Bornholm Eye Disease

Description

Bornholm eye disease consists of X-linked high myopia, amblyopia, and deuteranopia. Associated signs include optic nerve hypoplasia, reduced electroretinographic (ERG) flicker, and nonspecific retinal pigment abnormalities (Schwartz et al., 1990).

Clinical Features

Haim et al. (1988) described a large Danish family with X-linked myopia combined with astigmatism, impaired vision, and moderate hypoplasia of the optic nerve heads. Deuteranopia (303800) was present in all affected males. Myopia was diagnosed at 1.5 to 5 years of age. The syndrome was traced in 5 generations of the family, which had its origin on the island of Bornholm.

Young et al. (2004) reported a Minnesota family of Danish descent with a similar X-linked phenotype. All affected males had an early onset and seemingly nondegenerative high-grade myopia, myopic fundus changes, and reduced cone function on ERG testing. The only difference between the Minnesota family and the original BED family was the color vision defect. Whereas affected members of the BED family had deuteranopia, those affected in the Minnesota family had protanopia (303900), raising the question of whether color vision deficiency is part of the syndrome. They noted that the visual cone pigment (opsin) genes (300821, 300822) are located on Xq28. Because red-green and green-red hybrid genes resulting in X-linked color vision defects are common, Young et al. (2004) suggested that the color vision defects in these patients are unrelated to the underlying disease. They proposed that both phenotypes are novel forms of X-linked myopia and nonprogressive cone dysfunction.

Michaelides et al. (2005) described 4 British nonconsanguineous families with an X-linked cone dysfunction syndrome associated with myopia similar to the disorder in the Minnesota family described by Young et al. (2004). Affected members had moderate to high myopia, astigmatism, moderately reduced acuity, normal fundi, and protanopia. ERG showed abnormal cone but normal rod responses. Psychophysical testing showed a selective impairment of long (L) cones (300822) in combination with well-preserved middle (M) cone (300821) and short (S) cone (613522) function.

Inheritance

In the large Danish family studied by Haim et al. (1988), only males were affected and transmission of the trait was through normal females, thus indicating X-linked inheritance.

Mapping

In the large Danish family reported by Haim et al. (1988), Schwartz et al. (1990) found linkage of the disorder to the factor VIII gene (F8; 300841) at Xq28, with a maximum lod of 4.8 at theta = 0.0. They designated the disorder Bornholm eye disease.

Young et al. (2004) performed linkage analysis in the Minnesota family as well as in the original BED family and found the disorder in both to map to a 6.8-cM interval at Xq28. The haplotype at Xq28 was different in each family, however, suggesting that independent mutational events led to the phenotype. In addition, the red and green pigment gene arrays of the affected individuals in the 2 families were different, one containing a red-green hybrid gene (Minnesota family) consistent with the protanopia, and the other containing a green-red hybrid gene (BED family) consistent with deuteranopia.

Molecular Genetics

Michaelides et al. (2005) performed molecular analysis of the opsin gene array in 4 British families with an X-linked cone dysfunction syndrome with myopia and protanopia. Two families had a long/middle hybrid gene and 1 family had the commonly described deleterious C203R mutation (300822.0003) in both the long and middle opsin genes. In the fourth family the only abnormality was absence of a middle opsin exon 2, making the cause of the protanopia uncertain. In 3 families no alterations in the opsin gene array were identified that could account for the cone dysfunction. The authors considered the C203R mutation in 1 family to be a possibility; however, the presence of normal M and L opsin genes in an expanded opsin gene array in this family made this uncertain.

In a Danish family from Bornholm, a Minnesota family of Danish descent, and 3 families from the UK, all segregating X-linked high myopia with cone dysfunction and originally reported by Haim et al. (1988), Young et al. (2004), and Michaelides et al. (2005), respectively, Metlapally et al. (2009) used array CGH to compare affected individuals with controls. Affected male individuals had 4 copies of CXORF2 in the Bornholm pedigree, and 5 copies in the Minnesota pedigree, in contrast to the 3 copies seen in unaffected males. Two of the UK families showed either fewer (1) or greater (4) numbers of copies in affected samples compared with unaffected samples. Metlapally et al. (2009) suggested that CXORF2 gene CNVs appear to be associated with the X-linked myopia with cone dysfunction phenotype.

Nomenclature

Both Bornholm eye disease and a form of isolated X-linked myopia (MYP1; 310460) map to the same region of Xq28 (Ratnamala et al., 2011).