Natalie A. Afshari

Missense Mutations in TCF8 Cause Late-Onset Fuchs Corneal Dystrophy and Interact with FCD4 on Chromosome 9p

Fuchs corneal dystrophy (FCD) is a degenerative genetic disorder of the corneal endothelium that represents one of the most common causes of corneal transplantation in the United States. Despite its high prevalence (4% over the age of 40), the underlying genetic basis of FCD is largely unknown. Here we report missense mutations in TCF8, a transcription factor whose haploinsufficiency causes posterior polymorphous corneal dystrophy (PPCD), in a cohort of late-onset FCD patients. In contrast to PPCD-causing mutations, all of which are null, FCD-associated mutations encode rare missense changes suggested to cause loss of function by an in vivo complementation assay. Importantly, segregation of a recurring p.Q840P mutation in a large, multigenerational FCD pedigree showed this allele to be sufficient but not necessary for pathogenesis. Execution of a genome-wide scan conditioned for the presence of the 840P allele identified an additional late-onset FCD locus on chromosome 9p, whereas haplotype analysis indicated that the presence of the TCF8 allele and the disease haplotype on 9p leads to a severe FCD manifestation with poor prognosis. Our data suggest that PPCD and FCD are allelic variants of the same disease continuum and that genetic interaction between genes that cause corneal dystrophies can modulate the expressivity of the phenotype.

Trends in the indications for penetrating keratoplasty, 1980-2001.

Purpose: To study the leading indications and changing trends for penetrating keratoplasty (PK) over the past 3 decades. Methods: This is a retrospective review of 696 cases of PK. The indications for PKs performed at the Duke University Eye Center during the years 1980-1981, 1990- 1991, and 2000-2001 were tabulated to determine trends over the past 3 decades. The main outcome measures were indications for PK. Results: During this study, 696 PKs were performed. The leading indications for PK and their respective frequencies during 1980-1981, 1990-1991, and 2000-2001 were failed grafts (10.8%, 19.0%, 27.0%, respectively), pseudophakic bullous keratopathy (PBK)/aphakic bullous keratopathy (ABK) (19.4%, 20.6%, 16.7%, respectively), Fuchs dystrophy (15.6%, 13.0%, 23.8%, respectively), keratoconus (13.4%, 8.2%, 11.8%, respectively), and corneal scar (7.0%, 8.9%, 10.7%, respectively). The number of PKs for failed grafts and Fuchs dystrophy increased over time. Conclusions: In this study, failed graft has gradually become the leading indication for PK, whereas most other studies have reported PBK as the leading indication. Unlike many other studies, Fuchs dystrophy was a common indication for PK.

Refractive change after descemet stripping automated endothelial keratoplasty surgery and its correlation with graft thickness and diameter.

Purpose: The purpose of this study was to evaluate the refractive change after Descemet stripping automated endothelial keratoplasty (DSAEK) surgery and its correlation with graft thickness and diameter. Methods: We retrospectively analyzed the refractive outcomes of 45 cases of DSAEK surgery that were performed at Duke University Eye Center between August 2005 and December 2006. We divided our study groups into DSAEK triple cases and pseudophakic DSAEK cases. We measured manifest refraction preoperatively and postoperatively in each group and compared the difference between the preoperative and the postoperative spherical equivalent. We evaluated the correlation of the refractive change with graft thickness and diameter. Results: Forty-five DSAEK cases in 44 patients (27 women and 17 men) were evaluated and analyzed. Mean age of the patients at surgery was 67.6 years (15-81 years, SD 10.7 years). Forty cases were treated for Fuchs endothelial dystrophy and 5 for pseudophakic bullous keratopathy/bullous keratopathy. Seventeen cases were DSAEK triple cases and 28 pseudophakic DSAEK cases. In the DSAEK triple group, the mean change in refraction at an average of 4 months postoperatively was +1.15 D (range −0.02 to 2.87, SD 1.15). In the pseudophakic DSAEK group, the mean change in refraction at an average of 5 months postoperatively was +0.71 D (range −1.75 to 3.0, SD 1.11). The overall refractive change was +0.88 D (range −1.75 to 3.0, SD 1.02). Correlation of refractive change with graft diameter was modest (r = 0.29, P = 0.05), and a small correlation was found with respect to graft thickness (r = −0.16, P = 0.31). Conclusions: Our study of DSAEK grafts demonstrated a hyperopic refractive shift after DSAEK surgery. This observation should be taken into consideration when deciding on the appropriate intraocular lens power in DSAEK triple surgery and may also aid in anticipating refractive outcomes after pseudophakic DSAEK surgery. Further studies to follow these refractive changes over a longer follow-up period and to investigate the mechanism of this refractive change after DSAEK surgery are warranted.

Replication of TCF4 through Association and Linkage Studies in Late-Onset Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18 near TCF4 which confer susceptibility to FECD. Here, we report the findings of our independent validation study for TCF4 using the largest FECD dataset to date (450 FECD cases and 340 normal controls). Logistic regression with sex as a covariate was performed for three genetic models: dominant (DOM), additive (ADD), and recessive (REC). We found significant association with rs613872, the target marker reported by Baratz et al.(2010), for all three genetic models (DOM: P = 9.33×10−35; ADD: P = 7.48×10−30; REC: P = 5.27×10−6). To strengthen the association study, we also conducted a genome-wide linkage scan on 64 multiplex families, composed primarily of affected sibling pairs (ASPs), using both parametric and non-parametric two-point and multipoint analyses. The most significant linkage region localizes to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5 at rs1145315 (75.58cM) under the DOM model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies.

Nutrition and the prevention of cataracts.

