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Abstract
Background Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A gene (GLA) leading to deficiency of α-galactosidase A and ultimately in progressive glycosphingolipid accumulation, especially globotriaosylceramide (Gb3) and its deacylated derivative globotriaosylsphingosine (Lyso-Gb3). The aim of the study was to assess plasma Lyso-Gb3 levels as a possible factor associated with adverse outcomes in FD.
Methods In a cohort of 66 patients with genetically confirmed FD (26 males and 40 females), we analysed serum Lyso-Gb3 as a factor associated with adverse clinical outcomes in a long-term study. The main outcome was a composite endpoint of incident kidney replacement therapy, atrial fibrillation, pacemaker and/or implantable cardioverter defibrillator, cerebrovascular events or death, whichever occurred first.
Results During the median follow-up time of 68 (40–80) months, events occurred in 19 (29%) of the patients. In a Cox multivariate regression analysis, Lyso-Gb3 levels (HR 4.62 (1.55 to 13.81); p=0.006) and the pretreatment exposure to Lyso-Gb3 (HR 3.41 (1.11 to 10.49); p=0.03) (both per SD increase) were significantly associated with adverse outcomes. If pretreatment Lyso-Gb3 exposure was added to multivariable logistic regression models containing age, sex, phenotype and enzyme replacement therapy as other covariates with the composite outcome as dependent variable, the area under the curve for the composite outcome significantly improved from 0.72 to 0.86 (p comparison=0.04).
Conclusion Lyso-Gb3 is a significant risk factor associated with important clinical events. Whether treatment-related amelioration of Lyso-Gb3 levels will be associated with improved long-term outcome needs to be established in prospective intervention trials.
- genetics
- medical
- human genetics
- phenotype
- genotype
Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Deidentified participant data is available from the first author upon reasonable request as a data file under the email address albina.nowak@usz.ch.
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Data availability statement
Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Deidentified participant data is available from the first author upon reasonable request as a data file under the email address albina.nowak@usz.ch.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Correction notice This article has been corrected since it first published. The provenance and peer review statement has been included.
Contributors AN contributed to conception and design of the work, acquisition, analysis and interpretation of data and drafting the manuscript. FB contributed to interpretation of data and final approval of the last version. VS and DK contributed to acquisition of data, interpretation of data and final approval of the last version. DGW contributed to design of the work, acquisition, analysis and interpretation of data and final approval of the last version.
Funding The Lyso-Gb3 measurements were determined by ARCHIMED Life Science, Vienna, Austria. The ARCHIMED Life Science laboratory member DCK participated in writing and approving the manuscript. The laboratory members were blinded to patients' names and all clinical and biochemical information and had no role in the collection of samples, interpretation of data and the decision to submit the article for publication.
Competing interests AN received lecturing honoraria and research support from Sanofi Genzyme, Takeda and Amicus and received financial publication support for this article from Sanofi Genzyme. DGW serves as a consultant for Amicus, Protalix, and Chiesi Pharma.
Provenance and peer review Not commissioned; externally peer reviewed.
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