1.

HPRT gene mutations in LND and its variants. The nine exons of HPRT are shown as boxes, with coding regions and noncoding regions indicated. Mutations causing LND are shown above the gene, and those causing less severe manifestations of the disease are shown below. Symbols depict locations of known missense mutations, nonsense mutations, insertions and deletions. Splice site mutations are not shown.

Figure 2.

Role of HPRT in purine metabolism. (a) Pathways for synthesis, metabolism and degradation of purines, including salvage reactions by HPRT. (b) HPRT catalyses the transfer of the 5‐phosphoribosyl group from PP‐ribose‐P to the 9 position of hypoxanthine or guanine to form the respective nucleotide and pyrophosphate. 5′NT, 5′‐nucleotidase; ADA, adenosine deaminase; ADP, adenosine diphosphate; AK, adenosine kinase; AMP, adenosine monophosphate; APRT, adenine phosphoribosyltransferase; AS, adenylosuccinate; ASL, adenine succinate‐synthetase/lyase; ATP, adenosine triphosphate; GA, guanase; GDP, guanosine diphosphate; gln, glutamine; gly, glycine; GMP, guanosine monophosphate; GTP, guanosine triphosphate; HPRT, hypoxanthine guanine phosphoribosyltransferase; IDH, IMP dehydrogenase; IMP, inosine monophosphate; PNP, purine nucleoside phosphorylase; PRPP, phosphoribosylpyrophosphate; XMP, xanthylate; XO, xanthine oxidase.

Figure 3.

Uric acid in LND and its variants. Serumuric acid (a) and 24 h urine uric acid (b) are shown for patients with HPRT‐related hyperuricemia only, hyperuricemia with neurological dysfunction and classic LND.

Figure 4.

Tissue damage resulting from repeated self‐injury. Lip showing remote and recent scarring (a), and brow showing mostly chronic tissue reaction (b).



Anderson LT and Ernst M (1994) Self‐injury in Lesch–Nyhan disease. Journal of Autism and Developmental Disorders 24: 67–81.

Ceballos‐Picot I, Mockel L, Potier MC et al. (2009) Hypoxanthine‐guanine phosphoribosyl transferase regulates early developmental programming of dopamine neurons: implications for Lesch–Nyhan disease pathogenesis. Human and Molecular Genetics 18: 2317–2327.

Edwards A, Voss H, Rice P et al. (1990) Automated DNA sequencing of the human HPRT locus. Genomics 6: 593–608.

Ernst M, Zametkin AJ, Matochik JA et al. (1996) Presynaptic dopaminergic deficits in Lesch–Nyhan disease. New England Journal of Medicine 334: 1568–1572.

Guibinga GH, Hsu S and Friedmann T (2010) Deficiency of the housekeeping gene hypoxanthine‐guanine phosphoribosyltransferase (HPRT) dysregulates neurogenesis. Molecular Therapy 18: 54–62.

Harris JC, Lee RR, Jinnah HA et al. (1998) Craniocerebral magnetic resonance imaging and findings in Lesch–Nyhan syndrome. Archives of Neurology 55: 547–553.

Jinnah HA, De Gregorio L, Harris JC, Nyhan WL and O'Neill JP (2000) The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutation Research 463: 309–326.

Jinnah HA and Friedmann T (2000) Lesch–Nyhan disease and its variants. In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, pp. 2537–2570. New York: McGraw‐Hill.

Jinnah HA, Harris JC, Nyhan WL and O'Neill JP (2004) The spectrum of mutations causing HPRT deficiency: an update. Nucleosides Nucleotides and Nucleic Acids 23: 1153–1160.

Jinnah HA, Visser JE, Harris JC et al. (2006) Delineation of the motor disorder of Lesch–Nyhan disease. Brain 129: 1201–1217.

Jinnah HA, Wojcik BE, Hunt MA et al. (1994) Dopamine deficiency in a genetic mouse model of Lesch–Nyhan disease. Journal of Neuroscience 14: 1164–1175.

Jolly DJ, Okayama H, Berg P et al. (1983) Isolation and characterization of a full‐length expressible cDNA for human hypoxanthine phosphoribosyltransferase. Proceedings of the National Academy of Sciences of the United States of America 80: 477–481.

Lesch M and Nyhan WL (1964) A familial disorder of uric acid metabolism and central nervous system function. American Journal of Medicine 36: 561–570.

Lewers JC, Ceballos‐Picot I, Shirley TL et al. (2008) Consequences of impaired purine recycling in dopaminergic neurons. Neuroscience 152: 761–772.

Lloyd KG, Hornykiewicz O, Davidson L et al. (1981) Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch–Nyhan syndrome. New England Journal of Medicine 305: 1106–1111.

Matthews WS, Solan A and Barabas G (1995) Cognitive functioning in Lesch–Nyhan syndrome. Developmental Medicine and Child Neurology 37: 715–722.

Saito Y, Ito M, Hanaoka S et al. (1999) Dopamine receptor upregulation in Lesch–Nyhan syndrome: a postmortem study. Neuropediatrics 30: 66–71.

Schretlen DJ, Harris JC, Park KS, Jinnah HA and del Pozo NO (2001) Neurocognitive functioning in Lesch–Nyhan disease and partial hypoxanthine‐guanine phosphoribosyltransferase deficiency. Journal of the International Neuropsychology Society 7: 805–812.

Seegmiller JE, Rosenbloom FM and Kelley WN (1967) Enzyme defect associated with a sex‐linked human neurological disorder and excessive purine synthesis. Science 155: 1682–1684.

Visser JE, Bär PR and Jinnah HA (2000) Lesch–Nyhan disease and the basal ganglia. Brain Research Reviews 32: 449–475.

Visser JE, Schretlen DJ, Bloem BR and Jinnah HA (2011) Levodopa is not a useful treatment for Lesch–Nyhan disease. Movement Disorders (in press).

Wong DF, Harris JC, Naidu S et al. (1996) Dopamine transporters are markedly reduced in Lesch–Nyhan disease in vivo. Proceedings of the National Academy of Sciences of the United States of America 93: 5539–5543.

Further Reading

Christie R, Bay C, Kaufman IA et al. (1982) Lesch–Nyhan disease: clinical experience with nineteen patients. Developmental Medicine and Child Neurology 24: 293–306.

Emmerson BT and Thompson L (1973) The spectrum of hypoxanthine‐guanine phosphoribosyltranferase deficiency. Quarterly Journal of Medicine 166: 423–440.

Official website of the Lesch–Nyhan Disease International Study Group. http://www.lesch‐nyhan.org

Puig JG, Torres RJ, Mateos FA et al. (2001) The spectrum of hypoxanthine‐guanine phosphoribosyltransferase deficiency: clinical experience based on 22 patients from 18 Spanish families. Medicine 80: 102–112.

Watts RWE, Spellacy E, Gibbs DA et al. (1982) Clinical, post‐mortem, biochemical and therapeutic observations on the Lesch–Nyhan syndrome with particular reference to the neurological manifestions. Quarterly Journal of Medicine 201: 43–78.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Visser, JE, and Jinnah, HA(May 2011) Lesch–Nyhan Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006106.pub2]