Lesch–Nyhan Syndrome

Abstract

Lesch–Nyhan syndrome is a dramatic X‐linked disease caused by deficient activity of the purine‐salvage enzyme hypoxanthine–guanine phosphoribosyltransferase (HPRT), leading to hyperuricemia and all of its clinical consequences. These manifestations, which the disease shares with gout, include hematuria, renal calculi, renal failure resulting from urate deposition in the parenchyma of the kidney, acute very painful arthritis, and tophaceous deposits in the cartilage of joints and the ears. The disease also includes a neurologic syndrome in which dystonia and its involuntary movements are associated with spasticity, making most patients wheelchair bound. Behavioural manifestations, possibly the most memorable feature of the disease, include self‐injurious behaviour. This takes a spectrum of forms, the most drastic of which is biting which leads to loss of tissue. The activity of the enzyme is readily measured in red blood cells. In the classic syndrome the activity is zero.

Key Concepts:

  • Lesch–Nyhan disease was the first example of a stereotyped pattern of abnormal behaviour in which there was a fundamental molecular etiology, the absence of activity of an enzyme.

  • The disease led to the development of the concept of behavioural phenotypes, and the coining of this phrase.

  • The gene is located on the X chromosome, and its expression in disease is almost exclusively in males.

  • Mutations in the gene represent the entire spectrum from missense and nonsense mutations to large deletions, and the rule in any family is for the mutation to be private.

  • The discovery of allopurinol, which lowers uric acid concentrations by inhibiting xanthine oxidase, has changed the pattern of disease from one of death in early infancy to childhood; now there are adults with the disease.

  • Successful treatment for neurologic and behavioural features of the disease has been elusive.

  • The enzyme is active in every cell. This fact has permitted some control of the disease in a family by heterozygote detection and pre‐natal diagnosis.

  • Heterozygote detection and pre‐natal diagnosis may be made by mutational analysis if mutation in the proband is known.

Keywords: HPRT; hyperuricemia; mutation; allopurinol

Figure 1.

Diagram of purine metabolic pathways (hypoxanthine–guanine phosphoribosyltransferase, HPRT; AMP, GMP and IMP, adenosine, guanine and inosine‐5′monophosphates, respectively). Illustration and legend unchanged.

Figure 2.

A 7‐year‐old boy with Lesch–Nyhan syndrome, illustrating the motor disability as exemplified by an inability to sit without support. Reprinted with permission from Nyhan WL, Barshop BA and Ozand PT (2005) Atlas of Metabolic Disease, Hodder Arnold, London. (This illustration unchanged. Legend updated to 2005 edition from 1998.)

Figure 3.

A 14‐year‐old boy, illustrating an extreme degree of mutilation around the face. Reprinted with permission from Nyhan WL, Barshop BA and Ozand PT (2005) Atlas of Metabolic Disease, Hodder‐Arnold London. (This illustration unchanged. Legend updated to the 2005 edition.)

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References

deGemmis P, Anesi L, Lorenzetto E et al. (2010) Analysis of the HPRT1 Gene in 35 Italian Lesch–Nyhan families: 45 patients and 77 potential female carriers. Mutation Research 692: 1–5.

Jinnah HA, Ceballos‐Picot I, Torres RJ et al. (2010) Attenuated variants of Lesch–Nyhan disease. Brain 133: 671–689.

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.

Nguyen KV, Naviaux RK, Paid KK and Nyhan WL (2011) Novel mutations in the human HPRT gene. Nucleosides, Nucleotides and Nucleic Acids 6: 440–445.

Sarafoglou K, Grosse‐Redlinger K, Boys CJ et al. (2010) Lesch–Nyhan variant syndrome: variable presentation in 3 affected family members. Archives of Neurology 67: 761–764.

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.

Miller AD, Jolly DJ, Friedmann T and Verma IM (1983) A transmissible retrovirus expressing human hypoxanthine phosphoribosyltransferase (HPRT): gene transfer into cells obtained from humans deficient in HPRT. Proceedings of the National Academy of Science of the USA 80: 4709–4713.

Nyhan WL, Barshop BB and Al‐Aqeel A (2012) Lesch–Nyhan disease. In: Atlas of Inherited Metabolic Disease. London: Hodder Arnold.

Nyhan WL, O'Neill JP, Jinnah HA and Harris JC (2009) Lesch–Nyhan Syndrome in Gene Reviews. www.geneclinics.org/profiles.

Nyhan WL, Page T, Gruber HE and Parkman R (1986) Bone marrow transplantation in Lesch–Nyhan disease. Birth Defects Original Article Series 22: 113–117.

Page T, Bakay B, Nissinen E and Nyhan WL (1981) Hypoxanthine–guanine phosphoribosyltransferase variants: correlation of clinical phenotype with enzyme activity. Journal of Inherited Metabolic Disease 4: 203–206.

Sege‐Peterson K, Chambers J, Page T et al. (1992) Characterization of mutations in phenotypic variants of hypoxanthine phosphoribosyltransferase deficiency. Human Molecular Genetics 1: 427–432.

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 Science of the USA 93: 5539–5543.

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How to Cite close
Nyhan, William L(Mar 2012) Lesch–Nyhan Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001457.pub2]