Lesch–Nyhan Disease

Abstract

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).

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Further Reading

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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.

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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]