Enzyme replacement therapy in Fabry disease, towards individualized treatment

Fabry disease is a very heterogeneous disorder for which expensive enzyme replacement therapy is available since more than 15 years. Because of the variety of symptoms and disease course, individual choices need to be made to improve the appropriate use of therapy. Supported by ZONWM, we have been able to create a unique, independent, database, of almost 600 Fabry disease patients from three European Fabry disease centers of excellence. The aim of this thesis was to describe the differences in the disease course between treated and untreated male and female patients with a classical or a non-classical phenotype and the effects of two different enzymes. We established that phenotype (classical or non-classical) and gender were major determinants for the disease severity in untreated patients. This crucial information could then be used to study effects of enzyme replacement therapy, showing that, after adjustment for gender, phenotype and age, we could identify risk factors for disease progression, including renal function at baseline, a history of one or more events and left ventricular mass. Importantly, we have also been able to show differences in effect of enzyme replacement therapies, with less immunogenicity of agalsidase alfa, but better biochemical and, albeit limited, clinical improvement for the higher dosed agalsidase beta. In conclusion, the results of this thesis will fuel the discussion on start and stop criteria for enzyme replacement therapy and highlight the importance of phenotype, gender and age in the evaluation of the disease course.