12 Chapter 1 young adulthood, which is progressive throughout adulthood [25, 26]. In women angiokeratoma are not observed, cornea verticillata and neuropathic pain are present in a subset of patients and cardiac and cerebral disease develop in average 10 years later and not all patients are affected [27, 28]. Non-classical FD patients have higher residual activity of the AGAL enzyme due to the less disruptive GLA mutations. In the non-classical patient group, involvement of only the heart is more common. The diagnosis of non-classical FD is usually made at a later age than classical FD, as it often presents with more atypical symptoms and lacks the ‘classical triad’ of FD symptoms [2931]. The abovementioned categorization by phenotype and sex is essential for prognostication, guiding treatment and follow-up. Diagnosing FD Diagnosing FD in individuals with non-classical disease and women with classical FD, which often lack Fabry specific- symptoms, can be challenging since not all GLA- gene variants cause disease [26]. Genetic testing panels may help diagnose Fabry cardiomyopathy, which can mimic hypertrophic cardiomyopathy (HCM) [32]. If there is any uncertainty regarding the pathogenicity of a GLA variant this can be assessed by biochemical and enzymatic test, segregation studies in the family and if uncertainty persists by organ imaging and biopsies [33]. A GLA variant is deemed to be pathogenic if it leads to: 1) an increased level of lysoGb3 in the range of FD patients (male and female patients) [34, 35], 2) a significantly reduced enzyme activity level (in all male patients and some female patients) and if 3) a biopsy of an affected organ showing typical zebra body inclusions in a relevant cell type or the appearance of a low native T1-value on cardiac MRI, most likely representing myocardial sphingolipid accumulation [36]. Cardiac involvement of FD Common cardiac manifestations of FD include LVH [37-40], valvular heart disease [41], myocardial fibrosis [20, 42], microvascular disease [43, 44] and conduction abnormalities [45, 46]. Clinically, Fabry cardiomyopathy is manifested by chronic heart failure with a preserved ejection fraction (HFpEF) [47], angina pectoris (often without underlying coronary artery disease) [44] and/or (supra)ventricular arrhythmias (e.g., sinus bradycardia, atrial fibrillation (AF), and (non)sustained ventricular tachycardia). Fabry patients often suffer from brady-tachycardia syndromes warranting the implantation of a pacemaker and/or implantation of a ICD to prevent acute cardiac death due to malignant arrhythmias [48]. Cardiovascular death is the most common cause of death in patients with FD [7]. Given the cardiac morbidity and mortality in FD patients, research should
RkJQdWJsaXNoZXIy MTk4NDMw