Corneal Dystrophy, Fuchs Endothelial, 2

Description

Late-onset Fuchs endothelial corneal dystrophy (FECD) is a degenerative disorder affecting roughly 4% of the population older than 40 years. It is distinguished from other corneal disorders by the progressive formation of guttae, which are microscopic refractile excrescences of the Descemet membrane, a collagen-rich basal lamina secreted by the corneal endothelium. From onset, it usually takes 2 decades for FECD to impair endothelial cell function seriously, leading to stromal edema and impaired vision (Sundin et al., 2006).

For a discussion of genetic heterogeneity of Fuchs endothelial corneal dystrophy, see FECD1 (136800).

Nomenclature

This disorder, a late-onset form of Fuchs endothelial corneal dystrophy mapping to chromosome 13pter-q12.13, is referred to in OMIM as FECD2. Some references in the literature (e.g., Riazuddin et al., 2010) have used the designation 'FCD1 locus' to refer to the genetic locus for FECD on chromosome 13.

Clinical Features

Late-onset FECD is a common disease of the aging cornea. Corneal degeneration begins with a circumscribed area of central or paracentral cornea guttae and endothelial edema, and progresses with more horizontal than vertical expansion. Epithelial changes are secondary; endothelial dystrophy is primary. Most cases were thought to be sporadic, but some reports (Falls, 1968; Cross et al., 1971) suggest autosomal dominant inheritance with greater expression in females. Rosenblum et al. (1980) studied 23 patients and their first-degree relatives and found familial occurrence of corneal changes in 21, strongly corroborating autosomal dominant inheritance for most cases. High penetrance, variable expressivity, and age dependency with increased severity in females were noted. Rosenblum et al. (1980) reported families with male-to-male transmission of FECD. Rosenblum et al. (1980) found a sex ratio close to 1.0 in family studies. Other reports (e.g., Fuchs, 1910; Krachmer et al., 1978) have found an approximately 2.5:1 ratio of affected females to males.

Sundin et al. (2006) studied a 4-generation white pedigree in which 20 individuals had late-onset FECD in an autosomal dominant pattern of inheritance. At early to intermediate stages of the disorder, the clinical appearance of the posterior cornea was characterized by large, individual guttae with a distinctive peaked appearance. Those affected in generation 2, who ranged from 74 to 84 years of age, all showed advanced FECD at grades 3 or 4, whereas in generation 3, affected sibs of ages 45 to 64 were typically at grades 1 and 2, with only a few at grades 3 and 4. In 2 exceptional sibships, however, children aged 10 and 13 years had FECD. In each sibship, both parents were found to be affected, but genotype results were not consistent with consanguinity of the parents, who appeared to have independent cases of FECD.

Meadows et al. (2009) used retroillumination photography to quantify and document the progression of gutta formation in 13 affected members of the pedigree with late-onset FECD reported by Sundin et al. (2006). There was an increase of 29.1% in the total number of guttae over approximately 30 months, with a mean increase of 669 guttae per eye (p less than 0.001). A rapid rate of progression began at approximately age 50, representing an exponential increase among individuals mildly affected for decades. A significantly greater proportion of guttae were present in the inferotemporal quadrant of the cornea (p less than 0.001), an effect that grew in significance over time. Meadows et al. (2009) noted that 3 individuals with the disease haplotype who had 2 affected parents demonstrated an earlier disease onset.

Pathogenesis

Li et al. (2001) investigated the potential role of apoptosis in the pathogenesis of Fuchs endothelial dystrophy. They found DNA fragmentation in the epithelium, stroma, and endothelium in 6 of 7 corneas with Fuchs dystrophy that came to penetrating keratoplasty. They found increased levels of BAX (600040) and its mRNA in the stroma but not in the endothelium of Fuchs dystrophy corneas. Following exposure to camptothecin (a DNA synthesis inhibitor known to induce apoptosis in vitro), keratocytes from patients produced an increased level of BAX and a low level of BCL2 (151430), distinctly different from the response of normal keratocytes. The authors concluded that their results point to a disease-related disturbance in the regulation of apoptosis in Fuchs dystrophy. They proposed that excessive apoptosis might be an important mechanism in the pathogenesis of Fuchs dystrophy.

Gottsch et al. (2003) performed serial analysis of gene expression (SAGE) on normal and Fuchs endothelium. Fuchs endothelium showed diminished expression of mitochondrial genes, pump function, and antiapoptotic cell defense genes.

Mapping

Sundin et al. (2006) obtained the genotypes of small tandem repeat polymorphisms of 17 affected and 3 unaffected members of a large family segregating late-onset Fuchs corneal dystrophy. They performed a whole-genome linkage scan and found linkage of the disorder to chromosome 13pter-q12.13, with significant 2-point lod scores of 3.91 at D13S1236 and 3.80 at D13S1304. Sundin et al. (2006) screened 10 genes in this region and did not identify any causative mutations. The authors suggested that the exceptional early onset of the disease observed in 2 children might be the result of digenic mutations.