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Fuchs Endothelial Corneal Dystrophy

Update on Pathogenesis and Future Directions

Sarnicola, Caterina, M.D.; Farooq, Asim V., M.D.; Colby, Kathryn, M.D., Ph.D.

doi: 10.1097/ICL.0000000000000469
Review Article

Abstract: Fuchs endothelial corneal dystrophy (FECD) is the most common indication for corneal transplantation in the United States, accounting 36% of the almost 47,000 transplants performed in 2016. Although the surgical management of FECD has undergone a revolution over the past 20 years, its pathogenesis remains elusive, with multiple putative disease pathways and an ever increasing number of candidate genes thought to play a role. This review will summarize the recent advancements in our understanding of the biology of FECD, including potential parallels with neurodegenerative disease like amyotrophic lateral sclerosis and will highlight prospects for future treatment advances.

Department of Biomedical and Specialty Surgical Sciences, Section of Ophthalmology (C.S.), University of Ferrara, Ferrara, Italy; and Department of Ophthalmology and Visual Science (C.S., A.V.F., K.C.), University of Chicago, Chicago, IL.

Address correspondence to Kathryn Colby, M.D., Ph.D., Department of Ophthalmology and Visual Science, The University of Chicago Medicine and Biological Sciences, 5841 S Maryland Avenue, MC2114, Chicago, IL 60637; e-mail: kcolby@bsd.uchicago.edu

The authors have no funding or conflicts of interest to disclose.

Accepted December 04, 2017

Fuchs endothelial corneal dystrophy (FECD), the most common posterior corneal dystrophy, was first described by Ernst Fuchs in 1910.1 At present, it is the leading indication for corneal transplantation in the United States, accounting for 17,000 of the 46,900 of transplants performed in 2016.2,3 The surgical management of FECD has undergone tremendous evolution in the past 20 years.4 Selective replacement of the dysfunctional endothelium is now the most commonly performed technique, having surpassed penetrating keratoplasty (PKP) in a number of cases performed in the year 2012. In contrast to the advancements in the surgical management of FECD, our understanding of the pathophysiology of this condition remains woefully incomplete, with numerous different genetic associations described and multiple disease pathways purported to be involved. In this review, we will summarize the present knowledge of FECD pathogenesis with a goal of introducing a framework within which we can begin to unravel the seemingly disparate mechanisms hypothesized to be involved in this disease. We will describe the potential relevance of disease mechanisms from neurodegenerative diseases associated with nucleotide repeat expansions (see Glossary in Appendix 1). Finally, we will conclude with a discussion of future directions in our quest to understand this common corneal disease.

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BASICS OF FUCHS ENDOTHELIAL CORNEAL DYSTROPHY

The corneal endothelium, a monolayer of hexagonal cells derived from neural crest cells that arise from the neuroectoderm, is halted in the G1 phase of the cell cycle and therefore does not divide after birth.5,6 The corneal endothelium maintains corneal deturgescence (and therefore transparency) through both a passive barrier function and active adenosine triphosphate (ATP)–dependent ionic pumps. To remain functional, the corneal endothelium must maintain a minimum cell density of 400 to 500 cells per square millimeter. The response of the endothelium to cell loss involves spreading or migration or both of neighboring endothelial cells, which change in size and shape to cover the affected area.7,8

Fuchs endothelial corneal dystrophy is a slowly progressive dysfunction of the corneal endothelium that eventually results in corneal edema and reduced vision. The initial clinical finding (corneal guttae) usually manifests in the fourth decade of life. Typically, patients do not require intervention until much later, generally in their 60s or 70s. The classic form of the disease has a female predominance with female-to-male ratio of 2.5:1 to 3:1. There is an uncommon early-onset form of FECD that begins in the first decade of life and shows a similar progression as the classic phenotype. Early-onset FECD affects females and males equally.9–11

Guttae, excrescences on or within Descemet membrane, are the main clinical finding in early FECD. Guttae are associated with thickening of Descemet membrane, although this finding is not generally measured clinically at the present time. Guttae themselves can interfere with visual functioning as a result of scatter of incoming light.12 Interestingly, guttae may occur in up to 4% of patients in the United States, although a much smaller percentage progress to corneal edema, warranting a diagnosis of FECD.13

Most patients with early FECD are not symptomatic. Central corneal guttae may be discovered as an incidental finding during a routine ophthalmology examination. Endothelial imaging reveals a reduction in endothelial cell density with abnormalities of cell shape (pleomorphism) and variations in cell size (polymegethism), along with the guttae formation.

