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Frontiers in Medicine 2023The pathogenic role of variants in TCF4 and COL8A2 in causing Fuchs' endothelial corneal dystrophy (FECD) is not controversial and has been confirmed by numerous...
INTRODUCTION
The pathogenic role of variants in TCF4 and COL8A2 in causing Fuchs' endothelial corneal dystrophy (FECD) is not controversial and has been confirmed by numerous studies. The causal role of other genes, SLC4A11, ZEB1, LOXHD1, and AGBL1, which have been reported to be associated with FECD, is more complicated and less obvious. We performed a systematic review of the variants in the above-mentioned genes in FECD cases, taking into account the currently available population frequency information, transcriptomic data, and the results of functional studies to assess their pathogenicity.
METHODS
Search for articles published in 2005-2022 was performed manually between July 2022 and February 2023. We searched for original research articles in peer-reviewed journals, written in English. Variants in the genes of interest identified in patients with FECD were extracted for the analysis. We classified each presented variant by pathogenicity status according to the ACMG criteria implemented in the Varsome tool. Diagnosis, segregation data, presence of affected relatives, functional analysis results, and gene expression in the corneal endothelium were taken into account. Data on the expression of genes of interest in the corneal endothelium were extracted from articles in which transcriptome analysis was performed. The identification of at least one variant in a gene classified as pathogenic or significantly associated with FECD was required to confirm the causal role of the gene in FECD.
RESULTS
The analysis included 34 articles with 102 unique ZEB1 variants, 20 articles with 64 SLC4A11 variants, six articles with 26 LOXHD1 variants, and five articles with four AGBL1 variants. Pathogenic status was confirmed for seven SLC4A11 variants found in FECD. No variants in ZEB1, LOXHD1, and AGBL1 genes were classified as pathogenic for FECD. According to the transcriptome data, AGBL1 and LOXHD1 were not expressed in the corneal endothelium. Functional evidence for the association of LOXHD1, and AGBL1 with FECD was conflicting.
CONCLUSION
Our analysis confirmed the causal role of SLC4A11 variants in the development of FECD. The causal role of ZEB1, LOXHD1, and AGBL1 variants in FECD has not been confirmed. Further evidence from familial cases and functional analysis is needed to confirm their causal roles in FECD.
PubMed: 37441688
DOI: 10.3389/fmed.2023.1153122 -
Journal of Ophthalmology 2022To evaluate the global prevalence of Fuchs endothelial corneal dystrophy (FECD).
PURPOSE
To evaluate the global prevalence of Fuchs endothelial corneal dystrophy (FECD).
DESIGN
Systematic review and meta-analysis.
METHODS
A systematic electronic literature search was conducted on PubMed/MedLine, Cochrane Library, and Google Scholar, in order to select papers analysing the prevalence rate of FECD. Two authors independently conducted the electronic search. After removal of duplicates, title and abstract screening, and full-text analysis, data from selected articles were archived in a customized Excel spreadsheet. Risk of bias assessment was performed using the Joanna Briggs Institute Prevalence Critical Appraisal Tool. Meta-analysis was conducted using R (version 1.4.1106, package "meta").
RESULTS
A total of 6660 eligible articles were retrieved from the initial electronic search. Only 4 original works were included in the qualitative and quantitative analysis. Of the 4746 patients included in this meta-analysis (i.e., 2232 male (M) and 2322 female (F)), we retrieved 269 FECD cases (81 M; 188 F), with a pooled prevalence estimates of 7.33% (95% CI: 4.08-12.8%). Statistically significant gender-related differences in the prevalence of FECD emerged by the analysis (OR: 2.22; 95% CI: 1.66-2.96, =0.0016). While the total number of people aged >30 years with FECD is nowadays estimated at nearly 300 million, an increase of 41.7% in the number of FECD-affected patients is expected by 2050, when the overall figure is supposed to rise up to 415 million.
CONCLUSION
This study provides a reliable figure of the present and future epidemiological burden of FECD globally, which might be useful for the design of FECD screening, treatment, rehabilitation, and related public health strategies.
