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

• 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
• Journal Title: Molecular Genetics and Genomic Medicine
• Volume: Volume 6, Number 4
• Publisher: Wiley Open Access | 2018-07-01, Pages 492-503
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1002/mgg3.389
• Subjects: Biology, Genetics; Biology, Molecular; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Genetics & Heredity; cardiac variant; Fabry disease; GLA; p. Asn215Ser; p. N215S; phenotype; ALPHA-GALACTOSIDASE-A; NATURAL-HISTORY DATA; ATYPICAL VARIANT; CARDIAC VARIANT; POINT MUTATIONS; OUTCOME SURVEY; GENE; MANIFESTATIONS; CARDIOMYOPATHY; IDENTIFICATION

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.