Fabry disease (FD) is an X-linked lysosomal rare disease due to a deficiency of α-galactosidase A activity. The accumulation of glycosphingolipids mainly affects the kidney, heart, and central nervous system. Although the accumulation of undegraded substrate is considered the primary cause of FD, it is established that secondary dysfunctions at the cellular, tissue, and organ levels ultimately give rise to the clinical phenotype. To parse this biological complexity, a large-scale deep plasma targeted proteomic profiling is performed. In this report the plasma protein profiles of FD deeply phenotyped patients (n = 55) is analyzed compared to controls (n = 30) using next-generation plasma proteomics including 1463 proteins. Systems biology and machine learning approaches is used. The analysis enables the identification of proteomic profiles that unambiguously separates FD patients from controls. The findings highlight the pro-inflammatory cytokines’ involvement in FD pathogenesis along with extracellular matrix remodeling. This study shows a tissue-wide metabolic remodeling connection to plasma proteomics in FD. These results will facilitate further studies to understand the molecular mechanisms in FD to pave the way for better diagnostics and therapeutics. Read the full article here.