173 Plasma globotriaosylsphingosine and the natural Fabry disease course plasma lysoGb3 at the time of diagnosis could help predict the disease course in an individual patient, irrespective of the age at diagnosis. The strict association of plasma lysoGb3 with disease type (e.g. classical or non-classical disease) − regardless of the age of analysis− further supports this observation (figure 2, [14, 17, 27, 28]). In fact, we showed that plasma lysoGb3 levels can differentiate between the classical and non-classical phenotype with 99% accuracy in male patients and 92% accuracy in female patients and could thus be used as the decisive parameter to determine the disease type in an individual with a GLA variant of unknown significance. We confirmed the reverse association of plasma lysoGb3 with decline in renal function (figure 3a, [14, 16]) and verified that this association was not mainly driven by male patients with the classical disease type (who are known to have more renal involvement compared to patients with the other phenotypes). A similar effect was found when looking at albuminuria: higher lysoGb3 levels in plasma were associated with a faster increase in uACR (figure 3b). The strongest association we found, is that between plasma lysoGb3 levels and increase in LVMi (figure 4a, [16, 17]). In non-FD patients, LVH is strongly associated with overall mortality, myocardial infarction and stroke [29]. In FD patients, higher LVMi on echocardiography was also associated with higher clinical event rate [9]. A new finding is the association of plasma lysoGb3 with markers of diastolic (dys)function, measured by echocardiography (e’, E/e’ and LAVI). This is particularly relevant since heart failure with preserved ejection fraction (HFpEF), the clinical syndrome caused by diastolic dysfunction, is a major cause of heart failure in FD [30] and heart failure is currently the leading causes of symptoms and death in FD patients [2]. In many other diseases, higher e’, E/e’ and LAVI values are strongly associated with increased mortality and increased occurrence of clinical cardiac endpoints [31-34]. The associations indicate that lysoGb3 does not only have a relationship with cardiac morphology, but also with cardiac function and the risk of developing HFpEF. Lastly, we found that higher lysoGb3 levels were associated with a faster progression of white matter lesions in the brain on MRI. One of the main drawbacks of this study was that this was not a prospective study with longitudinal data collection after an initial lysoGb3 measurement. This represents the real world situation in which many patients were started on treatment and long term untreated data of new patients are simply not available. Strictly speaking, this makes our dataset unfit to be used for prediction modelling. However, we showed the stability of lysoGb3 in individual (untreated) patients, suggesting that the measured lysoGb3 value represents a static individual FD trait which justifies its use in prognostication. 5
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