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

• Type of Material: Article
• Authors: David J. Schretlen, Johns Hopkins University; Wynne Callon, Johns Hopkins University; Rebecca E. Ward, Johns Hopkins University; Rong Fu, Emory University; Tiffany Ho, Johns Hopkins University; Barry Gordon, Johns Hopkins University; James C. Harris, Johns Hopkins University; Hyder A Jinnah, Emory University
• Language: English
• Date: 2016-01-01
• Publisher: Springer Verlag (Germany)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015, SSIEM.
• Final Published Version (URL): http://dx.doi.org/10.1007/s10545-015-9869-x
• Title of Journal or Parent Work: Journal of Inherited Metabolic Disease
• ISSN: 0141-8955
• Volume: 39
• Issue: 1
• Start Page: 85
• End Page: 91
• Grant/Funding Information: H. A. Jinnah 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.; David Schretlen received grant support from the National Institutes of Health (R01 HD053312) for the study described in this article.; Rong Fu 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.
• Keywords: PURINE METABOLISM; Genetics & Heredity; Endocrinology & Metabolism; Enzyme Activity Level; Science & Technology; Hypoxanthine Phosphoribosyltransferase; Hyperuricemia; ENZYME; Dystonia; Research & Experimental Medicine; ATTENUATED VARIANTS; Hypoxanthine; HPRT DEFICIENCY; ABNORMALITIES; Medicine, Research & Experimental; SERUM URIC-ACID; UPDATE; SPECTRUM; COGNITIVE FUNCTION; Life Sciences & Biomedicine; GENOTYPE-PHENOTYPE CORRELATIONS
• Research Categories: Biology, Genetics; Biology, Neuroscience

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.