The Inflammatory Pathogenetic Pathways of Fabry Nephropathy and Agalopathy: GLA Variant Induction of Endoplasmic...

Fabry disease (FD) is a monogenic disease with highly variable clinical features. This variability suggests that additional pathogenetic pathways may exist besides the intra-lysosomal deposition of globotriaosylceramide (Gb3) and its deacylated form globotriaosylsphingosine (LysoGb3) caused by an enzyme deficiency.

It has been demonstrated that intralysosomal accumulation of Gb3 and LysoGb3 triggers an inflammatory response. Monocytes, macrophages, and dendritic cells overexpress the adhesion molecules, and cytokines release occurs, including interleukin β, tumor necrosis factor-alpha (TNFα), and transforming growth factor beta. These processes determine the activation of inflammation processes associated with chronic inflammation and tissue fibrosis. The pathogenetic mechanisms stimulated by Gb3 and LysoGb3 deposition could break free from the original activation, causing an irreversible effect, in which Fabry disease-specific therapy can play a limited role. A new disease mechanism, "Agalopathy" would coexist with enzyme deficiency. Missense variants in the coding sequence of the GLA gene would generate the misfolding of the altered protein alpha-galactosidase A. Emergence of misfolded proteins may generate stress of the endoplasmic reticulum, leading to induction of the unfolded protein response (UPR). The UPR causes the release of pro-inflammatory cytokines and contributes to inflammatory status. This mechanism could be activated independently of glycolipid deposition, and its relationship with inflammatory pathways deserves more research. Strikingly, a zebrafish GLA knockout model that naturally lacks the enzyme that synthesizes Gb3 shows many alterations in lysosomal functions.

These pieces of evidence suggest the involvement of alternative pathways independent of Gb3 in FD pathogenesis. This review aims to describe these processes' role in the pathogenesis of renal damage in FD or Agalopathy nephropathies.