Fuchs endothelial corneal dystrophy progression generally occurs over two to three decades. Progression is initially characterized by an increase in the size and number of guttae, which can eventually become confluent and affect the peripheral cornea. Corneal thickness increases as the endothelial function decreases. Worsening stromal edema leads to the development of subepithelial and epithelial bullae, which can rupture causing pain. Corneal scarring can occur in advanced FECD, although this is an uncommon finding in the developed world because of the success of modern endothelial replacement techniques.14 There are several grading scales to assess the state and progression of FECD. Clinicians can also follow central corneal thickness or endothelial cell count and morphology as an indication of disease progression.13,15

Multiple pathways have been implicated in FECD. The following sections will review what is known thus far regarding these putative disease mechanisms.

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Mitochondria in Fuchs Endothelial Corneal Dystrophy

Numerous groups have suggested the involvement of mitochondrial dysfunction in the pathogenesis of FECD. This is not surprising because maintenance of corneal deturgescence by means of active ion pumps requires expenditure of tremendous amounts of ATP, thus rendering the endothelial function highly dependent on the proper functioning of the mitochondria.

More than 30 years ago, Tuberville et al.16 demonstrated reduced cytochrome oxidase activity in areas of corneal edema in FECD corneas, which they hypothesized might represent reduced metabolic activity or a decreased number of mitochondria. Later work demonstrated profound ultrastructural abnormalities in mitochondria from FECD patients undergoing transplantation.17 More recently, degenerated mitochondria were noted in a mouse model of early-onset FECD.18 Studies using human endothelial cells harvested during keratoplasty in FECD have confirmed an increase in mitochondrial number, presumably as a mechanism to compensate for mitochondrial dysfunction.19

Eye involvement is common in diseases caused by abnormalities in the mitochondrial DNA (mtDNA). The mtDNA is maternally inherited and is replicated, transcribed, and translated independently from nuclear DNA. The mtDNA codes for proteins, transfer RNAs, and ribosomal RNAs, which, in combination with products from the nuclear DNA, are necessary for mitochondrial homeostasis and energy production. Mitochondrial DNA is prone to mutation as a result of both structural and environmental factors, as discussed in the following section.

Corneal abnormalities have been reported in patients with systemic mitochondrial diseases. Corneal endothelial abnormalities have been noted in Kearns–Sayre syndrome, which results from deletions in the mtDNA.20,21 Additionally, structural abnormalities in endothelial cell mitochondria were demonstrated in two patients with mitochondrial myopathy associated with point mutations in mtDNA.22

Mitochondrial protection is currently under investigation as a therapeutic approach in FECD. There is an ongoing phase II clinical trial of elamipretide in patients with mild-to-moderate corneal edema from FECD. Elamipretide is thought to stabilize the inner mitochondrial membrane, reduce oxidative stress, and improve mitochondrial function. Primary endpoints include safety and tolerability, whereas secondary endpoints include vision, pachymetry, and endothelial cell counts. Additionally, Nischal et al. have suggested that Coenzyme Q10, an antioxidant and regulator of mitochondrial permeability pores, may have some applicability in the medical treatment of FECD based on a favorable effect on two cases of Kearns–Sayre syndrome with endothelial abnormalities.23

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Oxidative Stress and Apoptosis in Fuchs Endothelial Corneal Dystrophy

Reactive oxygen species (ROS) are highly reactive molecules such as superoxide anion (O2 ), hydroxyl radical (OH), and hydrogen peroxide (H2O2). The mitochondrial electron transport chain is a major source of ROS in cells. However, ROS can also be produced in response to ultraviolet (UV) light exposure, ionizing radiation, or heavy metal ions. Reactive oxygen species are involved in multiple physiological functions, including cell proliferation, host defense, signal transduction, and gene expression. Cells have several antioxidative defense mechanisms to control the level of ROS. When a pro-oxidative or antioxidative cellular imbalance occurs, oxidative stress may affect DNA (especially mtDNA), protein, and lipid.24,25

