Macular Dystrophy, Vitelliform, 3

A number sign (#) is used with this entry because of evidence that vitelliform macular dystrophy-3 (VMD3) is caused by heterozygous mutation in the RDS gene (PRPH2; 179605) on chromosome 6p21.

Mutations in the RDS gene also cause a form of retinitis pigmentosa (608133), patterned dystrophy of the retinal pigment epithelium (169150), and other macular dystrophies.

Description

Adult-onset foveomacular vitelliform dystrophy, also known as adult vitelliform macular dystrophy, adult-type foveomacular dystrophy, adult vitelliform macular degeneration, pseudovitelliform macular degeneration, and adult-onset foveomacular pigment epithelial dystrophy, is characterized by a solitary, oval, slightly elevated yellowish subretinal lesion of the fovea that is similar in appearance to the vitelliform or egg-yolk stage of Best disease (153700). Initially the yellow lesion may be present in only one eye. The size is generally one-third to one disc diameter, and small yellow flecks are seen in the paracentral lesion. Patients usually become symptomatic in the fourth or fifth decade of life with a protracted decrease of visual acuity and mild metamorphopsia. Electrooculographic testing reveals a normal or only slightly reduced Arden ratio, which is intensely abnormal in Best disease. The prognosis is optimistic, as most patients retain reading vision throughout life (Felbor et al., 1997; Yamaguchi et al., 2001).

For a discussion of genetic heterogeneity of vitelliform macular dystrophy, see VMD1 (153840).

Clinical Features

Gass (1974) described a 3-generation family and 6 sporadic patients with what he termed 'peculiar foveomacular dystrophy.' The foveomacular dystrophy in these patients was characterized by bilateral, subfoveal, vitelliform lesions (one-third disc diameter) with onset between the ages of 30 and 50 years accompanied by slowly progressive visual loss. Additional features included occasional paracentral drusen, normal to slightly subnormal response on electrooculogram (EOG), normal electroretinogram, and normal color vision.

Patrinely et al. (1985) reported a woman with AVMD characterized by oval subpigment epithelial deposits centered in the fovea of each eye. She initially complained of blurred central vision while reading. Postmortem examination showed marked focal atrophy of the outer nuclear layer of the macula, with photoreceptor degeneration. The retinal pigment epithelium (RPE) in the foveolar area showed focal flattening and atrophy, bordered by hypertrophic RPE cells. Cells in the macular RPE showed massive accumulation of lipofuscin pigment.

Cohen et al. (1993) reported monozygotic twin sisters with adult vitelliform macular dystrophy. At 75 years of age, 1 sister had bilateral vitelliform lesions (one-disc diameter) and a subnormal EOG. The other sister had several smaller vitelliform lesions (one-third disc diameter) and a normal EOG.

Benhamou et al. (2003) studied adult-onset foveomacular vitelliform dystrophy via optical coherence tomography (OCT). The noninvasive test demonstrated yellowish deposits between the neurosensory retina and RPE, corresponding to the late staining seen on fluorescein angiography. The foveal thinning in all cases documented by OCT probably explains the progressive visual loss and possible evolution toward a full-thickness macular hole.

Yang et al. (2004) examined 40 members of 2 unrelated families segregating autosomal dominant adult-onset foveomacular dystrophy. Fourteen individuals exhibited RPE changes and 6 had decreased vision in at least 1 eye, ranging from 20/25 to 20/400, with most in the 20/30 to 20/40 range. Other visual complaints included reduced color vision, metamorphopsia, photophobia, and impaired night vision due to distortion or difficulty with lights. Major fundus findings in the affected individuals included central subretinal hypopigmented lesions and geographic atrophy. Fluorescein angiography demonstrated lesions with central hypofluorescence surrounded by areas of hyperfluorescence, consistent with the diagnosis of AOFMD. In 1 patient, a unilateral choroidal neovascular membrane was observed. No changes were found on electrooculography or visual field testing.

Clinical Variability

Vine and Schatz (1980) observed choroidal neovascularization in 2 of 33 patients (3 of 58 eyes) with adult-onset foveomacular pigment epithelium dystrophy. The rare feature was not described, however, in any of the 18 patients covered in their literature review.

