172 Chapter 5 Table 2: Summary of the performed statistical analyses for every included disease manifestation of FD (continued) FD disease manifestation Included variables In analyses Estimate Of effect Confidence Interval (95%) P value Min Max LAVI (ml/m2) - Excluding CMFD* Log10(LysoGb3) -18.69 -35.61 -1.778 0.031 Age (years) 0.014 -0.266 0.294 0.921 Log10(LysoGb3)*Age 0.534 0.190 0.879 0.003 Fazekas score - Excluding CMFD* Log10(LysoGb3) -1.612 -3.434 0.177 0.079 Age (years) 0.011 -0.021 0.043 0.485 Log10(LysoGb3)*Age 0.062 0.021 0.103 0.003 All analyses are done using linear mixed effect models correcting for multiple measurements using patient ID as a random variable (random intercept). LysoGb3 was transformed (Log10) to improve fit of the models. For each analyses the variables ‘sex’ and ‘presence of cardiovascular risk factors‘ (e.g. one or more of the following risk factors were present: hypertension, obesity, smoking) were tested alongside age and individual lysoGb3 values (lysoGb3 was used as a continues variable). Apart from age and lysoGb3 value, only variables that significantly influenced the model (p<0.05) were included in the final model. P values below 0.05 are underlined. *CMFD classical male Fabry patients, To assess if the effect remains after excluding male patients with classical FD analyses are performed with and without this group. For some variables, we lacked sufficient data of untreated classical male patients above the age of 30. *uACR was measured as mg/mmol before transformation to logscale (log10). Discussion In this study, we show for the first time that plasma lysoGb3 stays stable over decades in individual FD patients from childhood onwards (figure 1). Additionally, we showed that plasma lysoGb3 levels are associated with either the severity or progression of nearly all measured FD manifestations. Combined, these findings suggest that plasma lysoGb3 reaches a stable level early on, and indicates which disease burden can be expected later in life. This is in contrast to Gb3 accumulation in -for example- podocytes, which has been shown to slowly increase over time [25]. Interestingly, after start of ERT, plasma lysoGb3 levels reach a new equilibrium within a year after start of treatment (in the absence of anti-drug antibodies) [26]. Once this new level is established, it only changes if the ERT dose is changed [26] or treatment is stopped. Why plasma lysoGb3 remains stable in the untreated state and rapidly reaches a new equilibrium during treatment is currently unknown. Clinically, FD is a slowly progressive disease and children/young adults do not always show clinical signs of the disorder yet. Our data suggest that measuring
RkJQdWJsaXNoZXIy MTk4NDMw