Abstract
Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.
Highlights
Fabry disease Fabry disease is a rare X-linked hereditary disease caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase [1]
A) Pathogenesis of Fabry fibrosis a) Conventional view: Fibrosis is a consequence of ischemic injury secondary to glycolipid accumulation inside endothelial cell lysosomes in the microvasculature Therapeutic implication: Enzyme replacement therapy (ERT) clearance of endothelial deposits as sole approach b) Novel concepts: 1. accumulated glycolipids promote the release of secondary mediators of injury from target cells that include parenchymal cells
2. ischemia promotes the release of secondary mediators of injury Therapeutic implication: a correct understanding of the molecular mechanisms involved may provide new add-on therapeutic approaches
Summary
Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. The time-course of kidney fibrosis is not as clearly established as in DN, but emerging evidence points to a similar pattern: early podocyte injury and fibrosis generated by epithelial cells that increase as disease progresses [17,21,22,23] (Figure 2).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
