159 Plasma globotriaosylsphingosine and the natural Fabry disease course Levels of Globotriaosylsphingosine (lysoGb3), the water soluble, deacylated form of Gb3, are strongly associated with both disease type (classical or nonclassical) and sex of the patient [14, 15]. Additionally, lysoGb3 was found to be associated with several disease severity parameters in small studies, including left ventricular mass [16, 17], white matter lesions [17] and overall disease severity measured using the Mainz Severity Score Index (MSSI) [14, 16, 17]. Interestingly, even in patients that share the same GLA variant, those with higher lysoGb3 levels were more severely affected compared to those with lower plasma lysoGb3 levels [16]. In a more recent study, high lysoGb3 levels were linked to an increased risk for the development of clinically relevant endpoints, including kidney replacement therapy, ICD/pacemaker implantation and cerebrovascular events [18]. However, most studies were small, cross sectional and some included both treated and untreated patients. It is currently unknown whether plasma lysoGb3 levels are stable throughout life and represent an individual patient trait that can be assessed at any time, or that it increases/decreases with age. We hypothesized that, in untreated FD patients, plasma lysoGb3 remains stable and reflects how severely an individual FD patient is or will be affected. In this study, we investigated whether or not plasma lysoGb3 levels remained stable over time in untreated FD patients, we defined optimum cut-off values to classify patients (classical vs non-classical) and we used linear mixed models to test the relation of plasma lysoGb3 levels to disease manifestations and progression. Materials and Methods Patients This study was conducted in accordance with the principles of the Helsinki Declaration, as revised in 2013. Data were collected retrospectively from clinical records at the Amsterdam University Medical Center (Amsterdam UMC), location AMC, the national referral center for FD in the Netherlands. All included patients had a confirmed FD diagnosis and all patients and/or legal guardian signed informed consent. Data included basic diagnostic data, clinical and biochemical parameters, medication use, and the presence of comorbidities and cardiovascular risk factors. The risk factor ‘Smoking’ was scored as present in case of current or former smoking. Obesity was defined as a body mass index >30kg/m2 at time of lysoGb3 analyses. Hypertension was defined as either a previous diagnosis of hypertension treated with anti-hypertensive medication or an increased systolic or diastolic blood pressure measured on at least two occasions (i.e. 140/90 mmHg). Patients were classified as having a classical or non-classical phenotype as previously described by Arends et al [1]. A flow chart used to phenotype classification in clinical practice is added in the supplemental material (SM2). 5
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