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"Fuchs"
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Ultraviolet A light induces DNA damage and estrogen-DNA adducts in Fuchs endothelial corneal dystrophy causing females to be more affected
Fuchs endothelial corneal dystrophy (FECD) is a leading cause of corneal endothelial (CE) degeneration resulting in impaired visual acuity. It is a genetically complex and age-related disorder, with higher incidence in females. In this study, we established a nongenetic FECD animal model based on the physiologic outcome of CE susceptibility to oxidative stress by demonstrating that corneal exposure to ultraviolet A (UVA) recapitulates the morphological and molecular changes of FECD. Targeted irradiation of mouse corneas with UVA induced reactive oxygen species (ROS) production in the aqueous humor, and caused greater CE cell loss, including loss of ZO-1 junctional contacts and corneal edema, in female than male mice, characteristic of late-onset FECD. UVA irradiation caused greater mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage in female mice, indicative of the sex-driven differential response of the CE to UVA, thus accounting for more severe phenotype in females. The sex-dependent effect of UVA was driven by the activation of estrogen-metabolizing enzyme CYP1B1 and formation of reactive estrogen metabolites and estrogen-DNA adducts in female but not male mice. Supplementation of N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS), diminished the morphological and molecular changes induced by UVA in vivo. This study investigates the molecular mechanisms of environmental factors in FECD pathogenesis and demonstrates a strong link between UVA-induced estrogen metabolism and increased susceptibility of females for FECD development.
Journal Article
Imaging improvements reveal guttae development and posterior fibrillar layer formation in fuchs endothelial corneal dystrophy
Guttae are a hallmark of Fuchs endothelial corneal dystrophy (FECD) and the disease’s progression. A posterior fibrillar layer (PFL) that covers central guttae has been previously described, but its formation and progression remain unclear. This study aims to further investigate the characteristics of guttae and the PFL in FECD. In a well-characterized prospective FECD patient cohort, a total of 43 DMEK (Descemet membrane endothelial keratoplasty) specimens were immunostained for ZO1 or COL1, flat-mounted, and analyzed using differential interference contrast (DIC), autofluorescence (excited at 480 nm), and polarized light microscopy. Guttae and PFL were quantified and correlated with clinical data. Guttae were visualized by DIC and autofluorescence imaging and classified into two types with gradual transition: peripheral, knob-like guttae and central, flat guttae. Guttae with low autofluorescence often were covered by corneal endothelial cells (CEnC). Central guttae were found to be covered by a PFL that contained COL1 and was visualized using polarized light microscopy. The PFL displayed a fibrous structure that blurred guttae in DIC illumination. Its presence correlated with clinical parameters, such as anterior scatter and post-operative corneal edema resolution providing insight into the relation of PFL and FECD severity. The combination of DIC, autofluorescence, and polarized light microscopy provides a robust method for investigating guttae and the PFL. This could facilitate preoperative assessment of corneal donor tissue and enhance postoperative clinical diagnostics by detailed detection of guttae and PFL in patients.
Journal Article
Preoperative and perioperative factors that predict endothelial cell loss 1 year after uncomplicated Descemet membrane endothelial keratoplasty
To identify pre/perioperative variables that shape endothelial cell loss (ECL) after uncomplicated Descemet membrane endothelial keratoplasty (DMEK).
This retrospective study included all consecutive patients with Fuchs endothelial corneal dystrophy who underwent DMEK surgery without perioperative or postoperative complications in 2015-2023 and were followed for 12 months. To identify covariates that predicted 12-month ECL, primary hierarchical multivariable analysis was conducted with 12 variables: patient age and sex; donor age; preoperative axial length, visual acuity, central corneal thickness, and graft endothelial cell density; endotamponade with sulfur hexafluoride (SF6) or air; triple-DMEK or pseudophakic-DMEK; operative time; graft marking; and rebubbling.
137 eyes (112 patients) were included. Multivariable analysis showed that SF6 predicted 13.6 ± 3.4% greater ECL vs. air (p < 0.0001) and accounted for 10% of total ECL variation. Longer operative time and multiple (≥2) rebubbling also predicted 0.4 ± 0.7% (p = 0.046) and 11.7 ± 5.1% (p = 0.02) higher ECL, respectively. SF6 significantly reduced rebubbling on univariable analysis (13% vs. 41% for air, p = 0.01).
SF6 use for endotamponade may increase ECL after DMEK. There is an urgent need for randomized controlled trials that estimate the relative disadvantages (endothelial toxicity) and advantages (less bothersome rebubbling) of SF6.