Mitochondrial DNA is highly susceptible to oxidative damage because it exists in a sea of ROS generated as part of ATP generation. Mitochondrial DNA lacks protective histones and sophisticated DNA repair mechanisms, both of which protect nuclear DNA. Finally, there are no introns in the mitochondrial genome, and thus, deletions or mutations affect coding regions with downstream effects on important proteins or RNA.26

To date, oxidative stress has been implicated in the pathogenesis of multiple ocular diseases, including glaucoma, Leber hereditary optic neuropathy, traumatic optic neuropathy, diabetic retinopathy, and age-related macular degeneration.24 Oxidative stress is believed to play a role in neurodegenerative disorders, such as Alzheimer disease, Parkinson disease, and prion diseases.27

Because of its location, the cornea is regularly exposed to UV irradiation from the sun, an exogenous source of ROS. Oxidative stress has been implicated in the pathogenesis of different corneal diseases, such as keratoconus, granular corneal dystrophy type 2, and FECD.28,29 In particular, several lines of evidence suggest an unfavorable pro-oxidative state in FECD corneas, manifested by either an increase in pro-oxidative enzymes or by reductions in a variety of antioxidants, supporting the role of oxidative stress in the pathogenesis of this disease.30–34 Jurkunas et al.30 demonstrated an increased oxidative mtDNA damage in FECD endothelium compared with normal controls and pseudophakic bullous keratopathy This same group subsequently showed that damage to both mtDNA and nuclear DNA with mitochondrial dysfunction could be produced by an agent (menadione) that promotes endogenous oxidative stress.35 Recent work using explants from FECD corneas has shown a reduction in telomere length, supportive of oxidative stress in FECD.19

Apoptosis (programmed cell death) is a genetically regulated physiologic pathway to eliminate damaged or unnecessary cells. Apoptosis plays a critical role in normal development and organismal homeostasis. Insufficient apoptosis can lead to uncontrolled growth or immortality of cells, as can be seen in some forms of cancer, whereas overactive apoptosis has been linked to neurodegenerative diseases, including Alzheimer, Huntington, and Parkinson diseases. Oxidative stress is known to be a major cause of apoptosis.

Several lines of evidence support the role of aberrant apoptosis in FECD.36,37 Apoptosis was associated with mtDNA damage in both ex vivo FECD specimens and cultured endothelial cells.31 In these same model systems, later studies demonstrated increased apoptosis in FECD after stimulation of oxidative stress; this was associated with an increase in p53 expression.38 Sulforaphane, an organic sulfur antioxidant compound found in cruciferous vegetables that is purported to slow cancer growth, reduced oxidative stress–induced apoptosis in FECD.39 Most recently, UV-A light, known to promote oxidative stress, was shown to increase apoptosis through the activation of p53/caspase3 in immortalized human endothelial cells.38,40

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Unfolded Protein Response and Endoplasmic Reticulum Stress

One of the tasks of the endoplasmic reticulum (ER) is to ensure proper “folding” of proteins before their export to the Golgi apparatus. If this process goes awry, accumulation of misfolded or unfolded proteins with the ER lumen induces ER stress, eventually activating the unfolded protein response (UPR) (see Glossary in Appendix 1). The UPR is a compensatory mechanism that attempts to get the cell back on the correct path, by temporarily halting translation of RNA into protein, degrading the misfolded proteins, and activating cellular mechanisms to improve protein folding.

However, if these strategies are unable to solve the problem, the UPR triggers apoptosis.41 Activation of UPR is involved in neurodegenerative diseases, including Alzheimer disease, amyotrophic lateral sclerosis (ALS), Parkinson disease, and Huntington disease.42

Jun et al. initially suggested the involvement of the UPR in FECD, after demonstration of the upregulation of several markers of the UPR and a marker of apoptosis in corneas removed during transplantation.43 Enlargement of the rough ER was also noted in this study. These authors showed similar findings in a mouse model of early-onset FECD, which demonstrated dilated ER, and activation of the UPR and subsequent apoptosis.44 Most recently, pretreatment with oxotremorine (a muscarinic receptor agonist) or mefenamic acid (a nonsteroidal agent) reduced several markers of UPR in immortalized human corneal endothelial cells (CECs) subjected to pharmacological activation of the UPR, suggesting the possibility of future development of compounds able to interfere with the activation of the UPR in FECD.45