PubMed: 35462618
DOI: 10.1155/2022/3091695 -
BMC Ophthalmology Jun 2015Studies investigating the associations between transcription factor 4 (TCF4) genetic polymorphisms and Fuchs' endothelial dystrophy (FED) have reported controversial... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Studies investigating the associations between transcription factor 4 (TCF4) genetic polymorphisms and Fuchs' endothelial dystrophy (FED) have reported controversial results. Therefore, this meta-analysis aims to clarify the effects of TCF4 polymorphisms on FED risk.
METHODS
A meta-analysis was conducted to assess the association between four single nucleotide polymorphisms (SNPs) inTCF4 and the risk of FED. Relevant studies were selected through an extensive search of PubMed, EMBASE, and the Web of Science databases. Pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated using the random-effects model.
RESULTS
Thirteen studies were included in this systematic review and meta-analysis. The pooled results showed that there was a strong positive association between the TCF4 rs613872 polymorphism and FED risk in all the genetic models tested (G allele vs. T allele: OR = 4.19, 95 % CI = 3.53-4.97; GG vs.
GT/TT
OR = 4.27, 95 % CI = 2.54-7.19; GG/GT vs. TT: OR = 6.29, 95 % CI = 4.23-8.93; GG VS. TT: OR = 10.64, 95 % CI = 5.28-21.41; GT VS. TT: OR = 6.08, 95 % CI = 4.28-8.64). Statistic evidence was also detected for a significant association between three other SNPs and the risk of FED.
CONCLUSIONS
This meta-analysis suggested a genetic association between four TCF4 polymorphisms (rs613872, rs2286812, rs17595731, and rs9954153) and the risk of FED.
Topics: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Fuchs' Endothelial Dystrophy; Genetic Predisposition to Disease; Humans; Polymorphism, Single Nucleotide; Transcription Factor 4; Transcription Factors
PubMed: 26087656
DOI: 10.1186/s12886-015-0055-6 -
Ophthalmic Research 2020Comorbidity of keratoconus (KC) and Fuchs' corneal endothelial dystrophy (FD) has been sporadically reported in the literature since the early nineties. This review...
INTRODUCTION
Comorbidity of keratoconus (KC) and Fuchs' corneal endothelial dystrophy (FD) has been sporadically reported in the literature since the early nineties. This review summarizes findings from the related literature while examining the possibilities related to the concurrent development of these disorders and the clinical significance for the clinician.
METHODS
NLM/PubMed, Ovid, Google Scholar, Cornea, and Cochrane database were reviewed for research papers presenting cases of comorbid KC and FD published between January 1990 and July 2019.
RESULTS
Fifteen papers which presented 69 cases were included in the study. Most cases were women (56.5%), involvement was bilateral (59.4%), and the age range was wide (15-82 years) with a normal distribution. Incidence is expected to be approximately 1 per 100,000. FD is the most frequent comorbid corneal dystrophy diagnosed in KC patients. There are 4 distinct possibilities for the cooccurrence of KC and FD, the most likely being that of chance.
CONCLUSION
The overall incidence of these disorders found in combination is very low and, in absence of other conclusively proven hypotheses, most likely attributable to chance. The treatment plan should be tailored to the needs of the individual patient, since the diagnosis can be made in any stage of life and could be part of a more complex presentation that includes another pathology of the cornea or senile cataract. The inclusion of preoperative topography and specular microscopy as routine in cataract preoperative assessment would protect against any postoperative complications in these patients.
