26 Chapter 2 Introduction Fabry disease (FD) is a rare X-linked lysosomal storage disease that is caused by mutations in the galactosidase alpha (GLA) gene, resulting in reduced alphagalactosidase A enzyme activity [1, 2]. Accumulation of the enzyme’s substrate globotriaosylceramide (Gb3) and its derivatives is the primary trigger for damage and dysfunction of various tissues and organs, including vascular endothelium and the heart [3-5]. Due to the X-linked mode of inheritance, men are generally more severely affected and disease manifestations occur earlier compared to women. In addition, a distinction is made between classical and non-classical disease phenotype, with significant differences in onset and progression of symptoms, organ damage, and outcome between these two groups. The classical form of FD in men is characterized by greatly reduced or absent alpha-galactosidase A activity, resulting in manifestations in multiple organs, starting from late adolescence [6, 7]. Non-classical disease manifests itself later in adulthood and often affects only the heart [8-10]. Early cardiac manifestations of FD are bradycardia, shortened PR interval, low native T1 value on cardiac MRI and, in male and a subset of female patients, cardiac hypertrophy [11, 12]. As the disease progresses, conduction abnormalities (CA), supraventricular arrhythmias, ischemic heart disease, diastolic and systolic dysfunction and ultimately overt heart failure (HF), leading to cardiac death, may occur [3, 13-22]. On the other hand, a significant number of patients will remain asymptomatic, even at an advanced age [7]. Limited evidence is available on the risk and timing of cardiac manifestations and events in different patient groups (i.e. men versus women, classical versus non-classical FD phenotype) [3, 23]. It is important to generate these data, as it will guide patient-specific followup and timing of treatment initiation, risk assessment (e.g. for sudden cardiac death) and evaluation of new FD therapies that are currently in various stages of development. To answer the open questions, we performed a retrospective study in a FD cohort under follow-up at the Amsterdam UMC, which is unique in both its size, as well as the length of systematic follow-up of patients, providing detailed clinical data on cardiac outcome.
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