Fabry disease is a rare lysosomal storage disease, caused by pathogenic mutations in the alpha-galactosidase-A gene resulting in a dysfunctional enzyme. Over two decades ago, enzyme replacement therapy (ERT) became available for patients, with approval based on mostly surrogate (pre-clinical) endpoints. Over the years it became evident that treatment may slow down disease progression when initiated early in the disease process, but cannot fully halt disease progression. Therefore, research into new treatment methods has recently increased, with a multitude of new drugs currently in (clinical) research. Meanwhile, the availability of a treatment for Fabry disease has led to an increase in (genetic) diagnostics and the discovery of many GLA variants associated with a milder- or uncertain disease course. The clinical distinction between ‘classical’ disease (more severe) and ‘non-classical’ disease (milder) has helped to improve prognostic information and clinical decision making. However, Fabry disease appears to be more of a spectrum then a dichotomous disease, ranging from the GLA variant impacting cardiovascular risk only, to severe monogenetic multi-organ disease. Finally, the negative impact of the development of neutralizing antibodies against ERT has long been underestimated. The aim of this thesis is therefore threefold, I. to improve prognostic information in newly diagnosed patients regarding their expected disease course. II. Examining the clinical effects of antibodies against ERT and analyzing which patients are most at risk for developing them. III. Finding leads to make the treatment of FD more effective, by optimizing the timing of treatment initiation and by preventing antibody formation.