Topics: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Comorbidity; Corneal Topography; Female; Fuchs' Endothelial Dystrophy; Humans; Incidence; Keratoconus; Keratoplasty, Penetrating; Male; Middle Aged; Sex Distribution; Visual Acuity
PubMed: 31865313
DOI: 10.1159/000505579 -
BMJ Open Ophthalmology 2019Rare ophthalmic diseases have a devastating impact on a patient's vision and consequently negatively affect their independence, ability to work and overall quality of... (Review)
Review
Rare ophthalmic diseases have a devastating impact on a patient's vision and consequently negatively affect their independence, ability to work and overall quality of life. Methylation is an important emerging biomarker of disease and may improve understanding of rare ophthalmic disorders. This systematic review sought to identify and evaluate literature on methylation and rare ophthalmic disease. MEDLINE, EMBASE, PubMed, Cochrane Database of Systematic Reviews and grey literature resources were searched for publications prior to 20 August 2019. Articles written in English which featured key terms such as 'methylation' and rare ophthalmic diseases were included. Titles, abstracts, keywords and full texts of publications were screened, as well as reference lists for reverse citations and Web of Science 'cited reference search' for forward citation searching. Study characteristics were extracted, and methodological rigour appraised using a standardised template. Fourteen articles were selected for full inclusion. Rare ophthalmic conditions include congenital fibrosis of extraocular muscles, retinitis pigmentosa, Fuchs endothelial corneal dystrophy, granular corneal dystrophy, choroideraemia, brittle cornea syndrome, retinopathy of prematurity, keratoconus and congenital cataracts. Outcomes include identification of methylation as contributor to disease and identification of potential novel therapeutic targets. The studies included were heterogeneous with no scope for meta-analysis following review; a narrative synthesis was undertaken. Differential methylation has been identified in a small number of rare ophthalmic diseases and few studies have been performed to date. Further multiomic research will improve understanding of rare eye diseases and hopefully lead to improved provision of diagnostic/prognostic biomarkers, and help identify novel therapeutic targets.
PubMed: 31799411
DOI: 10.1136/bmjophth-2019-000342 -
Clinical and Translational Medicine Dec 2017Corneal diseases are an extensive cause of blindness worldwide and continue to persist as a challenging public health concern. Recently, various lipid-based therapies... (Review)
Review
Corneal diseases are an extensive cause of blindness worldwide and continue to persist as a challenging public health concern. Recently, various lipid-based therapies have been advocated for the modulation of corneal diseases; however, the number of studies is still very limited. Here we focus on developments and challenges on lipid-based therapies for dry eye disease, diabetic neuropathy, and Fuchs' endothelial corneal dystrophy. All three diseases are highly prevalent conditions and involve corneal stress and inflammation. Lipid-based therapeutics discussed includes cyclooxygenase inhibitors, essential fatty acids, and resolvin analogs. Lipids also show increasing promise as biomarkers of disease and are explored in this review.
PubMed: 28782089
DOI: 10.1186/s40169-017-0158-1 -
PloS One 2014A meta-analysis of TCF4 and PTPRG gene variants in Fuchs' corneal dystrophy (FCD). (Meta-Analysis)
Meta-Analysis
TOPIC
A meta-analysis of TCF4 and PTPRG gene variants in Fuchs' corneal dystrophy (FCD).
CLINICAL RELEVANCE
To identify novel genetic markers in patients with FCD in different ethnic populations.
METHODS
MEDLINE and EMBASE were searched for eligible genetic studies on TCF4 and PTPRG in FCD. Odds ratios (OR) and 95% confidence intervals (CI) of each single-nucleotide polymorphism (SNP) in allelic, dominant and recessive models were estimated using fixed-effect model if I2<50% in the test for heterogeneity, otherwise the random effects model was used.
RESULTS
Thirty-three records were obtained, with 8 being suitable for meta-analysis, which included five SNPs in TCF4 and two in PTPRG. There were 1610 FCD patients and 1565 controls tested for TCF4 rs613872. This SNP was strongly associated with FCD in Caucasians (P = 5.0×10-106), with the risk allele G conferring an OR of 3.95 (95% CI: 3.49-4.46). A further 4 TCF4 SNPs (rs17595731, rs2286812, rs618869 and rs9954153) were also significantly associated with FCD in Caucasians (P<10-8). However, we found no SNP associated with FCD in Chinese. In addition, there was no significant association between FCD and PTPRG.
