Challenging the Conventional Treatment Initiation Paradigm: Early Detection of Irreversible Cellular Damage in Cardiac Biopsies of Fabry Disease Before the Formation of Gb3 Inclusion Bodies

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Abstract
Background Fabry disease (FD) is a rare X-linked lysosomal storage disorder that affects multiple organs including the heart. In this study, we investigated if early-stage globotriaosylceramide (Gb3) accumulation, before occurrence of inclusion bodies, could cause significant stress and irreversible damages of the cardiomyocytes in FD patients. Methods Immunofluorescent (IF) staining was performed on fibroblasts from FD patients with IVS4 mutation and myocardial biopsies from G3Stg/GLAko mice and IVS4 FD patients. The staining targeted interleukin-18 (IL-18), nuclear factor-κB (NF-κB), and inducible nitric oxide synthase (iNOS) as inflammatory and oxidative stress markers. Remarkably, the mouse and human myocardial biopsies selected for this study showed detectable Gb3 accumulation under fluorescence but did not exhibit typical FD (Gb3 inclusion body) pathology. Additionally, alpha-smooth muscle actin (α-SMA) IF staining was conducted to detect fibrosis. Results The results showed that fibroblasts and cardiomyocytes of mice and patients had significant accumulation of inflammatory markers IL-18 and NF-κB, and oxidative stress marker iNOS. The presence of fibrosis was confirmed in these myocardial biopsies through strong positive staining of α-SMA, despite the absence of typical FD pathology. Conclusions This study suggests that significant cellular stress and even irreversible damages could exist before the typical pathological changes (inclusion bodies formation) in cardiomyocytes of FD. Based on our findings, it is evident that to prevent irreversible damage and improve the prognosis of patients with FD, treatment should be initiated much earlier than we currently thought. What Is New? Evidence suggests significant cellular stress and potential irreversible damage may precede inclusion body formation in Fabry cardiomyocytes. Inclusion body formation likely represents a later stage event following intracellular Gb3 accumulation past a critical threshold. What Are the Clinical Implications? These findings indicate a need to re-evaluate conventional Fabry diagnostic criteria. There is an emphasis on early therapeutic intervention to mitigate progressive cellular dysfunction, inflammation, and fibrosis.

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