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Epithelial to Mesenchymal Transition

Periocular neural crest cells arise from the neuroectoderm and undergo a mesenchyme-to-epithelial transition to form the corneal endothelium. Interestingly, the reverse process, epithelial–mesenchymal transition (EMT) (see Glossary in Appendix 1), is thought to be involved in FECD pathogenesis.5,46

When cells undergo EMT, they lose the cell-to-cell junctions and apical–basilar polarity that characterize epithelium. Instead, cells become highly motile and acquire an invasive mesenchymal phenotype. Epithelial–mesenchymal transition is essential for numerous developmental processes and is involved in normal wound healing. When the process goes awry, it can give rise to invasive cancer cells or aberrant fibrosis.47

Several lines of evidence suggest that EMT may participate in FECD. It is well established that aberrant deposition of extracellular matrix (ECM) occurs in FECD, manifested as thickening of the Descemet membrane. Almost 50 years ago, Iwamoto and DeVoe48 described ultrastructural evidence that endothelial cells in FECD take on fibroblast-like morphological and functional characteristics, depositing collagen and basement membrane into Descemet membrane.

Several of the genes implicated in FECD (ZEB1/TCF8 and TCF4) are known to induce EMT in other systems.47,49 Okumura et al.50 demonstrated that the EMT-inducing genes ZEB1 and Snail1 are expressed in cultured endothelial cells from patients with FECD and contribute to the excessive production of ECM proteins. Finally, EMT-related cytokines have been shown to be elevated in aqueous humor from pseudophakic FECD patients and correlated with corneal thickness, although this finding was not seen in phakic FECD patients.51

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GENETICS OF FUCHS ENDOTHELIAL CORNEAL DYSTROPHY

Fuchs endothelial corneal dystrophy has been classically described as having an autosomal dominant inheritance.9

However, the late age of symptom onset, and variable penetrance and expressivity of FECD makes the determination of the exact mode of inheritance challenging. Although most patients have no knowledge about a family history of the disease, it is quite possible that early or asymptomatic cases are not diagnosed.

Multiple genetic abnormalities have been described in FECD. Using linkage analysis, four loci (on chromosomes 5, 9, 13, and 18)52–54 and several linkage peaks (on chromosomes 1, 5, 7, 8, 10, 15, 17, 20, and X)55,56 were associated with FECD.

The first mutation identified, COL8A2, is associated with the uncommon early-onset form of the disease.10,57,58 The more typical late-onset FECD has been associated with at least four different mutations (SLC4A11, ZEB1, LOXHD1, and AGBL1).54,59–61

However, these mutations together account for only a minority of cases, whereas more than 70% of FECD in white patients is associated with a cytosine–thymine–guanine (CTG) trinucleotide repeat expansion (TNT) in the TCF4 gene.62 Genotyping of FECD patients reveals that more genetic mutations remain to be discovered, as some patients undergoing corneal transplantation for FECD manifest neither TNT repeats nor any other known mutations. Indeed, a recent publication from the Fuchs Consortium has identified 3 novel loci for FECD in a genome-wide association study of more than 2,000 patients with FECD.63 In the present section, we will review several genes that have been implicated in FECD, along with their proposed pathogenic pathways. A comprehensive list of FECD-associated genes can be found in Table 1.

TABLE 1

TABLE 1

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CoL8A2

Early-onset FECD, an uncommon form of the disease, is associated with mutations in the COL8A2 gene, which encodes for the α-2 chain of collagen VIII, a major component of Descemet membrane.10 COL8A2-associated FECD is characterized by the accumulation and abnormal assembly of collagen VIII within the region of Descemet membrane.64 Ultrastructural analysis in vivo has also demonstrated a dilated ER, suggesting that ER stress, UPR activation, and apoptosis may be involved. This may be the result of alterations in the secondary or tertiary structure of the COL8A2 protein.18,44

