Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study

• Type of Material: Article
• Authors: Dominique Germain, University of Paris-Saclay; Eva Brand, University Hospital Münster; Alessandro Burlina, St Bassiano Hospital; Franco Cecchi, Careggi University Hospital; Scott C. Garman, University of Massachusetts Amherst; Judy Kempf, Sanofi Genzyme; Dawn A Laney, Emory University; Ales Linhart, Charles University; Laszlo Marodi, University of Debrecen; Kathy Nicholls, University of Melbourne; Alberto Ortiz, Universidad Autónoma de Madrid; Federico Pieruzzi, University of Milano‐Bicocca; Suma Shankar, Emory University; Stephen Waldek, University of Sunderland; Christoph Wanner, University Hospital of Würzburg; Ana Jovanovic, Salford Royal NHS Foundation Trust
• Language: English
• Date: 2018-07-01
• Publisher: Wiley Open Access
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/mgg3.389
• Title of Journal or Parent Work: Molecular Genetics and Genomic Medicine
• ISSN: 2324-9269
• Volume: 6
• Issue: 4
• Start Page: 492
• End Page: 503
• Grant/Funding Information: The Fabry Registry is sponsored by Sanofi Genzyme.; D.P. Germain was supported by the Plan National Maladies Rares of the French Ministry of Health and A. Ortiz was supported by Intensificación FIS and FEDER Funds REDINREN RD012/0021.; The authors received editorial/writing support in the preparation of this manuscript from Tom Rouwette of Excerpta Medica, funded by Sanofi Genzyme, and Hans Ebels of Sanofi Genzyme.
• Keywords: phenotype; CARDIOMYOPATHY; GENE; OUTCOME SURVEY; GLA; cardiac variant; MANIFESTATIONS; Genetics & Heredity; ALPHA-GALACTOSIDASE-A; POINT MUTATIONS; IDENTIFICATION; p. Asn215Ser; CARDIAC VARIANT; NATURAL-HISTORY DATA; p. N215S; Life Sciences & Biomedicine; Science & Technology; Fabry disease; ATYPICAL VARIANT
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics; Biology, Molecular

Abstract

Background: The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. Methods: To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. Results: In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25–34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55–64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65–74 years), and rarely in females (3%). Conclusion: p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.