REVIEW: Current understanding of the pathogenesis of Fuchs' endothelial corneal dystrophy

Abstract

Fuchs' endothelial corneal dystrophy (FECD) is the most prominent reason for corneal-endothelial transplantations across the globe. The disease pathophysiology manifests through a combination of various genetic and non-heritable factors. This review provides a comprehensive list of known genetic players that cause FECD, and discusses the prominent pathological features that participate in disease progression, such as channel dysfunction, abnormal extracellular matrix deposition, RNA toxicity, oxidative stress, and apoptosis. Although current practices to correct visual acuity involve surgical intervention, this review also discusses the scope of various non-surgical therapeutics to remedy FECD.

Figure 1

Pathomechanisms in FECD. Alterations in DNA, such as mutations or polymorphic variations, cause several deregulatory events. Post-transcriptional byproducts of expanded repeats in the TCF4 and DMPK genes sequester splice-machinery proteins (MBNL-1) that elevate RNA toxicity and mis-spliced transcript levels. Channel and pump proteins, such as SLC4A11, MCTs, NA⁺/K⁺ ATPases, and aquaporins, are sub-optimally functional, or show reduced surface density, which affect the basic endothelial pump–barrier function. Increased endoplasmic reticulum (ER) stress elicits unfolded protein response and oxidative stress, which cause mitochondrial fragmentation and DNA lesions. Cells produce excessive and abnormal extracellular matrix materials that thicken Descemet’s membrane and form guttae. Progressive escalation of these processes causes apoptosis, and depletes most of the endothelial population.