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SLC4A11

Mutations in the SLC4A11 gene, which encodes a plasma membrane transport protein, have been associated with FECD,59 autosomal recessive congenital hereditary endothelial dystrophy,65 and Harboyan syndrome, a congenital hereditary disorder characterized by endothelial dystrophy and progressive sensorineural hearing loss.66

Most characterized SLC4A11 mutant proteins are retained in the ER and show characteristics of misfolded membrane proteins.59 Cells containing mutant SLC4A11 are more vulnerable to oxidative and mitochondrial damage, express reduced levels of antioxidant genes, and are more prone to apoptotic cell death. Agents that reduce mitochondrial dysfunction have been suggested to decrease the cellular damage induced by mutations of SLC4A11.67

An in vitro study has shown that glafenine, and perhaps other nonsteroidal anti-inflammatory drugs, can rescue misfolded proteins from the ER, suggesting that this may be a potential therapeutic approach for the management of SLC4A11 mutations.68

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ZEB1/TCF8

The TCF8 gene, located on chromosome 10, encodes for TCF8/ZEB1, a zinc finger E-box binding homeobox 1 transcription factor; this can act as either a transcriptional enhancer or repressor.

Nonsense mutations in TCF8 result in a premature stop codon that leads to the truncation of the ZEB1 protein (resulting in nonfunctional protein) and have been associated with posterior polymorphous corneal dystrophy type 3.69–71

In contrast, TCF8 missense mutations, where a single nucleotide is changed causing a different amino acid to be inserted into the resulting protein, have been associated with FECD.54,72 TCF8 is thought to be important in EMT by repressing the transcription of genes that maintain the epithelial phenotype.47 The EMT-inducing gene ZEB1 is involved in the production of ECM proteins, such as type I collagen and fibronectin, through the transforming growth factor-β signaling pathway. Excessive production of ECM proteins results in guttae and thickening of Descemet membrane, but it also increases the unfolded protein burden. As described above, this can lead to the UPR and eventually apoptosis.43,50,73,74

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TCF4

The majority of FECD cases in whites are associated with a CTG TNT in the third intron of transcription factor 4 (TCF4) on chromosome 18. In this mutation, multiple copies of the CTG repeat are found (more than 1,000 in some cases, although the presence of more than 50 repeats are associated with FECD).62 TCF4 is a member of the basic helix–loop–helix family of transcription factors that play important roles in numerous developmental processes, including cell proliferation and differentiation. Recent data implicate TCF4 as an important regulator of neurodevelopment and EMT. TCF4 mutations have been associated with other diseases, including schizophrenia and primary sclerosing cholangitis.49

TCF4 CTG18.1 repeat expansion is thought to be a major contributor to FECD pathogenesis across ethnic groups, although the prevalence varies: 73% among Caucasians,75 44% among a Singapore Chinese cohort,76 34% among Indians,77 and 26% among Japanese.78 The length of the trinucleotide repeat has also been positively correlated with the Krachmer grade of clinical FECD severity and a higher risk of requiring corneal transplantation at a younger age.79,80

Simultaneous reports in early 2015 documented the presence of RNA nuclear foci in the corneal endothelium of patients with FECD. These foci consist of RNA products from transcription of the DNA repeat expansions and exert a deleterious effect on cellular functions by sequestering necessary RNA binding proteins, so-called RNA toxicity (see Glossary in Appendix 1).49,81,82

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INSIGHTS FROM OTHER REPEAT EXPANSION DISEASES

Microsatellites, short tandem repeats of 2 to 10 base pairs, represent 3% of the human genome.83 Microsatellites act as regulatory elements for transcription84,85 and modulate DNA splicing activity86 and translation.87

Errors in DNA replication, recombination, and repair can cause microsatellite instability, leading either to expansion or contraction of the repeat sequences. The majority of diseases caused by microsatellite expansion are dominantly inherited neurologic or neuromuscular disorders, although many of the affected genes are expressed ubiquitously.88 The question of why some cells are selectively affected by the repeat expansions remains unanswered.