CONCLUSION
TCF4 rs613872 is strongly associated with FCD in Caucasians but not in Chinese, which may suggest ethnic diversity in FCD SNP associations. SNPs in PTPRG were not associated with FCD in Caucasians or Chinese populations. Results of this meta-analysis indicate the need for larger-scale and multi-ethnic genetic studies on FCD to further explore the associated gene variants and their roles on the mechanism and genetic basis of FCD.
Topics: Aged; Alleles; Asian People; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Case-Control Studies; Fuchs' Endothelial Dystrophy; Genetic Markers; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Single Nucleotide; Receptor-Like Protein Tyrosine Phosphatases, Class 5; Transcription Factor 4; Transcription Factors; White People
PubMed: 25299301
DOI: 10.1371/journal.pone.0109142 -
The Cochrane Database of Systematic... Jun 2018Corneal endothelial transplantation has become the gold standard for the treatment of corneal endothelial dysfunctions, replacing full thickness transplantation, known... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Corneal endothelial transplantation has become the gold standard for the treatment of corneal endothelial dysfunctions, replacing full thickness transplantation, known as penetrating keratoplasty. Corneal endothelial transplantation has been described using two different techniques: Descemet's membrane endothelial keratoplasty (DMEK) and Descemet's stripping automated endothelial keratoplasty (DSAEK). Both are still performed worldwide.
OBJECTIVES
To compare the effectiveness and safety of Descemet's membrane endothelial keratoplasty (DMEK) versus Descemet's stripping automated endothelial keratoplasty (DSAEK) for the treatment of corneal endothelial failure in people with Fuch's endothelial dystropy (FED) and pseudophakic bullous keratopathy (PBK).
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 7); MEDLINE Ovid; Embase Ovid; LILACS BIREME; the ISRCTN registry; ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The date of the search was 11 August 2017.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and non-randomised paired, contralateral-eye studies in any setting where DMEK was compared with DSAEK to treat people with corneal endothelial failure.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened the search results, assessed trial quality and extracted data using the standard methodological procedures expected by Cochrane. Our primary outcome was best corrected visual acuity (BCVA) measured in logarithm of the Minimum Angle of Resolution (logMAR). Secondary outcomes were endothelial cell count, graft rejection, primary graft failure and graft dislocation. We graded the risk of bias of non-randomised studies (NRSs) using ROBINS-I.
MAIN RESULTS
We did not identify any RCTs but found four non-randomised studies (NRSs) including 72 participants (144 eyes), who had received DSAEK in the first eye followed by DMEK in the fellow eye. All the studies included adult participants where there was evidence of FED and endothelial failure requiring a corneal transplant for the treatment of visual impairment. We did not find any studies that included PBK. The trials were published between 2011 and 2015, and we assessed them as high risk of bias due to potential unknown confounding factors since DSAEK preceded DMEK in all participants. Two studies reported results at 12 months, one at 6 months, and one between 6 and 24 months. At one year, using DMEK in cases of endothelial failure may result in better BCVA compared with DSAEK (mean difference (MD) -0.14, 95% confidence interval (CI) -0.18 to -0.10 logMAR, 4 studies, 140 eyes, low-certainty evidence). None of the participants had severe visual loss (BCVA of 1.0 logMAR or more; very low-certainty evidence). Regarding endothelial cell count data (4 studies, 134 eyes) it is hard to draw any conclusions since two studies suggested no difference and the other two reported that DMEK provides a higher cell density at one year (very low-certainty evidence). No primary graft failure and only one graft rejection were recorded over four studies (144 eyes) (very low-certainty evidence). The most common complications reported were graft dislocations, which were recorded in one or two out of 100 participants with DSAEK but were more common using DMEK, although this difference could not be precisely estimated (risk ratio (RR) 5.40, 95% CI 1.51 to 19.3; 4 studies, 144 eyes, very low-certainty evidence).
AUTHORS' CONCLUSIONS
This review included studies conducted on people with corneal endothelium failure due to FED for whom both DMEK and DSAEK can be considered, and found low-certainty evidence that DMEK provides some advantage in terms of final BCVA, at the cost of more graft dislocations needing 're-bubbling' (very low-certainty of evidence).
