Fibrosis: a key feature of Fabry disease with potential therapeutic implications

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.

Figure 1

Conceptual framework for the design of novel therapeutic approaches to Fabry disease: lessons from diabetic nephropathy. A) Pathogenesis of Fabry fibrosis. The traditional view is that this is a late event secondary to endothelial glycolipid deposition leading to luminal obstruction and ischemia. However, fibrosis in other metabolic disorders, such as diabetes, is known to result from recruitment of secondary mediators of injury by both direct actions of accumulated metabolites (in this case glucose) on target organ cells and also by ischemia. Recent evidence suggests that certain metabolites that accumulate in Fabry disease may recruit secondary mediators of injury in target organ cells. Such pathways might be amenable to therapeutic targeting by preventing the effects of accumulated metabolites on target cell or by targeting the secondary mediators that are recruited. B) Potential impact on therapy of an improved understanding of the pathogenesis of fibrosis in Fabry disease. Current therapy of Fabry disease consists of enzyme replacement therapy (ERT). Substrate reduction therapy (SRT) in under investigation and may further decrease the levels of certain metabolites identified as pro-fibrotic. Identification of metabolites recruiting secondary mediators of injury may eventually lead to therapies preventing their binding to receptors. In addition, anti-proteinuric therapy may decrease the pro-inflammatory, pro-fibrotic effects of proteinuria in the kidney. Certain anti-proteinuric agents have additional anti-fibrotic actions in the kidney and vasculature. Finally, targeting of secondary mediators of fibrosis may further prevent fibrosis progression in patients with more advanced disease for whom correction of the initial metabolic defect may not be sufficient.

Figure 2

Kidney biopsy. A) PAS staining. Histology of the kidney with characteristic changes of advanced Fabry nephropathy. Please note glomerular segmental sclerosis (A), adhesion and Bowman capsule reduplication (B), tubular atrophy and tubular cell related fibrosis (thickened basement membranes) (C) and arteriolar hyalinosis (D). Original magnification 63×. Courtesy of Prof. Justus Müller, Department of Pathology, University Hospital of Würzburg, Würzburg, Germany. B) Sirius red staining of collagen fibers illustrates peri-glomerular fibrosis (E) and interstitial fibrosis (F). Original magnification × 20.

Figure 3

Cardiac fibrosis. A magnet resonance imaging short axis view of a 54-year-old male Fabry patient. The arrow indicates the late enhancement positive region of the left ventricle.

Figure 4

Central nervous system white matter lesions. 45-year-old male. T2 Brain MR image showed widespread, punctuated and confluent white matter lesions from periventricular to subcortical spaces. These lesions are associated with severe axonal injury (gliosis).