Nucleotide repeat expansions can be located either in protein coding regions or in noncoding regions of their respective genes. Repeat expansion in a protein-coding region induces toxic protein aggregate formation, leading to altered homeostasis of multiple cellular pathways. Examples include Huntington disease, spinocerebellar ataxias (types 1, 2, 3, 6, 7, and 17), and spinobulbar muscular atrophy (Kennedy disease).89,90

Repeat expansions within noncoding regions are found in myotonic dystrophy, fragile X-associated tremor or ataxia syndrome, and a particular form of ALS, similar to what has been found in FECD. Interestingly, recent work suggests an association between FECD and myotonic dystrophy, both of which are characterized by CTG repeats, albeit in different genes.91 Noncoding region repeat expansions undergo both sense and antisense transcription into aberrant RNA. This aberrant RNA can sequester RNA-binding proteins into RNA foci within the nucleus, leading to the disruption of multiple pathways that results in cellular dysfunction.88,90 This so-called RNA toxicity has already been suggested in FECD.81,82

Aberrant RNA transcribed from repeat expansions can also be exported from the nucleus into the cytoplasm, where it can undergo an unusual form of translation, in the absence of a traditional ATG start codon. These repeat-associated non-ATG peptides (RAN peptides) (see Glossary in Appendix 1) can also disrupt cellular functions.92,93 Work is ongoing to determine if RAN peptides are present in FECD.

A subtype of ALS that results from a hexanucleotide repeat expansion in a noncoding region of chromosome 9 (ALS associated with frontotemporal dementia, “c9ALS/FTD”) may yield insights relevant for FECD. Patients affected by c9ALS/FTD manifest progressive paralysis and dementia. This type of ALS is the most common inherited form of ALS and accounts for approximately 7% of sporadic ALS cases.94

Both nuclear RNA foci and cytoplasmic RAN peptides have been demonstrated in c9ALS/FTD.95–99 There seems to be a mutually exclusive mechanism in which the transcribed repeats are either sequestered into nuclear RNA foci or are exported to the cytoplasm for RAN translation.99 This observation suggests that some cell types may preferentially promote the formation and nuclear retention of toxic RNA foci, whereas other cells allow nuclear export of the aberrant RNA and subsequent RAN translation.88 The implications of this finding remain to be determined.

Furthermore, many cellular functions perturbed in c9ALS/FTD are regulated by communications that mitochondria make with a specialized region of the ER (mitochondria-associated ER membranes) (see Glossary in Appendix 1). The mitochondria-associated ER membranes regulate calcium and phospholipid exchange, intracellular trafficking, autophagy, inflammasome formation, mitochondrial homeostasis, ER stress, and the UPR.100 As we have seen above, many of these pathways have already been implicated in FECD, suggesting that future studies of ER–mitochondria interactions may yield insights into disease mechanisms of FECD.

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TOWARD A UNIFIED THEORY FOR FUCHS ENDOTHELIAL CORNEAL DYSTROPHY PATHOGENESIS

Although multiple putative pathogenic pathways have been suggested as contributing to the clinical manifestations of FECD, the etiology of this disease remains an enigma. Despite the fact that numerous genetic mutations that have been identified in FECD, the clinical phenotype is virtually identical, suggesting convergence on a single cellular pathway or organelle. Any unifying theory of pathogenesis must take this into account.

Among the potential pathways that we have reviewed, common features include oxidative stress, perturbations in mitochondrial homeostasis, and increased apoptosis. It is therefore our hypothesis that the mitochondria, which function to produce ATP and limit apoptosis, are a likely common denominator in FECD pathogenesis. Figure 1 details our current thinking of how the various cellular pathways and genetic mutations may be involved in the pathogenesis of FECD. Indeed, mitochondrial dysfunction seems to play an important role in Parkinson disease, and possibly Alzheimer, Huntington, and ALS.101,102 Study of the very common disease FECD may yield insights into nonophthalmologic conditions characterized by mitochondrial dysfunction.

