Genotypic and Phenotypic Spectrum in Attenuated Variants of Lesch-Nyhan Disease

Mol Genet Metab. 2014 Aug;112(4):280-5. doi: 10.1016/j.ymgme.2014.05.012. Epub 2014 May 28.


Lesch-Nyhan disease and its attenuated variants are caused by deficiency of the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). All patients exhibit excessive production of uric acid, which increases the risk for nephrolithiasis, renal failure, gouty arthritis and tophi. The mildest phenotype includes only problems related to overproduction of uric acid. The most severe clinical phenotype includes prominent neurological abnormalities and the universal feature is self-injurious behavior. In between the mildest and most severe syndromes is a broad spectrum of phenotypes with varying degrees of neurological, neurocognitive and behavioral abnormalities. The effect of HPRT1 gene mutations on residual HGprt enzyme activity is the most relevant factor contributing to disease phenotype. Attenuated clinical phenotypes are associated with residual enzyme function, whereas the most severe phenotype is usually associated with null activity. In cases of gouty arthritis with urate overproduction, a careful evaluation for motor impairments or neurocognitive abnormalities may help to identify attenuated variants of Lesch-Nyhan disease for better management.

Keywords: Genotype; Lesch–Nyhan disease; Lesch–Nyhan variant; Phenotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Behavior
  • Genetic Association Studies*
  • Humans
  • Hypoxanthine Phosphoribosyltransferase / deficiency
  • Lesch-Nyhan Syndrome / diagnosis
  • Lesch-Nyhan Syndrome / genetics*
  • Lesch-Nyhan Syndrome / pathology*
  • Lesch-Nyhan Syndrome / therapy
  • Mutation / genetics*
  • Uric Acid / metabolism


  • Uric Acid
  • Hypoxanthine Phosphoribosyltransferase