Topics: Adult; Cell Count; Corneal Diseases; Corneal Transplantation; Descemet Membrane; Descemet Stripping Endothelial Keratoplasty; Endothelial Cells; Fuchs' Endothelial Dystrophy; Humans; Non-Randomized Controlled Trials as Topic; Postoperative Complications; Visual Acuity
PubMed: 29940078
DOI: 10.1002/14651858.CD012097.pub2 -
The Cochrane Database of Systematic... Feb 2014Fuchs endothelial dystrophy (FED) is a condition in which there is premature degeneration of corneal endothelial cells. When the number of endothelial cells is reduced... (Comparative Study)
Comparative Study Review
BACKGROUND
Fuchs endothelial dystrophy (FED) is a condition in which there is premature degeneration of corneal endothelial cells. When the number of endothelial cells is reduced to a significant degree, fluid begins to accumulate within the cornea. As a result, the cornea loses its transparency and the individual suffers a reduction in vision. The only successful surgical treatment for this condition is replacement of part or all of the cornea with healthy tissue from a donor. The established procedure, penetrating keratoplasty (PKP), has been used for many years and its safety and efficacy are well known. Endothelial keratoplasty (EK) techniques are relatively new surgical procedures and their safety and efficacy relative to PKP are uncertain.
OBJECTIVES
The objective of this review was to compare the benefits and complications related to two surgical methods (EK and PKP) of replacing the diseased endothelial layer of the cornea with a healthy layer in people with FED.
SEARCH METHODS
We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2014, Issue 1), MEDLINE (January 1950 to January 2014), EMBASE (January 1980 to January 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to January 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) and ClinicalTrials.gov (www.clinicaltrials.gov). There were no date or language restrictions in the electronic searches for trials. The electronic databases were last searched on 27 January 2014.
SELECTION CRITERIA
We included all randomised controlled trials (RCTs) comparing EK versus PKP for people (of any age and gender) who had been clinically diagnosed with FED.
DATA COLLECTION AND ANALYSIS
Two authors independently screened the search results, assessed trial quality and extracted data using the standard methodological procedures expected by The Cochrane Collaboration.
MAIN RESULTS
We included three RCTs that enrolled a total of 139 eyes of 136 participants and analysed 123 (88%) eyes. Two RCTs randomised eyes into either the endothelial keratoplasty (EK) group or penetrating keratoplasty (PKP) group and one RCT randomised eyes into either the femtosecond laser-assisted endothelial keratoplasty (FLEK) group or PKP group. The RCTs comparing EK with PKP did not show any significant differences between procedures with respect to best corrected visual acuity (BCVA) at two years (mean difference (MD) 0.14 logMAR; 95% confidence interval (CI) -0.08 to 0.36; P = 0.23) or at one year (MD 0.09 logMAR; 95% CI -0.05 to 0.23; P = 0.22), whereas the trial comparing FLEK with PKP showed significantly better BCVA after PKP (MD 0.20 logMAR; 95% CI 0.10 to 0.30; P = 0.0001). Only one RCT reported on irregular astigmatism (higher-order aberration), which was less with EK than PKP (MD -1.20 µm; 95% CI -1.53 to -0.87; P < 0.001). Only one RCT reported on endothelial cell counts (lower after FLEK than PKP: MD -969 cells/mm²; 95% CI -1161 to -777; P < 0.001), primary graft failure (higher after FLEK than PKP: RR 7.76; 95% CI 0.41 to 145.22; P = 0.10), and graft rejection (more after FLEK than PKP: RR 1.11; 95% CI 0.07 to 17.12; P = 0.94). Only one RCT reported that 27.8% of participants had graft dislocation, 2.8% had epithelial ingrowth and postoperative pupillary block, and 13.9% had intraocular pressure (IOP)-related problems in the FLEK group compared with the PKP group, in whom 10% had suture-related problems, 5% had wound dehiscence and 10% had suture revision to correct astigmatism. Overall, the adverse events in the FLEK group appeared to be more frequent than in the PKP group. No trials reported information about quality of life or economic data. The overall methodological quality of the three trials was not satisfactory as most did not perform allocation concealment or masking of participants and outcome assessors, and all trials had a small sample size.