Gorin et al. (1995) examined 51 members of a large 4-generation family, 12 of whom were affected with both peripheral retinal and macular degeneration that had been diagnosed in patients seen individually as age-related macular degeneration, retinitis pigmentosa, fundus flavimaculatus (Stargardt disease), adult vitelliform degeneration, dominant drusen, or pattern dystrophy. The affected individuals ranged in age from 16 to 75 years and exhibited broad variability of retinal findings, which included diffuse fine hard drusen in the macula, a butterfly pattern, extensive retinal atrophy, diffuse pigment epithelial disturbances, and severe atrophic macular degeneration. No choroidal neovascularization was observed. Visual acuity ranged from 20/20 to 20/200, with central vision loss correlating with the degree of central retinal atrophy. Perimetric findings also varied widely, with severe peripheral field loss documented in several members of the pedigree, whereas others showed general threshold elevation and/or central/paracentral scotomas. Of 11 patients who underwent electroretinography, only 1 had normal responses; the remaining 10 had rod and cone system abnormalities, with some showing greater dysfunction of cones than rods. Gorin et al. (1995) also studied an affected mother and son from an unrelated family. The mother developed metamorphopsia at 43 years of age, at which time her visual acuity was 20/50 and 20/60 in right and left eyes and she was given a diagnosis of Stargardt disease; examination at age 50 showed a decline to 20/200 and 20/100. Her retinas showed yellowish subfoveal lesions with multiple radial projections and yellowish flecks in the retinal periphery. Her asymptomatic 11-year-old son had visual acuities of 20/30 and 20/25 in the right and left eyes, with small yellowish subfoveal lesions bilaterally. Reexamination at 16 years of age showed increased prominence of the subfoveal lesions and some early peripheral flecks, with no change in visual acuity.

Yamaguchi et al. (2001) reported a 58-year-old Japanese woman with adult-onset foveomacular vitelliform dystrophy who also exhibited stellate retinal folds surrounding the macular lesion. The folds were believed to represent steep elevation of the retinal pigment epithelium due to extracellular accumulation of vitelliform deposits.

Mapping

In 2 unrelated families segregating autosomal dominant adult-onset foveomacular dystrophy, Yang et al. (2004) performed genotype analysis using the short tandem-repeat polymorphism DNA markers D6S400, D6S1582, and D6S2410 and found linkage to the RDS/peripherin locus.

Inheritance

In 10 of 12 families of probands who presented with foveal lesions typical of adult vitelliform macular dystrophy, Brecher and Bird (1990) found a transmission pattern compatible with autosomal dominant inheritance. In the remaining 2 families, no familial involvement was detected, but autosomal dominant inheritance could not be ruled out since only 1 parent of each proband was available for examination. Brecher and Bird (1990) concluded that adult vitelliform macular dystrophy is an autosomal dominant disorder and stated that the term was best reserved for foveal lesions similar to that described by Gass (1974) with a dominant pattern of inheritance.

Molecular Genetics

In a woman with adult-onset vitelliform macular dystrophy, Wells et al. (1993) identified a nonsense mutation in the RDS gene (Y258X; 179605.0008). Her deceased father was also affected, as confirmed by fundus photographs.

To assess the frequency of peripherin/RDS mutations in the clinically heterogeneous group of adult-onset vitelliform macular dystrophies (AVMD), Felbor et al. (1997) analyzed the entire coding region of the gene in 28 unrelated German AVMD patients. They identified 5 novel mutations, including 2 presumed null mutations (see, e.g., 179605.0014 and 179605.0015). Thus, 5 (18%) of 28 AVMD patients carried point mutations in the RDS gene, suggesting that it is frequently involved in the pathogenesis of this macular disorder. Three of the mutation-positive patients exhibited multifocal disease, 1 showed a pattern-like maculopathy, and 1 had a 'Best-like' appearance of the fundus. Felbor et al. (1997) concluded that the variable phenotypes in AVMD are due, at least in part, to genetic heterogeneity and are likely to be caused by mutations in other, as yet unidentified genes.

In a man with adult-onset foveomacular dystrophy with choroidal neovascularization, Feist et al. (1994) identified heterozygosity for a missense mutation in the RDS gene (P210R; 179605.0012).

In a large 4-generation family, 12 members of which exhibited wide variability of retinal phenotypes, Gorin et al. (1995) identified heterozygosity for the P210R mutation in the RDS gene in all affected individuals. Heterozygosity for the P210R mutation was also detected in 3 affected members of a family with foveomacular dystrophy that was originally reported by Gass (1974), as well as in a mother and son with decreased visual acuity and bilateral yellowish subfoveal lesions. The mutation was not found in 100 controls.

In 2 unrelated families with autosomal dominant adult-onset foveomacular dystrophy (AOFMD) mapping to the RDS/peripherin locus, Yang et al. (2004) sequenced the RDS gene and identified a heterozygous missense mutation (Y141C; 179605.0024) that segregated with disease in both families and was not found in 200 control chromosomes. Yang et al. (2004) also identified the Y141C mutation in affected members of a family with patterned macular dystrophy (MDPT1; 169150). Haplotype analysis was consistent with an ancestral founder mutation in all 3 families. The authors stated that it was unclear why the Y141C mutation caused MDPT1 in 1 family and AOFMD in the other 2, and suggested that genetic modifiers or environmental influences may play a role in these phenotypic differences.