Purpose of review Oxidative stress is a major cause of cataract development. Numerous studies have been published regarding the effects of nutritional supplementation on cataract progression. Recent findings Basic science research has demonstrated a protective effect of antioxidants on lens tissue, and supplementation with vitamin C and lutein/zeaxanthin has been associated with a decreased risk of cataract formation in multiple observational studies. One large interventional trial demonstrated a significant difference in participants treated with high-dose vitamin C versus placebo, but a more recent interventional study did not replicate these findings. In a review of the carotenoids lutein and zeaxanthin, the Food and Drug Administration concluded there is insufficient evidence to suggest that supplementation with these carotenoids lowers the risk of cataract formation. While high doses of multivitamins, antioxidants, or lutein and zeaxanthin are unlikely to be of significant ophthalmic benefit to the general public, these nutrients may help individuals exposed to high oxidative stress, such as heavy smokers, and those with poor nutrition. Summary Supplementation with vitamin C, lutein, zeaxanthin, or a multivitamin may help certain populations, but is unlikely to affect the progression of cataracts in most patients.

Descemet stripping automated endothelial keratoplasty in a child

We present the case of a 9-year-old patient with corneal decompensation that was treated with Descemet stripping automated endothelial keratoplasty (DSAEK) and followed for 18 months. Although the procedure has been used successfully in adult populations, to our knowledge, this is the first report of DSAEK with long-term follow-up in a child. The outcome suggests that endothelial keratoplasty may be a good alternative to penetrating keratoplasty in children. Endothelial keratoplasty is a new form of corneal transplantation that promises faster visual recovery compared with penetrating keratoplasty. With endothelial keratoplasty, the corneal architecture is preserved; therefore, large spherical and astigmatic errors are not induced, and stable refraction is achieved earlier in the course of therapy.

Genome-wide Linkage Scan in Fuchs Endothelial Corneal Dystrophy

PURPOSE To perform a genome-wide linkage screen with a single-nucleotide polymorphism (SNP) linkage panel to identify regions of genetic linkage in Fuchs endothelial corneal dystrophy (FECD) and to analyze affected individuals for mutations in the COL8A2 gene. METHODS Ninety-two individuals from 22 families with FECD were identified from our multiplex FECD family cohort. A genome-wide linkage scan was performed using an SNP linkage panel. Parametric two-point linkage analyses were calculated and nonparametric multipoint linkage analyses were performed on chromosomes with two-point LOD scores (HLOD) > 1.0. All affected individuals were analyzed for the two previously reported FECD mutations in the COL8A2 gene (L450W and Q455K). RESULTS The genome-wide analysis identified five regions with linkage signals from all analyses on chromosomes 1, 7, 15, 17, and X. The highest two-point HLODs were found on the long arm of chromosome 15 with an HLOD of 3.26 for the recessive model and 2.48 for the dominant model. Multipoint linkage analysis also identified a linkage peak on the long arm of chromosome 15 with a LOD > 1. The region of linkage on chromosome 1p, driven by two multigenerational FECD families with a two-point LOD > 2, was adjacent to the previously identified COL8A2 gene; however, the two reported mutations in COL8A2 were not identified in any of the 56 affected individuals in the 92 samples tested. CONCLUSIONS Genome-wide linkage analysis was used to identify potential linkage regions on chromosomes 1, 7, 15, 17, and X for FECD. The previously reported mutations in the COL8A2 gene were not found in the 92 samples tested.

Perioperative antibiotics and anti-inflammatory agents in cataract surgery.

Purpose of review Cataract surgery has benefited from great technical advances but no consensus exists as regards optimal perioperative medical management of inflammation and infection prophylaxis. Recent findings The present article primarily reviews recent evidence about the most advantageous antibiotic regimen to minimize endophthalmitis, and the utility of steroids or nonsteroidal anti-inflammatory drugs (NSAIDs) in management of both postoperative inflammation and cystoid macular edema. Prospective data from Europe supports the efficacy of intracameral cephalosporins in reducing the incidence of endophthalmitis. We compare this with retrospective data from the United States describing a low incidence of endophthalmitis when using fourth-generation fluoroquinolones as chemoprophylaxis. Other studies demonstrate the anti-inflammatory effect of multiple perioperative topical NSAIDs. Further important questions remain, however, including whether NSAIDs exhibit a superior side-effect profile relative to corticosteroids, whether benefit exists to combination NSAID/corticosteroid therapy, as well as whether NSAIDS can reduce the incidence of cystoid macular edema. Summary New evidence clarifies the use of intracameral antibiotics, and other studies support a niche anti-inflammatory role for NSAIDs.

Calcineurin promotes infection of the cornea by Candida albicans and can be targeted to enhance fluconazole therapy.

ABSTRACT In an established Candida albicans murine keratitis model, combination therapy with ophthalmic preparations of fluconazole and cyclosporine A (CsA) demonstrated in vivo drug synergy and effectively resolved wild-type C. albicans infection more rapidly than monotherapy with either drug. Calcineurin, the target of CsA, was also found to contribute to pathogenicity.

The Genetics of Keratoconus: A Review

Keratoconus is the most common ectatic disorder of the corneal. Genetic and environmental factors may contribute to its pathogenesis. The focus of this article is to summarize current research into the complex genetics of keratoconus. We discuss the evidence of genetic etiology including family-based linkage studies, twin studies, genetic mutations, and genome-wide association studies. The genes implicated potentially include VSX1, miR-184, DOCK9, SOD1, RAB3GAP1, and HGF. Besides the coding mutations, we also highlight the potential contribution of DNA copy number variants in the pathogenesis of keratoconus. Finally, we present future directions for genetic research in the understanding of the complex genetics of keratoconus and its clinical significance. As new functional, candidate genes for keratoconus are being discovered at a rapid pace, the molecular genetic mechanisms underlying keratoconus pathogenesis will advance our understanding of keratoconus and promote the development of a novel therapy.