Fuchs endothelial corneal dystrophy (FECD) is a progressive, bilateral condition characterized by dysfunction of the corneal epithelium, leading to reduced vision. The prevalence of FECD has been estimated at about 5% among persons over the age of 40 ... Fuchs endothelial corneal dystrophy (FECD) is a progressive, bilateral condition characterized by dysfunction of the corneal epithelium, leading to reduced vision. The prevalence of FECD has been estimated at about 5% among persons over the age of 40 years in the United States. The vision loss in patients with FECD results from a loss of corneal transparency associated with irregularity of inner corneal layers in early disease and edema of the cornea in advanced disease. Ultrastructural features of FECD include loss and attenuation of endothelial cells, with thickening and excrescences of the underlying basement membrane. These excrescences, called guttae, are the clinical hallmark of FECD and become more numerous with progression of the disease. As the endothelial layer develops confluent guttae in the central cornea, the cells are no longer able to keep the cornea dehydrated and clear (summary by Baratz et al., 2010). - Genetic Heterogeneity of Fuchs Endothelial Corneal Dystrophy More common, late-onset forms of FECD have been shown to be caused by mutation in the SLC4A11 gene (610206) on chromosome 20p13-p12 (FECD4; 613268), the ZEB1 gene (189909) on chromosome 10p11.2 (FECD6; 613270), and the AGBL1 gene (615496) on chromosome 15q25 (FECD8; 615523). Other loci for late-onset FECD have been identified on chromosomes 13pter-q12.13 (FECD2; 610158), 18q21.2-q21.32 (FECD3; 613267), 5q33.1-q35.2 (FECD5; 613269), and 9p (FECD7; 613271).
Gottsch et al. (2005) restudied a family with early-onset Fuchs endothelial corneal dystrophy that had been reported by Magovern et al. (1979). They noted that the corneal guttae were small, rounded, and associated with the endothelial cell center, ... Gottsch et al. (2005) restudied a family with early-onset Fuchs endothelial corneal dystrophy that had been reported by Magovern et al. (1979). They noted that the corneal guttae were small, rounded, and associated with the endothelial cell center, whereas the guttae seen in common FECD are larger, sharply peaked, and initially positioned at edges of endothelial cells. Affected family members were found to have a mutation in the COL8A2 gene (120252.0003). Among affected family members were children as young as 3 years. All who were in the early stages of the disease in 1979 had progressed to corneal decompensation, and several had undergone penetrating keratoplasty. Gottsch et al. (2005) noted that this natural history fit well with the early-onset family with a mutation in the COL8A2 gene (120252.0001) reported by Biswas et al. (2001) in which FECD was diagnosed in individuals from ages 21 to 48, and those in their 30s and 40s had advanced stages of the disease. The profile of age and disease severity for the FECD kindred restudied by Gottsch et al. (2005) suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FECD patients in 62 other families in which mutations in COL8A2 were not found. The disorder progressed from early to late stages in 25 years, a rate similar to that estimated for the more common late-onset FECD. Gottsch et al. (2005) compared the sex distribution in their early-onset FECD kindred with that of 62 late-onset FECD pedigrees. There was an approximately 1:1 female:male ratio in the early-onset pedigree compared with a 2:1 ratio in the late-onset families. Hecker et al. (2011) studied whether keratocyte populations were different in 11 corneas excised during penetrating keratoplasty for FECD corneas, 5 control corneas of eyes enucleated for choroidal melanoma, and 20 age-matched control corneas. By histology, the mean (SD) number of cells in a full-thickness column of stroma in FECD (12,215 (1394) cells) was less than in control corneas (15,628 (710) cells; p less than 0.001). The mean (SD) number of keratocytes in the anterior 10% of the corneal stroma with FECD (682 (274) cells) was less than in the control corneas measured using histology (1858 (404) cells; p less than 0.001) and by confocal microscopy (1481 (397) cells; p less than 0.001). Hecker et al. (2011) concluded that keratocytes were depleted by 54 to 63% in the anterior 10% of the stroma of corneas that required penetrating keratoplasty for FECD. They suggested that keratocyte loss might contribute to anterior stromal changes that persist and degrade vision after endothelial keratoplasty.
Biswas et al. (2001) conducted a genomewide search of a 3-generation family with early-onset FECD and identified a critical region of 6 to 7 cM at chromosome 1p34.3-p32, which includes the COL8A2 (120252) gene. COL8A2 encodes a short-chain ... Biswas et al. (2001) conducted a genomewide search of a 3-generation family with early-onset FECD and identified a critical region of 6 to 7 cM at chromosome 1p34.3-p32, which includes the COL8A2 (120252) gene. COL8A2 encodes a short-chain collagen which is a component of endothelial basement membranes and which represented a strong candidate gene. Analysis of its coding sequence defined a gln455-to-lys missense mutation (Q455K; 120252.0001) within the triple helical domain of the protein in this family. Mutation analysis in other patients demonstrated further missense substitutions in familial and sporadic cases of FECD, as well as in a single family with posterior polymorphous corneal dystrophy (PPCD2; 609140). The authors suggested that the underlying pathogenesis of FECD and PPCD2 may be related to disturbance of the role of type VIII collagen in influencing the terminal differentiation of the neural crest-derived corneal endothelial cell. In affected members of the autosomal dominant kindred with early-onset Fuchs endothelial corneal dystrophy reported by Magovern et al. (1979), Gottsch et al. (2005) identified heterozygosity for a novel point mutation in the COL8A2 gene that resulted in a leu450-to-trp amino acid substitution (L450W; 120252.0003).