Exosome-Based Proteomic Profiling for Biomarker Discovery in Pediatric Fabry Disease: Insights into Early Diagnosis Monitoring

ABSTRACT: Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by GLA mutations, leading to deficient α-galactosidase A (α-Gal A) activity and progressive glycosphingolipid accumulation. While α-Gal A activity is the diagnostic gold standard, its sensitivity is reduced in late-onset or heterozygous patients. Conventional biomarkers such as lyso-Gb3 provide only limited insight into disease progression and therapeutic response. Exosomes, as stable carriers of disease-specific proteins, may offer complementary biomarkers for early detection and longitudinal monitoring. Methods: 21 pediatric FD patients with confirmed GLA mutations were enrolled. Clinical, enzymatic, renal, and cardiac parameters were assessed. Plasma-derived exosomes were characterized by transmission electron microscopy and proteomic profiling. Differentially expressed proteins were identified by mass spectrometry, analyzed by GO/KEGG enrichment, and validated using RT-PCR, ELISA, and immunofluorescence in patient samples and Gla-/- mice. Results: Male patients showed markedly reduced α-Gal A activity and elevated lyso-Gb3 compared to females. Although overt renal and cardiac dysfunction was uncommon, several patients exhibited early abnormalities such as proteinuria, elevated LVMI, or increased cTnI. Proteomic analysis identified 2,553 proteins, of which 188 were differentially expressed. Fibrosis- and inflammation-related proteins including THBS1 and CFHR5 were upregulated, while protective factors such as APM1, SERPINA10, and CAB39 were downregulated. IGFBP3 was also elevated and closely linked to tissue remodeling. Enriched pathways involved PPAR/AMPK signaling, lipid metabolism, and complement activation. Conclusions: Exosomal proteomic profiling reveals early molecular signatures of cardiorenal involvement in pediatric FD. Key proteins such as THBS1, CFHR5, IGFBP3, APM1, and CAB39 show strong potential as biomarkers for risk stratification, disease monitoring, and therapeutic evaluation.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Yu Xia  

LAB HEAD: Yu Xia

PROVIDER: PXD069403 | Pride | 2025-12-08

REPOSITORIES: Pride