11 General introduction and thesis outline related complications whilst being treated with enzyme replacement therapy (ERT) [13, 14]. This may be partly explained by the fact that in cardiac biopsies of FD patients, treatment with ERT did not result in significant Gb3 clearance from cardiomyocytes within five months [15]. However, the pathophysiology is probably more complex, several specific hypothetical pathways, that link the Gb3 storage to the cardiac impairment in FD have been described. First, as a consequence of Gb3 accumulation, cardiomyocytes, endothelial and smooth muscle cells proliferate. This proliferation leads to an increased oxygen demand of the cardiac muscle, which cannot be met because of microvascular dysfunction caused by low nitric oxide synthase (eNOS) expression in the affected endothelial cells. The microvascular dysfunction limits capillary elasticity and resulting oxygen deficit leads to ischemia and fibrosis [16]. Second, lysosomal glycosphingolipid accumulation suppresses the autophagic processes in the cell [17]. A disturbed autophagic flux also affects mitophagy, which in turn interferes with the mitochondrial energy production, resulting in reduced activity of the respiratory chain complexes I, IV and V and further drop in cellular levels of energy-rich phosphates (e.g. ATP). This cardiac energy metabolism dysfunction and the increased oxygen demand due to LVH may result in decreased ischemic tolerance [18-20]. Third, a deficiency of alpha-galactosidase A limits the degradation of lipidic antigens. In FD, Gb3 and lysoGb3 (a water- soluble deacylated form of Gb3) act as antigens, activating NK T-cells. This leads to the secretion of pro-inflammatory factors and oxidative species, which may enhance the processes of cell damage and death [21, 22]. Lastly, Birkel et al. (2019) also found an impaired sodium and calcium channel function in FD cardiomyocytes, derived from pluripotent stem cells, with a higher and shorter action potential [23]. These findings support the hypothesis that conduction abnormalities in FD are not only explained by tissue damage and fibrosis, but that an altered ion channel expression on cell membranes may contribute to the increased electrical depolarization velocities observed in FD [24]. The phenotype and genotype of FD Because of the X-linked chromosomal inheritance of FD, men typically have more severe symptoms and are affected earlier in life than women with FD. Additionally, classical and non-classical disease phenotypes are distinguished, with substantial variations in symptomatology, organ involvement and prognosis. Classical FD is characterized by a significantly reduced or, in men (almost), absent AGAL activity. These male patients often present in childhood with typical classical symptoms, including angiokeratomas, cornea verticillata and neuropathic pain. The presence of this triad is a strong predictor for the diagnosis of classical FD, in which the majority of classical FD patients develop multiorgan involvement of the kidneys, brain and heart during late adolescence or 1
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