A number sign (#) is used with this entry because the Avellino type of corneal dystrophy (CDA) is caused by mutation in the gene encoding keratoepithelin (TGFBI; 601692). Several other forms of autosomal dominant corneal dystrophy are caused ... A number sign (#) is used with this entry because the Avellino type of corneal dystrophy (CDA) is caused by mutation in the gene encoding keratoepithelin (TGFBI; 601692). Several other forms of autosomal dominant corneal dystrophy are caused by mutation in this gene, which maps to chromosome 5q31.
Avellino corneal dystrophy was first described by Folberg et al. (1988). They reported 4 patients who had been diagnosed clinically as having granular dystrophy. However, pathologic examination of the corneal buttons removed from each patient after penetrating keratoplasty ... Avellino corneal dystrophy was first described by Folberg et al. (1988). They reported 4 patients who had been diagnosed clinically as having granular dystrophy. However, pathologic examination of the corneal buttons removed from each patient after penetrating keratoplasty revealed characteristics of both granular and lattice corneal dystrophies. Typical granular deposits were located in the anterior third of the stroma in each corneal button. In addition, amyloid deposits, histochemically and morphologically identical to those of lattice corneal dystrophy, were found deep to the granular deposits. Although the patients were unrelated and came from Pennsylvania, Massachusetts, and Argentina, all 4 families traced their origins to the Italian province of Avellino. Holland et al. (1992) reported a Minnesota family, which also traced its origins to the Avellino region of Italy, with 27 of 92 family members affected with CDA. Granular deposits were the earliest and most common manifestations. Lattice lesions were present in some patients with granular lesions. Older patients had anterior stromal haze between deposits, which impaired visual acuity. Recurrent granular deposits were noted in donor corneal tissue after penetrating keratoplasty for this condition. Pathologic examination of corneal tissue from affected patients confirmed the presence of hyaline material usually seen in granular dystrophy as well as fusiform deposits of amyloid, similar to those seen in lattice corneal dystrophy type I (122200). Rosenwasser et al. (1993) reported phenotypic variation among family members with CDA. Visual acuity of 40 patients from 6 unrelated families ranged from 20/20 to 20/400. The granular stromal lesions reached their mature quantity and size early in life and appeared gray and crumb-shaped or superficial with an annular and planar distribution. The lattice component appeared gradually, beginning and maturing later in life. Proportions of lattice and granular changes varied widely, even within single sibships. Recurrent corneal erosions were present but infrequent. Subjective complaints included glare and decreased night vision. Penetrating keratoplasty was required to restore vision in 1 patient. Kennedy et al. (1996) presented the case of a 54-year-old woman of indigenous Irish extraction and no history of Italian ancestry with combined lattice type I and granular dystrophy. Akiya et al. (1999) reported 2 Japanese patients who had clinical appearance and histopathologic examination consistent with both granular and lattice dystrophies. They concluded that granular-lattice corneal dystrophy was found in a wider geographic distribution than previously proposed and suggested that this disease not be named after a geographic area. Meallet et al. (2004) reported unusual clinical features in the first African American with Avellino corneal dystrophy. The patient had multiple crumb-like opacities in the anterior corneal stroma of both eyes. Deep to those lesions were numerous faint, stellate lattice lesions. Corneal scraping confirmed the presence of both Masson trichrome and Congo red-positive subepithelial deposits. In addition, there were surface changes resembling vortex dystrophy (verticillata) and large granular deposits protruding through the anterior corneal surface. The patient was heterozygous for a missense mutation in the TGFBI gene (601692.0004).
