RT Journal Article SR Electronic T1 Lyso-Gb3 associates with adverse long-term outcome in patients with Fabry disease JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 287 OP 293 DO 10.1136/jmedgenet-2020-107338 VO 59 IS 3 A1 Nowak, Albina A1 Beuschlein, Felix A1 Sivasubramaniam, Visnuka A1 Kasper, David A1 Warnock, David G YR 2022 UL http://jmg.bmj.com/content/59/3/287.abstract AB 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.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.