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Mol Genet Genomic Med. 2018 Apr 12. doi: 10.1002/mgg3.389. [Epub ahead of print]

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

Author information

1
Division of Medical Genetics, University of Versailles, Paris-Saclay University, Montigny, France.
2
Department of Nephrology, Hypertension and Rheumatology, University Hospital Münster, Münster, Germany.
3
Neurological Unit, St Bassiano Hospital, Bassano del Grappa, Italy.
4
Referral Center for Cardiomyopathies, Cardiothoraco-vascular Department, Careggi University Hospital, Florence, Italy.
5
Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, MA, USA.
6
Formerly Sanofi Genzyme, Cambridge, MA, USA.
7
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
8
Second Department of Medicine - Department of Cardiovascular Medicine, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
9
Department of Infectious and Pediatric Immunology, University of Debrecen, Debrecen, Hungary.
10
Department of Nephrology, Royal Melbourne Hospital, and Department of Medicine, University of Melbourne, Parkville, VIC, Australia.
11
Unidad de Dialisis, IIS-Fundación Jiménez Díaz, School of Medicine, UAM, IRSIN and REDINREN, Madrid, Spain.
12
Department of Medicine and Surgery, Nephrology Unit, University of Milano-Bicocca, Monza, Italy.
13
Department of Pediatrics, Division of Genomic Medicine, UC Davis School of Medicine, Sacramento, CA, USA.
14
University of Sunderland, Sunderland, UK.
15
Renal Division, University Hospital of Würzburg, Würzburg, Germany.
16
Mark Holland Metabolic Unit, Salford Royal NHS Foundation Trust, Salford, UK.

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.

KEYWORDS:

GLA ; Fabry disease; cardiac variant; p.Asn215Ser; p.N215S; phenotype

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