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Page 8 of 11 Feriozzi et al. Rare Dis Orphan Drugs J 2024;3:11 https://dx.doi.org/10.20517/rdodj.2023.37

Figure 1. The molecular pathogenetic mechanisms causing renal damage in Fabry nephropathy. The GLA mutation causes the synthesis
of altered proteins with stimulation of endoplasmic reticulum stress. The unfolded protein response determines the release of
inflammatory cytokines and increases apoptosis (light blue boxes). The GLA mutation also causes the lysosomal deposition of
Gb3/Lyso-Gb3 with derangement of lysosomal functions and release of cytokines (pink boxes). The Gb3/Lyso Gb3 deposition can
stimulate the new cellular protein synthesis, activating the NOTCH1/NFkB pathway and releasing pro-inflammatory and profibrotic
cytokine (green boxes). All these pathways are interconnected, and the final result is the inflammation and fibrosis of the kidney. Gb3:
Globotriaosylceramide; Lyso-Gb3: globotriaosylsphingosine; NOTCH: notch receptor 1 human; NFkB: nuclear factor kappa B.

UPR, etc.) could explain the variability of the clinical picture in the same family: the individual biological
response to Gb3 deposition depends on numerous and complex variables. Furthermore, it is reasonable to
think that early therapy can interfere with and reduce cellular reactions to Gb3 while late treatment can
limitedly prevent the progression of FN.

DECLARATIONS
Acknowledgments
The authors thank Mrs. Vivienne Wall for the technical assistance in English.

Authors' contribution
Have closely designed the review and finalized the manuscript; wrote comprehensive ideas about Gb3,
inflammation, fibrosis, and the progression of renal damage, and conclusions: Feriozzi S, Rozenfeld P
Wrote introduction, the glomerular and vascular compartment, the role of therapy in modulating
pathogenetic mechanisms: Feriozzi S
Wrote evidence on the role of inflammatory processes and immune response, GLA gene and endoplasmic
stress: the role of unfolded protein response, the inflammatory processes and tubule-interstitial response:
Rozenfeld P

Availability of data and materials
This manuscript is a review, and all data supporting the text have been officially published in the literature.
All papers consulted for the text are quoted in the References.