ClinicalTrials.gov Identifier: NCT02535819.
Journal Article
Visual function after ultrathin Descemet’s stripping automated endothelial keratoplasty or Descemet’s membrane endothelial keratoplasty combined with cataract surgery: a randomised controlled clinical trial
AimsTo compare best-corrected visual acuity (BCVA), contrast sensitivity and endothelial cell density (ECD) after ultrathin Descemet’s stripping automated endothelial keratoplasty (UT-DSAEK) and Descemet’s membrane endothelial keratoplasty (DMEK).MethodsA randomised, single-blinded, single-centre design was used. 72 patients with Fuchs’ endothelial dystrophy and cataract were randomised to UT-DSAEK or DMEK combined with phacoemulsification and lens implantation. 27 patients with cataract were included in a control group and treated with phacoemulsification and lens implantation. The primary outcome was BCVA at 12 months.ResultsCompared with UT-DSAEK, DMEK resulted in better BCVA with mean differences of 6.1 early treatment diabetic retinopathy study (ETDRS) (p=0.001) after 3 months, 7.4 ETDRS (p<0.001) after 6 months and 5.7 ETDRS (p<0.001) after 12 months. The control group obtained significantly better BCVA with a mean difference of 5.2 ETDRS (p<0.001) compared with DMEK 12 months postoperatively. Compared with UT-DSAEK, contrast sensitivity was significantly better 3 months after DMEK with a mean difference of 0.10 LogCS (p=0.03). However, our study found no effect after 12 months (p=0.08). ECD was significantly lower after UT-DSAEK compared with DMEK with mean differences of 332 cells/mm2 (p<0.01) after 3 months, 296 cells/mm2 (p<0.01) after 6 months and 227 cells/mm2 (p=0.03) after 12 months.ConclusionsCompared with UT-DSAEK, DMEK resulted in better BCVA 3, 6 and 12 months postoperatively. Twelve months postoperatively, DMEK had a higher ECD than UT-DSAEK; however, no difference in contrast sensitivity was found.Trial registration number NCT04417959
Journal Article
Fuchs endothelial corneal dystrophy: an updated review
Purpose
The present review will summarize FECD-associated genes and pathophysiology, diagnosis, current therapeutic approaches, and future treatment perspectives.
Methods
Literature review.
Results
Fuchs' endothelial corneal dystrophy (FECD) is the most common bilateral corneal dystrophy and accounts for one-third of all corneal transplants performed in the US. FECD is caused by a combination of genetic and non-heritable factors, and there are two types: early-onset FECD, which affects individuals from an early age and is usually more severe, and late-onset FECD, which is more common and typically manifests around the age of 40. The hallmark findings of FECD include progressive loss of corneal endothelial cells and the formation of focal excrescences (guttae) on the Descemet membrane. These pathophysiological changes result in progressive endothelial dysfunction, leading to a decrease in visual acuity and blindness in later stages. The present review will summarize FECD-associated genes and pathophysiology, diagnosis, current therapeutic approaches, and future treatment perspectives.
Conclusion
With the characterization and understanding of FECD-related genes and ongoing research into regenerative therapies for corneal endothelium, we can hope to see more significant improvements in the future in the management and care of the disease.
Journal Article
High expression of the underexplored SLC4A11 protein-coding transcript is specific to the corneal endothelium
Fuchs’ endothelial corneal dystrophy (FECD) and congenital hereditary endothelial dystrophy (CHED) are corneal endothelial pathologies associated with
SLC4A11
gene variants. The principal findings on the expression and function of
SLC4A11
in the corneal endothelium have been based on studies of three major transcripts variants (v1, v2 and v3) and their protein products. We aimed to address gaps and resolve contradictions regarding the expression of
SLC4A11
. Our transcriptomic analysis revealed predominant expression of RefSeq-annotated protein-coding transcripts v6 and v3, but not v2 and v1, in the corneal endothelium of patients with FECD and controls. We also demonstrated the specificity of high
SLC4A11
and major transcript expression to corneal endothelium. Using the 5’ RACE method, we directly showed that the major transcription start site is at the beginning of v6, from which v3 with an extended 5’UTR is also transcribed. We estimated the fraction of v6 and v3 from the overall expression as 0.63 and 0.34, respectively. We also obtained evidence of full-length v6 expression in corneal endothelium and its ability to drive translation of the previously described v2M36 protein isoform. These findings provide new information on
SLC4A11
gene expression and functional consequences of some genomic variants identified in patients with FECD.
