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Author Notes:

Correspondence: dschret@jhmi.edu

Wynne Callon, Rebecca Ward, and Barry Gordon declare that they have no conflict of interest.

Under an agreement with Psychological Assessment Resources, Inc., Dr. Schretlen also is entitled to a share of royalty on sales of a test used in the study described in this article.

The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

Subjects:

Research Funding:

Rong Fu received grant support from the National Institutes of Health (R01 HD053312) for the study described in this article.

Tiffany Ho received grant support from the National Institutes of Health (R01 HD053312) for the study described in this article.

James Harris received grant support from the National Institutes of Health (R01 HD053312) for the study described in this article.

H. A. Jinnah received grant support from the National Institutes of Health (R01 HD053312) for the study described in this article.

David Schretlen received grant support from the National Institutes of Health (R01 HD053312) for the study described in this article.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Endocrinology & Metabolism
  • Genetics & Heredity
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • GENOTYPE-PHENOTYPE CORRELATIONS
  • SERUM URIC-ACID
  • PURINE METABOLISM
  • ATTENUATED VARIANTS
  • COGNITIVE FUNCTION
  • HPRT DEFICIENCY
  • ABNORMALITIES
  • SPECTRUM
  • ENZYME
  • UPDATE
  • Dystonia
  • Hypoxanthine
  • Hyperuricemia
  • Enzyme Activity Level
  • Hypoxanthine Phosphoribosyltransferase

Do clinical features of Lesch-Nyhan disease correlate more closely with hypoxanthine or guanine recycling?

Tools:

Journal Title:

Journal of Inherited Metabolic Disease

Volume:

Volume 39, Number 1

Publisher:

, Pages 85-91

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Lesch-Nyhan disease (LND) is a rare, X-linked recessive neurodevelopmental disorder caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGprt), an enzyme in the purine salvage pathway. HGprt has two functions; it recycles hypoxanthine and guanine. Which of these two functions is more relevant for pathogenesis is unclear because some evidence points to hypoxanthine recycling, but other evidence points to guanine recycling. In this study, we selectively assayed hypoxanthine (Hprt) and guanine (Gprt) recycling in skin fibroblasts from 17 persons with LND, 11 with an attenuated variant of the disease (LNV), and 19 age-, sex-, and race-matched healthy controls (HC). Activity levels of both enzymes differed across groups (p < 0.0001), but only Gprt distinguished patients with LND from those with LNV (p < 0.05). Gprt also showed slightly stronger correlations than Hprt with 13 of 14 measures of the clinical phenotype, including the severity of dystonia, cognitive impairment, and behavioral abnormalities. These findings suggest that loss of guanine recycling might be more closely linked to the LND/LNV phenotype than loss of hypoxanthine recycling.

Copyright information:

© 2015, SSIEM.

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