Macular Dystrophy With Central Cone Involvement

A number sign (#) is used with this entry because of evidence that macular dystrophy with central cone involvement (CCMD) is caused by compound heterozygous mutation in the MFSD8 gene (611124) on chromosome 4q28.

Clinical Features

Roosing et al. (2015) studied a Dutch family in which 5 sibs, ranging in age from 54 to 71 years, had macular dystrophy with central cone involvement. Affected individuals presented in the third to sixth decade of life with decreased visual acuity and only slight pigmentary changes and color vision abnormalities. Funduscopy findings were variable and included bull's eye maculopathy, severe atrophy of central fovea, relatively spared fovea with surrounding atrophic ring, central retinal pigment epithelium (RPE) and/or choroid changes, pale or atrophic peripapillary area, pale optic disc, relatively spared periphery, and slightly or moderately attenuated vessels. One sib showed only subtle macular changes with no other abnormalities at 50 years of age. Color vision testing showed a red-green defect, and visual field tests demonstrated decreased central vision with normal periphery. Fluorescein angiography in 4 patients revealed central hypofluorescence in 2 of them, 1 of whom had a surrounding hyperfluorescent ring and the other a mottled pattern of perimacular hypofluorescence; another patient showed hyperfluorescence in a small central area, whereas the fourth patient had symmetrical central alterations in the outer retinal layers. Photopic and scotopic responses were normal on full-field electroretinograms (ERGs), but multifocal studies (mfERGs) revealed severely reduced central responses. Roosing et al. (2015) also studied an unrelated 62-year-old Dutch man who was diagnosed with cone dystrophy at 27 years of age and whose visual acuity decreased to counting fingers by 40 years of age. Over the years, gradual enlargement of a central scotoma was documented. ERGs on 8 different occasions showed normal rod function with only mildly abnormal cone function; at 60 years of age, however, the results suggested a tendency toward a rod-cone pattern, consistent with progression of retinal atrophy toward the midperiphery. Color vision was normal at age 29 years but developed into a deutan (green) deficiency at 42 years of age. None of the Dutch patients experienced seizures, and all had normal mental and psychomotor abilities.

Mapping

In 4 affected sibs from a Dutch family with macular dystrophy with central cone involvement, Roosing et al. (2015) performed genomewide linkage analysis and identified 3 different linkage peaks, on chromosomes 1, 2, and 4. Microsatellite marker analysis revealed that only the haplotypes on chromosome 4 segregated with disease, and a maximum lod score of 3.4 was obtained.

Molecular Genetics

In a Dutch family in which 5 sibs had CCMD mapping to chromosome 4, Roosing et al. (2015) performed exome sequencing and identified compound heterozygosity for a missense mutation (E336Q; 611124.0008) and a nonsense mutation (E381X; 611124.0009) in the MFSD8 gene. Exome sequencing in an unrelated Dutch man with CCMD revealed compound heterozygosity for the E336Q mutation and a c.1102G-C transversion (611124.0010). Analysis of the effect of the latter mutation, which occurs in the last nucleotide of exon 11, revealed that it causes skipping of exon 11 and is thus predicted to result in a truncated protein. Neither truncating mutation was found in an in-house exome database or the Exome Variant Server or 1000 Genomes Project databases; both had previously been reported in patients with late infantile-onset neuronal ceroid lipofuscinosis (CLN7; 610951), but none of the Dutch patients exhibited any extraocular features. The E336Q missense variant, however, was present in 1 (0.3%) of 302 alleles from ethnically matched controls, in 9 (0.21%) of 4,190 alleles in an in-house exome database, and in 25 (0.19%) of 12,006 European American alleles in the Exome Variant Server database; it was not found in 2,184 alleles in the 1000 Genomes Project database. Screening for E336Q in a cohort of patients with inherited maculopathy and cone disorders (22 with achromatopsia, 110 with cone dystrophy, and 112 with cone-rod dystrophy) revealed 4 patients carrying the variant in heterozygous state; sequence analysis of MFSD8 did not identify a second variant on the other allele. Regarding the lack of neurologic features in the Dutch patients carrying 2 MFSD8 mutations, Roosing et al. (2015) hypothesized that E336Q represents a hypomorphic variant and proposed a threshold model in which residual activity of MFSD8 suffices for proper function in all organs except the eye, resulting in nonsyndromic eye disease.