AUTHORS' CONCLUSIONS
The rapid growth of endothelial keratoplasty as the treatment of choice for FED is based upon the belief that visual recovery is more rapid, surgically induced astigmatism (regular and irregular) is less and rates of transplant rejection are lower with EK. This change in practice also assumes that the rates of long term transplant survival are equal for the two procedures. The practical differences between the surgical procedures mean that visual recovery is inherently more rapid following EK, but this review found no strong evidence from RCTs of any difference in the final visual outcome between EK and PKP for people with FED. This review also found that higher order aberrations are fewer following EK but endothelial cell loss is greater following EK. The RCTs that we included employed different EK techniques, which may have a bearing on these findings. EK procedures have evolved over the years and can be performed using different techniques, for example deep lamellar endothelial keratoplasty, Descemets stripping endothelial keratoplasty (DSEK), Descemets stripping automated endothelial keratoplasty (DSAEK), femtosecond laser-assisted endothelial keratoplasty and Descemet membrane endothelial keratoplasty (DMEK). More RCTs are needed to compare PKP with commonly performed EK procedures such as DSEK, DSAEK and DMEK in order to determine the answers to two key questions, whether there is any difference in the final visual outcome between these techniques and whether there are differences in the rates of graft survival in the long term?
Topics: Corneal Surgery, Laser; Corneal Transplantation; Fuchs' Endothelial Dystrophy; Humans; Keratoplasty, Penetrating; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 24526345
DOI: 10.1002/14651858.CD008420.pub3 -
Acta Ophthalmologica Aug 2022To evaluate the efficacy of preventive treatment against allograft rejection after endothelial keratoplasty (EK), we conducted a systematic review and meta-analysis. (Meta-Analysis)
Meta-Analysis
PURPOSE
To evaluate the efficacy of preventive treatment against allograft rejection after endothelial keratoplasty (EK), we conducted a systematic review and meta-analysis.
METHOD
PubMed, Cochrane Library, Embase and ScienceDirect databases were searched until May 2021. We computed a random-effect meta-analysis on graft rejection rate stratified by the intervention (i.e. Descemet membrane EK (DMEK) and Descemet stripping (Automated) EK (DS(A)EK) or ultrathin (UT)-DSAEK), and postoperative treatment. Meta-regressions were performed to compare intervention, treatment and influence of putative confusion factors.
RESULTS
We included 49 studies and 12 893 EK (6867 DMEK and 6026 DS(A)EK/UT-DSAEK). Topical steroids were merged in two efficacy regimens: standard steroids (prednisolone acetate 1% or dexamethasone 0.1%) and soft steroids (fluorometholone 0.1% or loteprednol etabonate 0.5%). Globally, DMEK had a lower graft rejection rate than DS(A)EK/UT-DSAEK (coefficient - 3.3, 95 CI, -4.60 to -1.90; p < 0.001). No significant differences were observed between standard and soft steroids to prevent graft rejection after DMEK. After EK, the rate of ocular hypertension was 20% (95 CI, 14 to 26%) with the use of standard steroids and 7% (5 to 9%) with soft steroids. Comparisons of treatments were not feasible in DS(A)EK/UT-DSAEK due to a lack of studies.
CONCLUSIONS
Descemet membrane endothelial keratoplasty (DMEK) has less risk of graft rejection compared with DS(A)EK/UT-DSAEK. Furthermore, soft steroids seemed to be a valuable alternative to standard steroids to prevent graft rejection after DMEK, involving a safe profile against ocular hypertension. Further studies are needed to compare other drugs in the prevention of graft rejection after EK.
Topics: Allografts; Corneal Diseases; Descemet Membrane; Descemet Stripping Endothelial Keratoplasty; Endothelium, Corneal; Fuchs' Endothelial Dystrophy; Glaucoma; Humans; Ocular Hypertension; Retrospective Studies; Visual Acuity
PubMed: 35411680
DOI: 10.1111/aos.15154