Munier et al. (1997) identified mutations in keratoepithelin that resulted in four 5q31-linked autosomal dominant corneal dystrophies: Groenouw type I (CDGG1; 121900), Thiel-Behnke type (CDTB; 602082), lattice dystrophy type I (CDL1; 122200), and CDA. They studied 6 families ... Munier et al. (1997) identified mutations in keratoepithelin that resulted in four 5q31-linked autosomal dominant corneal dystrophies: Groenouw type I (CDGG1; 121900), Thiel-Behnke type (CDTB; 602082), lattice dystrophy type I (CDL1; 122200), and CDA. They studied 6 families in which progressive opacification of the cornea led to severe visual handicap. Missense mutations were identified in all 6 families, and all of the mutations occurred at the CpG dinucleotide of 2 arginine codons: arg555 to trp (R555W; 601692.0001) in 1 CDGG1 family, arg555 to gln (R555Q; 601692.0002) in 1 CDTB family, arg124 to cys (R124C; 601692.0003) in 2 CDL1 families, and arg124 to his (R124H; 601692.0004) in 2 CDA families. Because the last 2 diseases are characterized by amyloid deposits, Munier et al. (1997) concluded that arg124-mutated keratoepithelin forms amyloidogenic intermediates that precipitate in the cornea. They stated that their data established a common molecular origin for 5q31-linked corneal dystrophies. Okada et al. (1998) reported a severe corneal dystrophy phenotype in 5 patients from 4 Japanese families. The disease course was notable for juvenile onset, and the affected corneas were remarkable for confluent round opacities in the superficial stromal layer. All 5 patients were homozygous for the R124H keratoepithelin mutation that also causes CDA. Histopathologic examination was done on corneal tissue from 2 patients and showed granular, rod-shaped deposits. No amyloid or lattice-like changes were described. The authors concluded that homozygous R124H keratoepithelin mutations were the cause of this severe variant of granular corneal dystrophy. Kim et al. (2002) studied the molecular properties of wildtype and mutant TGFBI proteins: specifically, the arg124-to-leu (R124L; 601692.0007), R124C, R124H, R555W, and R555Q mutations commonly found in 5q31-linked corneal dystrophies. They found that the mutations did not significantly affect the fibrillar structure, interactions with other extracellular matrix proteins, or adhesion activity in cultured corneal epithelial cells. In addition, the mutations apparently produced degradation products similar to those of wildtype TGFBI. TGFBI polymerizes to form a fibrillar structure and strongly interacts with type I collagen (see 120150), laminin (see 150320), and fibronectin (135600). Mutations did not significantly affect these properties. These results suggested that mutant forms of TGFBI might require other cornea-specific factors to form the abnormal accumulations seen in 5q31-linked corneal dystrophies.
Mashima et al. (2000) evaluated the incidence of TGFBI gene mutations in 164 unrelated Japanese patients with autosomal dominant corneal stromal dystrophies: 72% carried the R124H mutation associated with CDA; 14% had the R124C mutation associated with lattice ... Mashima et al. (2000) evaluated the incidence of TGFBI gene mutations in 164 unrelated Japanese patients with autosomal dominant corneal stromal dystrophies: 72% carried the R124H mutation associated with CDA; 14% had the R124C mutation associated with lattice corneal dystrophy type I; and 6% had the pro501-to-thr mutation associated with lattice corneal dystrophy type IIIA (P501T; 601692.0005). The authors concluded that classification of corneal dystrophies according to genetic pathogenesis might be more appropriate than using clinical or histologic findings. Avellino corneal dystrophy shows allelic homogeneity, with the R124H mutation (601692.0004) in the TGFBI gene responsible for most cases. Types I and II have been described in homozygous Japanese patients: type I is a spot-like opacity present in the anterior stroma in which the lesions are confluent, whereas type II is a reticular opacity in the anterior stroma, with round translucent spaces. Heterozygote sibs do not show changes (Tsujikawa et al., 2007). Tsujikawa et al. (2007) found no differences in the sequence of the TGFBI gene between the 2 types of ACD in 14 patients. All homozygous patients carried the R124H mutation. The authors found 7 single-nucleotide polymorphisms (SNPs) compared with the normal control. All 14 homozygous patients were homozygotes for each SNP, which meant that all patients shared the same haplotype. Analysis of 45 heterozygous ACD patients showed strong linkage disequilibrium between disease alleles of each SNP and ACD. Tsujikawa et al. (2007) interpreted these results as suggesting that the allelic homogeneity of TGFBI in Avellino corneal dystrophy is caused by founder effect, not a mutation hotspot. As was pointed out by Munier et al. (1997), remarkable allelic homogeneity of the other TGFBI-associated corneal dystrophies has been found and may similarly have its basis in founder effect: corneal dystrophy, lattice type I (122200) is caused by the TGFBI mutation R124C (601692.0003); corneal dystrophy, Groenouw type I (121900) is caused predominantly by the R555W mutation of TGFBI (601692.0001); corneal dystrophy, Thiel-Behnke type (602082) is caused predominantly by the R555Q mutation of TGFBI (601692.0002); and as stated, most Avellino corneal dystrophy is caused by the R124H mutation (601692.0004). Whereas in European countries, Avellino corneal dystrophy constitutes only 12% of hereditary corneal dystrophies associated with TGFBI mutations, some of the families traced their ancestry to the Italian province of Avellino (Munier et al., 2002). Further, in Japanese individuals, Avellino corneal dystrophy is the most common form of hereditary corneal dystrophy, responsible for 72% of corneal dystrophies associated with TGFBI (Mashima et al., 2000).