190 Chapter 6 of onset. Consequently, there is still uncertainty about the need and timing of treatment for an individual female patients with (cFD) [13, 18, 19]. The previously mentioned minimal distinction between classical and non-classical and males and females has shown that the effect of therapy is most clear in classically affected males [20]. The natural history of classically affected males is also more uniform than the disease course in men with non-classical FD and classically affected females. At the other end of the spectrum, the non-classically affected females, the disease course is also better understood: in fact in this sub-group, the risk for complications related to FD is minimal. What is left, is the more heterogeneous group of “in between” patients: the classically affected females and non-classically affected males. Specifically classically affected females are a challenge, since random X-inactivation plays a role as well [21], contributing to the heterogeneity and thus the unpredictability of the disease course. Identifying those patients that will develop clinically significant organ involvement and dysfunction in this subgroup is therefore the most challenging. The hypothesis, is that some women with cFD exhibit progressive changes on, for example, the ECG or echocardiogram, but in another subset, little or no changes in disease markers were observed. From this perspective, it is crucial to determine when and which markers become progressive in this group in order to identify the patients who are at risk for disease progression and probable cardiovascular events. In the studies outlined in chapter 2-4, we identified electrophysiological and echocardiographic markers of FD cardiomyopathy (other than left ventricular mass) which are incorporated into a disease development model in figure 1 and 2. The model will primarily aid in detecting cardiac involvement at an earlier, asymptomatic disease stage in women with cFD. Secondarily, it will help evaluate the effect of (new) FD treatments [22] on cardiac disease progression in both men and women with cFD since overt clinical complications take decades to develop, far surpassing the duration of clinical trials. Implications of the findings in classically affected females for males with non-classical FD In the study described in chapter 2, men with non-classical FD formed 12% of the Fabry population at the AUMC at the time of the investigations [2]. This group is not included in the in the studies in chapter 3-4, which deal with early disease markers because these patients are often diagnosed later in life and the number of investigations prior to development of disease complications in these patients was too low for a longitudinal study. We do have information on the development of cardiac complications over time in this patient group (chapter 2). In agreement with previous studies, we found, that men with non-classical FD have an almost identical disease course as women with cFD [1, 23]. It could therefore be argued that the identified cardiac markers in the women with cFD
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