Fabry Disease: Insights into Pathophysiology and Novel Therapeutic Strategies

Abstract

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by deficiency of α-galactosidase A (α-GalA), leading to the accumulation of glycosphingolipids and multi-organ dysfunction, particularly affecting the cardiovascular and renal systems. Disease-modifying treatments such as enzyme replacement therapy (ERT) and oral chaperone therapy (OCT) have limited efficacy, particularly in advanced disease, prompting a need for innovative therapeutic approaches targeting underlying molecular mechanisms beyond glycosphingolipid storage alone. Recent insights into the pathophysiology of FD highlights chronic inflammation and mitochondrial, lysosomal, and endothelial dysfunction as key mediators of disease progression. Adjunctive therapies such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRAs) demonstrate significant cardiovascular and renal benefits in conditions including heart failure and chronic kidney disease. These drugs also modulate pathways involved in the pathophysiology of FD, such as autophagy, oxidative stress, and pro-inflammatory cytokine signaling. While theoretical foundations support their utility, dedicated trials are necessary to confirm efficacy in the FD-specific population. This narrative review highlights the importance of expanding therapeutic strategies in FD, advocating for a multi-faceted approach involving evidence-based adjunctive treatments to improve outcomes. Tailored research focusing on diverse FD phenotypes, including females and non-classical variants of disease, will be critical to advancing care and improving outcomes in this complex disorder.

Keywords: Fabry disease; chronic kidney disease; heart failure; inflammation.

Figure 1

Red flag clinical features, electrocardiogram, laboratory, and imaging findings in FD. Figure created in BioRender (https://biorender.com/) [accessed on 31 January 2025].

Figure 2

Progression of FD, including cellular and histological changes, clinical features, and cardiac MRI findings. Novel therapeutics and the proposed time at which they may be useful in FD. Figure created in BioRender (https://biorender.com/) [accessed on 31 January 2025].

Figure 3

(A) Primary mechanisms of disease in FD. (B) Secondary pathways implicated in the pathophysiology of FD. Activation of the TLR-4/NF-κB pathway by Gb3 stimulates the release of pro-inflammatory cytokines. (C) Accumulation of sphingolipid disrupts the function of mTOR, with downstream effects on autophagy, lysosomal, and mitochondrial function. Figure created in BioRender (https://biorender.com/) [accessed on 31 January 2025].

Figure 4

Indications for enzyme replacement therapy in FD. LVH—left ventricular hypertrophy; MWT—maximal wall thickness; GFR—glomerular filtration rate; MRI—magnetic resonance imaging; TIA—transient ischemic attack; GI—gastrointestinal.