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

Dominique P Germain,Eva Brand,Alberto Ortiz,Ana Jovanovic,Judy Kempf,Suma P Shankar,Aleš Linhart,Scott C Garman,Federico Pieruzzi,Christoph Wanner,Franco Cecchi,Kathy Nicholls,László Maródi,Stephen Waldek,Dawn A Laney,Alessandro Burlina

doi:10.1002/mgg3.389

Abstract

BackgroundThe p.Asn215Ser or p.N215S GLA variant has been associated with late‐onset cardiac variant of Fabry disease.MethodsTo 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.ResultsIn 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%).Conclusionp.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.

Highlights

Fabry disease (OMIM #301500) is an X-linked lysosomal storage disorder caused by mutations in the GLA (OMIM #300644; HGNC 4296; NCBI reference sequence NM_000169.2) gene encoding enzyme a-galactosidase (a-Gal, EC 3.2.1.22; Uniprot P06280) (Desnick, Ioannou, & Eng, 2001; Germain, 2010)
In p.N215S males, mildly abnormal mean interventricular septum thickness (IVST) and left ventricular posterior wall thickness (LVPWT) values were observed in patients aged 25–34 years, and values gradually increased with advancing age
It has been reported that cardiac variant patients may have significant levels of residual a-Gal activity [2%–20% of normal (Germain, 2001; Ishii et al, 1993, 2007; Spada et al, 2006)] and generally lack the early classic symptoms of Fabry disease, with manifestations being confined to the heart predominantly

Summary

Introduction

Fabry disease (OMIM #301500) is an X-linked lysosomal storage disorder caused by mutations in the GLA (OMIM #300644; HGNC 4296; NCBI reference sequence NM_000169.2) gene encoding enzyme a-galactosidase (a-Gal, EC 3.2.1.22; Uniprot P06280) (Desnick, Ioannou, & Eng, 2001; Germain, 2010). It has been reported that cardiac variant patients may have significant levels of residual a-Gal activity [2%–20% of normal (Germain, 2001; Ishii et al, 1993, 2007; Spada et al, 2006)] and generally lack the early classic symptoms of Fabry disease (e.g., neuropathic pain, gastrointestinal complaints, angiokeratoma, cornea verticillata), with manifestations being confined to the heart predominantly (left ventricular hypertrophy, conduction disturbances, arrhythmias) These patients generally present later in life than classic patients (Elleder et al, 1990; Germain, 2010; Nakao et al, 1995; Patel et al, 2015; Sachdev et al, 2002; von Scheidt et al, 1991), or may be diagnosed earlier as a result of neonatal, family or high-risk population screening initiatives.

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