Journal Article
Comprehensive identification of dysregulated extracellular matrix molecules in the corneal endothelium of patients with Fuchs endothelial corneal dystrophy
Fuchs endothelial corneal dystrophy (FECD) is a bilateral, progressive corneal endothelial disease characterized by the formation of extracellular matrix (ECM) excrescences called guttae. This study integrated proteomic and transcriptomic analyses to elucidate the molecular composition and spatial organization of ECM proteins in the Descemet membrane (DM) of FECD patients. Through shotgun proteomics of FECD-derived DM specimens and RNA sequencing data from FECD (
n
= 10) and control (
n
= 7) corneal endothelial cells, we identified 19 significantly upregulated molecules in FECD, including 13 ECM-related proteins. Gene Ontology and Reactome analyses revealed ECM-related pathways as central to FECD pathology. Immunofluorescence analyses of flat-mounted and cross-sectional specimens from FECD patients undergoing Descemet membrane endothelial keratoplasty (DMEK) and controls demonstrated distinct spatial patterns for six ECM proteins. Fibronectin and collagen VI α1 were detected on the outer surfaces of guttae, matrilin-3 and biglycan localized around guttae, while LTBP2 and tenascin were strongly associated with the posterior fibrillar layer (PFL). The peripheral corneal regions predominantly exhibited scattered guttae, whereas the central region displayed buried guttae encapsulated by ECM deposition. This study comprehensively examined ECM protein expression patterns, revealing distinct spatial distributions across guttae, PFL, and surrounding DM regions. These findings suggest that clinical assessments should incorporate both guttae confluence and the presence of ECM-rich PFL to achieve a more comprehensive understanding of FECD progression, thereby informing more accurate staging and optimal surgical planning.
Journal Article
Risk factors for corneal transplantation in Fuchs endothelial corneal dystrophy from a large Thai cohort
This study aimed to identify risk factors associated with corneal transplantation within five years among Thai patients with Fuchs endothelial corneal dystrophy (FECD) and to evaluate whether isolated cataract surgery could defer the need for corneal transplantation. We retrospectively reviewed 900 patients (1,743 eyes) at King Chulalongkorn Memorial Hospital between January 2017 and June 2023. Associations were assessed using logistic regression. Significant predictors of transplantation included advanced disease stage (Adamis’ grade ≥ 2; odds ratio [OR] = 6.40), reduced endothelial cell density (ECD ≤ 1600 cells/mm²; OR = 5.30), increased central corneal thickness (CCT ≥ 590 μm; OR = 2.64), and worse baseline best-corrected visual acuity (BCVA ≥ 0.3 logMAR; OR = 2.02). Among 274 phakic eyes undergoing isolated cataract surgery, preoperative ECD ≤ 1700 cells/mm² or CCT ≥ 550 μm were associated with postoperative progression. These thresholds should be regarded as exploratory, particularly in the cataract subgroup where event numbers were small and follow-up was short. Nevertheless, our findings may help improve risk stratification, guide preoperative counseling, and support efficient donor allocation in regions facing chronic shortages.
Journal Article
Emerging treatments for corneal endothelium decompensation — a systematic review
Purpose
Endothelial keratoplasty (EK) is the conventional treatment to improve visual acuity of corneal endothelium decompensation (CED) patients, with other therapies mainly for symptomatic relief. However, the shortage of corneal grafts and other limitations to EK urge the development of novel alternative treatments. In the last decade, novel options have been proposed, yet only a limited number of reviews have systematically reported on outcomes. Therefore, this systematic review evaluates the existing clinical evidence of novel surgical approaches for CED.
Method
We identified 24 studies that illustrated the clinical observations of the surgical approaches in interest. We included Descemet stripping only (DSO), Descemet membrane transplantation (DMT) where Descement membrane alone instead of corneal endothelium with cells is transplanted, and cell-based therapy.
Results
In general, these therapies may provide visual outcomes comparable with EK under specific conditions. DSO and DMT target CED with relatively healthy peripheral corneal endothelium like Fuchs’ corneal endothelial dystrophy, while cell-based therapy offers more versatile applications. Side effects of DSO would decrease with modifications to surgical techniques. Moreover, Rho-associated protein kinase inhibitor adjuvant therapy could enhance clinical results in DSO and cell-based therapy.
Conclusion
Long-term controlled clinical trials with larger sample size on the therapies are needed. The simplicity of DSO and the high translational potential of cell-based therapy to treat CED of most etiologies made these two treatment strategies promising.
Journal Article