FIG. 1

FIG. 1

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MANAGEMENT OF FUCHS ENDOTHELIAL CORNEAL DYSTROPHY IN 2018

The current management of FECD is based on subjective symptoms and objective findings. Patients notice blurred vision, which is typically worse on waking up in the morning because of corneal hydration under closed eyelids overnight and which improves throughout the day as the cornea is exposed to air and therefore relative dehydration occurs because of evaporation. A higher central corneal thickness in the morning compared with later in the day may serve to verify this hypothesis. Affected patients may own multiple pair of spectacles, which are useful at different times of day. Hypertonic saline drops or ointment may help decrease corneal hydration and mitigate refractive fluctuation.103

The threshold for surgical intervention in patients with FECD has relaxed over the past several decades, as surgical techniques have improved. In the past, PKP was the mainstay for the surgical management of FECD. Although PKP was an effective treatment, the long visual recovery, permanent weakening of tectonic strength of the eye, risk of rejection or intraoperative disasters during “open-sky” time, or suture-related problems, such as infection, meant that surgeons would often wait until disease was advanced before recommending surgery. Selective endothelial replacement techniques developed over the past 20 years have overcome many of the disadvantages of PKP, thus allowing FECD to be treated at an earlier stage. At the present time, endothelial keratoplasty is the surgical treatment of choice for FECD.104,105 In 2016, only 1,171 PKPs were performed for FECD, whereas almost 16,000 EKs were performed.3

Techniques of EK continue to evolve. According to the 2016 Eye Bank Association of America statistical report, Descemet-stripping automated EK (DSAEK) is the most commonly used technique in the United States, but the number of Descemet membrane EK (DMEK) surgeries performed annually has increased every year since 2011. These two techniques differ in the amount of transplanted tissue (Fig. 2).3,106–108 The primary advantages of DMEK over DSAEK are faster visual recovery, better final vision, and a lower rejection rate (1% in DMEK and 5%–14% in DSAEK); this may facilitate a reduction in the need for long-term topical corticosteroid use, resulting in a lower incidence of steroid-induced intraocular pressure elevation.104,109

FIG. 2

FIG. 2

Although several strategies to simplify DMEK surgery have been recently described, the initial learning curve remains somewhat steeper than DSAEK, given the challenges in unfolding and positioning the tissue.110–112 Furthermore, DMEK is not recommended in all cases of endothelial dysfunction; it should be avoided in aphakic eyes and is more challenging after a pars plana vitrectomy, anterior chamber intraocular lens implant, or glaucoma surgery. Despite these challenges, EK has revolutionized our ability to treat FECD.

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FUTURE DIRECTIONS

Endothelial keratoplasty is a highly effective treatment for FECD. However, because of the worldwide shortage of donor corneas, there is considerable interest in the development of alternative therapeutic options. The possibility of medical management of FECD with Rho-associated kinase (ROCK) inhibitors was first reported by Kinoshita.113 A 52-year-old male with late-onset FECD was found to have 20/63 vision OS, with corneal guttae and a central corneal thickness of 703 μm. He was treated with corneal endothelial denudation by cryotherapy followed by topical Y-27632, a ROCK inhibitor, for 1 week. After 6 months, the vision had improved to 20/16, and the central corneal thickness had decreased to 568 μm. Y-27632 has been shown to promote endothelial cell adhesion and proliferation and to suppress apoptosis, showing promise as a potential medical therapy for endothelial dysfunction.114,115

In recent years, research has also focused on regenerative medicine using cultured human CECs to treat endothelial dysfunction. Most of the work thus far has been performed in animal models, although at the American Academy of Ophthalmology Meeting in 2016, Shigeru Kinoshita presented data demonstrating corneal clearance after transplantation of cultured CECs and application of a topical Rho kinase inhibitor in 11 patients.116–118

Laboratory evidence has demonstrated that FECD endothelium is capable of returning to a normal molecular phenotype (as measured by telomere length, mtDNA levels, and gene expression profiles) after a time in cell culture, suggesting that there are “healthier” cells within the FECD cornea.19

Clinic evidence supports the idea that the corneal endothelium in FECD may be capable of self-regeneration after removal or destruction of the dysfunctional central endothelium and Descemet membrane, without endothelial transplantation.113,119–121 In the largest series to date, Borkar et al.122 reported the results of Descemet stripping without EK at the time of cataract surgery in 13 eyes of 11 patients. Preoperative visual acuities ranged from 20/25 to 20/400. Preoperative endothelial cell counts were graded as uncountable in all eyes. Ten eyes were noted to respond positively to the surgery, with final best-corrected visual acuities ranging from 20/15 to 20/20 in those patients without macular abnormalities, whereas the remaining 3 eyes required EK (Fig. 3). Subsequent work has shown similar efficacy of primary descemetorhexis only without cataract surgery.123 Of special interest from this study was the facilitation of corneal clearance after descemetorhexis by ripasudil, a Rho kinase inhibitor approved in Japan for the treatment of glaucoma.

