113 Echocardiographic changes in Fabry disease Introduction Fabry disease (FD) is a rare X-linked inherited lysosomal function disorder caused by mutations in the galactosidase alpha (GLA) gene (OMIM 301500), leading to reduced activity of the enzyme alpha- galactosidase A [1, 2]. The main enzyme substrate, globotriaosylceramide (Gb3) and its derivatives accumulate in different tissues causing progressive dysfunction of, most prominently, kidneys, brain and heart [3, 4]. This study focuses on the cardiac manifestations of the disease and how they can be tracked by the echocardiogram. Initial cardiac manifestations of FD may include bradycardia, a low native T1 value on cardiovascular magnetic resonance (CMR) and left ventricular hypertrophy (LVH). As the disease progresses, conduction abnormalities, (supra)ventricular arrhythmias, ischemic heart disease, left ventricular dysfunction and ultimately overt heart failure (HF) leading to cardiac death may develop [3-6]. Since FD has an X-linked inheritance pattern, the disorder is generally more severe in men than in women. FD can be classified into a classical phenotype with early onset of manifestations, or a non- classical, more attenuated (lateonset) phenotype. Even within disease groups stratified by sex and phenotype, there is large heterogeneity in cardiac disease severity and age of symptom onset [5-7]. This heterogeneous disease course (especially in women with classical FD) [6, 8] creates a significant challenge in distinguishing between patients at risk of developing cardiac events, requiring intensive monitoring and treatment from those who are unlikely to develop cardiac complications. Identification of patients at risk is critical, as an increasing number of studies suggest that Fabry specific therapy should be instigated at an early age in order to have impact on disease development [9, 10]. Potentially, early cardiac manifestations as detected by echocardiography might be helpful for identifying FD patients at risk of a severe disease course. Also, changes in echocardiographic markers may be useful to monitor whether or not the development or progression of FD cardiomyopathy is halted by new FD specific therapies [11]. One of the main advantages of the echocardiogram is that it is an easily accessible and affordable diagnostic tool, especially when FD patients are unable to undergo CMR due to an implantable cardiac device or because of claustrophobia. Initial echocardiographic functional alterations in FD are subtle, such as a reduced global longitudinal strain (GLS) [12, 13]. During adult life, LVH, left atrial dilatation and diastolic dysfunction, mainly with a preserved ejection fraction, can develop. At this stage there may also be secondary heart valve 4
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