Exploring a plasma proteomic biosignature associated with cardiac involvement in Fabry disease

Fabry disease (FD) is an X-linked lysosomal disorder caused by a deficiency in α-galactosidase A, leading to the accumulation of globotriaosylceramide (Gb3) and lysoGb3. While this accumulation was long seen as the leading cause of symptoms, FD pathogenesis now involves complex mechanisms like autophagy dysregulation, inflammation, oxidative stress, and inter-organelle communication. Cardiovascular diseases (CVD) remain a significant reason for premature death in FD. Gaining a better understanding of cardiac pathophysiology and developing new biomarkers for early detection and monitoring in FD are still essential. In this study, we proposed an FD-CVD protein signature by analyzing the plasma proteome of 55 FD patients, including 18 with CVD and 37 without (woCVD), and 30 non-FD controls. We found 141 altered proteins in FD-CVD compared to FD-woCVD. Among them, 38 differential proteins are related to cardiometabolism. Moreover, ten proteins were identified as potential biomarkers for differentiating FD-CVD from FD-woCVD. The 10-protein signature performed well in RF and partial least squares discriminant analysis models but had limited predictive ability in support vector machine and logistic regression. Importantly, this biosignature demonstrated an ability to classify FD and non-FD controls, regardless of CVD complications, with AUCs greater than 0.90. Using a local interpretable model-agnostic explanation, the RF model interpretation revealed the classification rule for FD-woCVD and highlighted the significance of GDF15, NOS1, CCN5, CTSF, and NAAA. Our findings suggest an early indication of combined cardiac involvement in FD, paving the way for future validation studies that may ultimately inform personalized treatment before irreversible heart damage develops. KEY MESSAGES: Cardiovascular diseases (CVD) remain the leading cause of premature death in Fabry. A ten-protein signature was identified to differentiate Fabry with and without CVD. The protein signature could classify Fabry with controls regardless of CVD status.