Cone-Rod Dystrophy, X-Linked, 3

A number sign (#) is used with this entry because of evidence that X-linked cone-rod dystrophy-3 (CORDX3) is caused by mutation in the CACNA1F gene (300110) on chromosome Xp11.

Cone-rod dystrophy is a retinal disorder with predominantly cone involvement. Rod impairment may occur at the same time as the cone impairment or appear later. Patients with CORD usually have reduced visual acuity, photophobia, and color vision defects (summary by Huang et al., 2013).

For a discussion of genetic heterogeneity of X-linked cone-rod dystrophy, see 304020.

Mantyjarvi et al. (2001) described a large 6-generation Finnish family in which 10 male members, ranging in age from 6 to 81 years, had progressive cone-rod dystrophy. Onset of symptoms was in early childhood for most patients, although some were not diagnosed until the fourth or fifth decade of life. Visual acuities ranged from 20/40 to counting fingers, and all were myopic. Concentrically constricted visual fields were observed in 5 patients, 1 of whom also had central scotomas; of the remaining 5, 3 showed general reduction of sensitivity in the central fields. Of 7 patients in whom color vision was assessed, 6 had red/green or red defects and 1 showed normal color vision. Of 5 patients in whom dark adaptation was examined, all had an elevated rod threshold and 3 also had an elevated cone threshold. Of 5 patients in whom ERG was performed, all exhibited defective cone responses, with 1 also showing reduction of the rod response. Funduscopic examination showed myopic changes and irregular pigmentation in the macular area. Two patients underwent surgery for unilateral retinal detachment. Follow-up over 12 to 14 years of 4 affected family members showed no changes in fundus appearance, visual fields, or dark adaptation; however, visual acuity had decreased in 1 patient, reduced sensitivity of the visual fields was noted in 2, and error scores in the Farnsworth-Munsell 100-hue (FM100) test had increased in 3, suggesting retinal progression of the disease. Examination of 6 obligate carriers showed normal fundi, visual fields, and color vision.

Hauke et al. (2013) examined 4 of 10 affected male members over 3 generations of a large German family with a progressive retinal disorder. Features typical of X-linked cone-rod dystrophy in these patients included slowly progressive loss of visual acuity, moderate to high myopia, color vision defects, elevated cone and rod thresholds in dark adaptation, reduced cone and rod responses on full-field ERGs, and irregular pigmentation in the macular area in the younger patients. In addition, 3 of the 4 exhibited nystagmus, and 2 had astigmatism of more than 1.5 diopters, both of which are features considered atypical in CORDX3. Examination of 2 asymptomatic female obligate carriers showed normal funduscopy, visual fields, and color vision, with responses in the low-normal range on ERGs.

Using a panel of 39 X-chromosome markers for linkage analysis in a large Finnish family with X-linked cone-rod dystrophy, originally described by Mantyjarvi et al. (2001), Jalkanen et al. (2003) excluded linkage to 2 previously mapped X-linked forms of the disorder and identified a third, which they symbolized COD3, located between markers DXS10042 and DXS8060 on Xp11.4-q13.1. Positive pairwise lod scores greater than 3 were obtained for 4 markers, one of which was monoamine oxidase B (MAOB; 309860) on Xp11.23. In a previously reported family (Bergen et al., 1993; Meire et al., 1994), it was not possible to determine whether the causative locus was CORDX1 (304020) or CORDX3 because of overlap of mapping intervals.

In a large 4-generation German family in which 10 male members had slowly progressive cone-rod dystrophy, Hauke et al. (2013) performed genomewide SNP analysis and identified linkage to 3 regions on the X chromosome, obtaining maximum lod scores of 2.4 for all 3. The linked intervals did not contain the CORDX1-associated RPRG gene (312610), nor did they overlap with the previously identified CORDX2 (300085) region; however, the linked interval at Xp11.3-p11.23 contained the CORDX3-associated gene CACNA1F.

In a large Finnish family with CORDX3, originally described by Mantyjarvi et al. (2001), Jalkanen et al. (2006) identified a splice site mutation in the CACNA1F gene (300110.0007). The mutation cosegregated completely with the disease phenotype in the family, which included 7 affected males, 10 carrier females, and 33 unaffected family members; it was not found in 200 control chromosomes. RNA studies revealed that the mutation caused altered splicing of the CACNA1F transcript, resulting in 5 variants with predicted premature termination and exonic deletions of the encoded protein. Noting that most mutations in CACNA1F had previously been identified in patients with congenital stationary night blindness-2 (CSNB2; 300071), Jalkanen et al. (2006) stated that CORDX3 is distinguishable from CSNB2 in that it is progressive, can begin in adulthood, has no nystagmus or hyperopic refraction, has only low grade astigmatism, and in dark adaptation lacks cone threshold and has small or no elevation of rod threshold.

By whole-exome sequencing in 47 Chinese probands with CORD, Huang et al. (2013) identified 1 male proband with a missense mutation in the CACNA1F gene (G848S; 300110.0009). Only limited clinical information was reported; the authors stated that all probands with identified mutations had an early-onset severe form of retinal dystrophy with predominantly cone involvement, and that fundus changes were primarily in the macular regions, with mild pigmentary changes and loss of foveal reflex.

In a large German family in which 10 male members exhibited progressive cone-rod dystrophy mapping to chromosome Xp11.3-p11.23, Hauke et al. (2013) performed next-generation sequencing and identified a large in-frame deletion encompassing exons 18 to 26 of the CACNA1F gene (300110.0010). The deletion segregated with disease in the family.