A number sign (#) is used with this entry because of evidence that progressive bifocal chorioretinal atrophy (PBCRA) is caused by heterozygous mutation in a DNase I (DNASE1; 125505) hypersensitivity site (DHS6S1; 616842) on chromosome 6q16, upstream of the PRDM13 gene (616741).

Heterozygous mutation in DHS6S1 can also cause the North Carolina type of macular dystrophy (MCDR1; 136550), an ocular disorder with features that overlap those of PBCRA.

Progressive bifocal chorioretinal atrophy (PBCRA) is a rare, autosomal dominant congenital chorioretinal dystrophy. The disorder is characterized by progressive macular and nasal retinal atrophic lesions, nystagmus, myopia, and poor vision. Invariably, there are 2 distinct foci of atrophy, a temporal focus that is present at birth and a nasal focus that appears early in life. Retinal detachment is an additional complication of the disease (Douglas et al., 1968; Kelsell et al., 1995).

Godley et al. (1996) examined 15 of 31 living affected individuals from a large 5-generation Scottish family segregating autosomal dominant progressive bifocal chorioretinal atrophy mapping to 6q14-q16.2, originally reported by Douglas et al. (1968). Patient ages ranged from 4 days to 63 years, and visual acuities ranged from 20/120 to counting fingers. Reductions in visual acuity did not correlate with the degree of chorioretinal atrophy, and subjective visual acuity remained stable over time. All patients exhibited coarse horizontal nystagmus oscillations, which dampened with fixation on a near accommodative target. Most patients had myopia, the degree of which did not correlate with age. There was marked variation in disease severity at any given age, suggesting that the rate of progression varied from person to person. Godley et al. (1996) therefore redefined the 3 stages of disease based on clinical characteristics rather than age: in the first, the earliest signs of disease included a large punched-out area of chorioretinal atrophy in the central macula, evident even at 4 days of age, within the vascular arcades. Optic nerve heads appeared vertically ovoid and heaped up. In addition, retinal abnormalities outside the macula were observed, with white deposits and areas of hyperpigmented retinal pigment epithelium (RPE). In stage 2, the central macular lesion extended beyond the vascular arcades, and foci of nasal geographic atrophy coalesced into a confluent white lesion of chorioretinal atrophy. White spots and pigmented clumps of RPE were evident in nonatrophic retina, suggestive of panretinal disease, and patients often experienced shimmering photopsias. The hallmark of stage 3 was marked expansion of both the macular and the nasal atrophic lesions toward the optic disc, resulting in a narrow vertical bridge of relatively intact retina passing vertically through the optic disc. Fluorescein angiography showed absence of choroidal perfusion in the atrophic areas. Electroretinography showed significantly diminished photopic (cone) and scotopic (rod) responses; cone flicker responses were grossly subnormal and delayed. Electrooculographic testing showed no light-induced rise in ocular potential, consistent with widespread abnormality of RPE and retinal function. Color contrast assessments showed marked reductions in protan, deutan, and tritan sensitivities. Retinal detachments occurred in 2 of the 15 patients studied. The authors noted that all affected individuals had severe macular abnormalities, in contrast to MCDR1, in which some individuals show mild macular disease. In addition, abnormal hyperpigmentation and mottling of the RPE nasal to the optic disc was seen in 3 affected infants, allowing differentiation of PBCRA from other causes of macular chorioretinal atrophy in young children.

Silva et al. (2019) reported a 3-generation French family (GC21086) with PBCRA in which 5 affected members presented the same progressive stages of disease as described by Godley et al. (1996) in a large 5-generation Scottish family (GC4059). At birth, the French patients experienced significant visual impairment, photophobia, and nystagmus. In stage 1, the primary lesion was located in the macular region, within the retinal vascular arcades of the posterior pole, with smaller atrophic lesions developing progressively around that central lesion. In stage 2, there was slow progression of chorioretinal atrophy, with structurally intact retina remaining in the peripapillary area and extreme periphery. Later in the second decade of life, a second smaller focus of chorioretinal atrophy appeared, and over time there was further progression of atrophic lesions in stage 3 of disease. Silva et al. (2019) also reported an affected mother and son (family GC20008); the mother showed typical features of the North Carolina type of retinal macular dystrophy (MCDR1; 136550), whereas the son had severe macular atrophy with associated nystagmus, features more typical of PBCRA. At age 3 years the boy developed a retinal detachment requiring surgical repair.

Kelsell et al. (1995) performed linkage analysis on a large 5-generation family based in Dundee, Scotland, with progressive bifocal chorioretinal atrophy. As 2 macular dystrophy genes had already been mapped to the region 6q11-q16.2, Stargardt disease-3 (600110) and the North Carolina type of macular dystrophy (136550), they chose to concentrate their linkage analysis first on that region. Two-point linkage analysis showed significant linkage with 9 microsatellite markers mapping to 6q. Multipoint analysis gave a maximum lod score of 11.8 (theta = 0.05) between D6S249 and D6S283, in the region 6q14-q16.2. This region overlaps with that to which the North Carolina macular dystrophy gene had been assigned. The range of differences in phenotype between the 2 retinal disorders led Kelsell et al. (1995) to conclude, however, that 'different mutation mechanisms are responsible for each disease.' Unlike PBCRA, the North Carolina macular dystrophy is nonprogressive and the vision tends to be good, unless complicated by the presence of choroidal neovascularization.

By whole-genome sequencing in 2 families with PBCRA, including the Scottish family (GC4059) originally reported by Douglas et al. (1968) and a French family (GC21068), Silva et al. (2019) identified heterozygosity for a point mutation within the noncoding DNase1 hypersensitivity region DHS6S1 (616842.0004), located 7.8 kb upstream of the transcription start site of the PDRM13 gene. The mutation, which segregated fully with disease in both families, appeared to have arisen independently in each family. In a mother and son (family GC20008) with PBCRA, who were negative for mutation in known MCDR1-associated variants, Silva et al. (2019) identified heterozygosity for a point mutation within DHS6S1 (616842.0005) that was 21 bp away from the variant present in the other 2 families with PBCRA. The mother, who was more mildly affected than her son, was shown to be mosaic for the mutation.

Exclusion Studies

In patients from 6q-linked multigenerational families diagnosed with PBCRA or MCDR1 (136550), as well as in a single patient from an autosomal dominant STGD family unlinked to STGD2 or STGD3 loci on 13q or 6q (see 600110), respectively, Gehrig et al. (1998) found no disease-associated mutations in the IMPG1 (602870) gene.