FIG. 3

FIG. 3

Descemetorhexis without EK may be an effective option in select patients who are symptomatic from FECD. The advantages of this procedure include no risk of rejection and no complications associated with the use of chronic topical steroids. Further investigation is required to determine the appropriate patient population for this procedure, the optimal descemetorhexis size and shape, and the role of topical ROCK inhibitors or other medical therapies to facilitate endothelial repopulation.

Future developments in FECD management may arise from improved knowledge regarding pathogenesis. Preliminary studies have suggested that agents like lithium, N-acetylcysteine, and sulforaphane may be useful in the management of FECD.39,124,125 The cornea may also be an ideal site for gene therapy, such as adenovirus vector therapy or CRISPR gene editing, although there are challenges that have thus far limited the efficacy of these approaches.126

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CONCLUSIONS

Fuchs endothelial corneal dystrophy is caused by diverse genetic defects that produce a virtually identical clinical phenotype. The pathogenic mechanisms that lead to this disease has not been yet well elucidated; in this review, we have reported recent findings that implicate mitochondrial dysfunction as a possible common denominator for FECD.

Insights from rare nucleotide expansions neurologic disorders such as c9ALS/FTD may shed light on relevant pathways to explore in FECD. Conversely, FECD, which is common and for which affected tissue is frequently removed and therefore available for study, may yield insights that will be relevant for understanding or treatment of other neurodegenerative diseases.

In the future, surgical treatment of FECD may be augmented with less invasive treatments, including cell-based therapies or primary descemetorhexis, both of which may be enhanced by concurrent use of Rho kinase inhibitors. Finally, a better understanding of the pathogenic mechanisms of FECD may allow the development of medical therapies to treat (or even better, to prevent) this common corneal condition.

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Glossary

Epithelial to mesenchymal transition: Physiological process during which cells undergo a transition from epithelial to mesenchymal phenotype, becoming highly motile and invasive. It is essential for numerous developmental processes and is involved in normal wound healing. When the process goes awry, it can give rise to invasive cancer cells or aberrant fibrosis.

Mitochondria-associated endoplasmic reticulum membranes: A specialized region of the endoplasmic reticulum that communicates with the mitochondria. It regulates many cellular processes, including those implicated in FECD, c9ALS/FTD, and other neurodegenerative diseases, such as mitochondrial homeostasis, endoplasmic reticulum stress, and the unfolded protein response.

Nucleotide repeat expansion: Increased copies of a certain nucleotides in the DNA that underlies several neurodegenerative disorders known as microsatellite expansion diseases. Trinucleotide repeat expansion in the TCF4 gene causes the majority of FECD cases.

RAN (repeat-associated non-ATG) peptides: Aberrant RNA, formed by transcription of nucleotide repeat expansions undergoes transport to the cytoplasm where it is translated in an atypical (non-ATG dependent) fashion into peptides that cause cellular dysfunction. RAN peptides have been identified in multiple nucleotide expansion diseases.

RNA toxicity: Nucleotide repeat expansions undergo transcription, forming nuclear aggregates with RNA binding proteins (RNA foci). The sequestration of RNA-binding proteins into toxic RNA foci can disrupt multiple cellular pathways. Known to occur in multiple neurodegenerative diseases, as well as in FECD.

Unfolded protein response (UPR): A compensatory mechanism of the endoplasmic reticulum (ER) to the accumulation of misfolded or unfolded proteins with the ER lumen, which induces ER stress. Activation of the UPR causes a temporary cessation of translation, with degradation of misfolded proteins and implementation of cellular mechanisms to improve protein folding. The UPR can trigger apoptosis if it cannot correct the cause of protein misfolding. Activation of UPR has been suggested to play a role in FECD and in some neurologic disorders.

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Keywords:

Fuchs dystrophy; Endothelium; Mitochondria; Nucleotide repeat expansion; Corneal transplantation; Descemet stripping; Descemetorhexis

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