158 Chapter 5 Introduction Fabry disease (FD; OMIM 301500) is a rare X-linked lysosomal storage disease, caused by pathogenic mutations in the alpha-galactosidase A (GLA) gene. Depending on the mutation, FD patients can either have total or partial alphagalactosidase A (αGalA) deficiency, which roughly corresponds with either a classical (more severe) or a non-classical (attenuated) disease phenotype [1]. Due to the X-linked inheritance, female patients develop a milder disease phenotype compared to male patients and some female patients can remain without clinical events up to the 8th decade of life [1, 2]. Due to the αGalA deficiency, the lipid Globotriaosylceramide (Gb3) cannot be broken down properly and accumulates in the lysosomes of the cell. The intracellular accumulation of Gb3 and its derivatives is thought to set in motion several pathophysiological processes, ultimately resulting in a variety of clinical symptoms. Left ventricular hypertrophy and myocardial fibrosis often occurs and may result in (diastolic) heart failure and arrhythmias [2], podocytes loss and fibrosis in the kidneys can cause proteinuria and renal failure [3, 4] and vascular dysfunction may result in the development of white matter lesions (WMLs), transient ischemic attacks (TIAs) and strokes [5]. Patients with the most severe phenotype (e.g. male patients with a classical disease type), always become symptomatic and seem to benefit from early treatment initiation with enzyme replacement therapy (ERT) [6-8]. Starting ERT in patients with more advanced disease (e.g. with advanced myocardial fibrosis or impaired renal function), no longer seems to alter disease course [9-12]. This supports early treatment initiation. However, while there is no discussion whether or not male patients with classical disease need treatment, the remaining groups contain both patients at risk for complications, as well as those with a (near) normal life expectancy, who will develop no or minimal FD related clinical symptoms [1, 2, 13]. It’s unlikely that this last group would significantly benefit from lifelong biweekly ERT infusions. This poses an important clinical dilemma; not all patients will develop clinically relevant symptoms of FD warranting targeted treatment, but those who will become symptomatic, seem to benefit from early treatment initiation [6]. In addition, for patients presenting with new GLA variants and minor and/or nonspecific symptoms, it’s not always clear whether the variant is disease causing- or benign, especially in women, in whom enzyme activity can be normal. Therefore, in current clinical practice, many patients are in routine follow up to identify early signs of organ manifestations so that the window of opportunity for treatment will not be missed. In order to reduce over-medicalization of patients and to improve efficiency of clinical care, there is a need for a tool to stratify FD patients by their risk for developing complications.
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