A number sign (#) is used with this entry because of evidence that retinitis pigmentosa-87 with choroidal involvement (RP87) is caused by heterozygous mutation in the RPE65 gene (180069) on chromosome 1p31.

Biallelic mutation in the RPE65 gene has been associated with a recessive form of retinitis pigmentosa (RP20; 613794) and with Leber congenital amaurosis (LCA2; 204100).

Retinitis pigmentosa-87 with choroidal involvement (RP87) is characterized by a slowly progressive visual disturbance, including night blindness and reduced central and peripheral vision, accompanied by extensive choroid/retinal atrophy that mimics certain aspects of choroideremia. Disease severity and age of onset are variable, and some carriers are unaffected (Hull et al., 2016; Li et al., 2019).

For a discussion of genetic heterogeneity of RP, see 268000.

Bowne et al. (2011) reported a large 4-generation Irish family (TCD-G) segregating autosomal dominant retinitis pigmentosa (adRP) with signs of choroidal involvement. Affected individuals presented in the second to the fifth decade of life with impaired dark adaptation, followed by progressive impairment of midperipheral visual fields. Some affected family members developed posterior subcapsular lens opacities in later life. Severity of disease varied widely among the patients, with mildly affected individuals showing a superficially normal retina with bone spicule as well as nummular pigmentary deposits in the midperiphery on funduscopy, whereas more severely affected individuals exhibited extensive diffuse chorioretinal atrophy with relatively sparse pigmentary deposits of the nummular type. Electroretinography (ERG) showed impairment of rod function even in mildly affected individuals, and rod-isolated responses were severely attenuated or nonrecordable in more severely affected individuals. A similar pattern was observed with mixed rod and cone responses to maximal intensity flashes in dark-adapted eyes.

Hull et al. (2016) studied 2 families of Irish ancestry with autosomal dominant retinal dystrophy. In the first family, the affected mother and son exhibited a choroideremia-like phenotype. The mother (patient 1.1) presented with decreased central vision in the seventh decade of life and showed later loss of peripheral vision, whereas the son (patient 1.2) experienced nyctalopia at age 18 years and developed impairment of central vision at age 33, which deteriorated to hand-movement-only vision by age 48, with patchy preservation of peripheral visual fields. Funduscopy showed extensive chorioretinal atrophy in both patients. Optical coherence tomography (OCT) in the son (1.2) showed extensive atrophy of the outer nuclear and photoreceptor layers, retinal pigment epithelium (RPE), and choroid, with outer retinal tubulations in areas of preserved retina and RPE. Fundus autofluorescence (FAF) imaging showed generalized loss of autofluorescence except for sparse scalloped areas of preserved retina and RPE. Fluorescein angiography revealed relatively well-preserved retinal vasculature, with readily visible choroidal vasculature and no leakage. ERGs in the son showed a rod-cone pattern of moderate severity with macular involvement, and there was no light rise on electrooculogram, indicating marked involvement of the RPE. In the second family, a mother and son presented at ages 45 and 35 years, respectively, with central vision impairment that slowly progressed to severe loss of vision. Both had widespread chorioretinal degeneration on funduscopy, with a well-demarcated preserved anterior retina and small clumps of increased pigment in the periphery. OCT in the son (patient 2.2) showed findings similar to those of patient 1.2; imaging through a pigment clump revealed a region of RPE hypertrophy rather than pigment migration. ERG testing of the mother (patient 2.1) showed extinguished rod responses with only residual cone function. Visual field testing in the son showed progressive increase in central scotomas from age 36 to 40 years, and extensive central field loss by age 59. His affected cousin (patient 2.3) developed central vision impairment at age 40 years, with symptoms of difficulty reading and recognizing faces. He had vitelliform-like yellow foveal deposits bilaterally, and OCT showed that the dome-shaped deposits involved the RPE and extended to the outer retina, displacing the outer plexiform layer.

Jauregui et al. (2018) provided 2-year follow-up of a 67-year-old man of Scottish ancestry who was diagnosed with choroideremia at age 53 after presenting with worsening night and peripheral vision. Funduscopy showed bilateral widespread chorioretinal atrophy with exposure of underlying larger choroidal vessels. An island of parafoveal sparing was observed in both eyes, and there was extensive intraretinal pigment migration in the periphery. Spectral-domain OCT showed widespread peripheral retinal atrophy with disruption of the outer nuclear layer and ellipsoid zone, as well as extensive RPE atrophy and choroidal sclerosis. FAF showed generalized hypoautofluorescent areas corresponding to RPE atrophy bound by sharply demarcated borders, with scalloped areas of preserved retinal tissue parafoveally. The authors stated that the clinical presentation and imaging were consistent with the diagnosis of choroideremia. Follow-up 2 years later, due to worsening night and peripheral vision, showed mild disease progression, although his visual acuity had improved after bilateral cataract extraction. A sister of the proband was diagnosed with choroideremia at age 52 but she was not available for evaluation.

In a large 4-generation Irish family (TCD-G) with adRP, Bowne et al. (2011) performed multipoint linkage analysis and obtained a maximum lod score of 3.6 at an approximately 20-Mb region on chromosome 1p31, flanked by rs2182241 and rs7522851. Recombination events narrowed the disease interval to an 8.8-Mb region between rs3861941 and D1S2895. The disease haplotype between the latter 2 markers was the same for all 20 affected individuals tested, and was also present in 4 unaffected family members, 1 of whom had an affected son.

The transmission pattern of retinitis pigmentosa in the family reported by Bowne et al. (2011) was consistent with autosomal dominant inheritance.

In a large 4-generation Irish family (TCD-G) with adRP mapping to chromosome 1p31, negative for mutations in known adRP genes, Bowne et al. (2011) sequenced 11 candidate genes and identified heterozygosity for a missense mutation in the RPE65 gene (D477G; 180069.0013) that segregated with disease. Concurrent whole-exome sequencing in 1 unaffected and 3 affected family members confirmed the D477G mutation in RPE65 as the only variant within the critical disease region that segregated with disease. The D477G mutation was not found in 684 Irish control chromosomes. However, screening for the D477G mutation in 12 Irish patients with a range of inherited retinal degenerations identified a male patient (family TCD-H) who was heterozygous for the mutation. This patient had been diagnosed with choroideremia but was negative for mutation in the CHM gene (300390). He had 2 affected daughters who also carried the D477G mutation, which was found to have occurred on the same haplotype as in family TCD-G. Linkage analysis of the D477G variant with disease in both families yielded a combined 2-point lod score of 5.3 at 0% recombination. The authors noted that the clinical phenotype in family TCD-H was consistent with the adRP phenotype observed in family TCD-G.

In 5 affected individuals from 2 families of Irish ancestry with autosomal dominant retinal dystrophy phenotypes, who were negative for mutation in 3 known retinal degeneration-associated genes, Hull et al. (2016) identified the RPE65 D477G mutation; the mutation was not found in the unaffected brother of 1 of the patients (patient 2.2). The authors noted that 4 of the 5 affected individuals exhibited severe disease resembling choroideremia, with much more extensive RPE and choroidal degeneration than retinal degeneration, although ERGs showed a rod-cone pattern of photoreceptor degeneration. In contrast, the fifth patient (patient 2.3) presented with adult-onset vitelliform macular dystrophy (see 153840), which the authors suggested might be unrelated to the D477G mutation; however, neither he nor his 80-year-old asymptomatic father, who also carried the D477G variant, were available for further study.

In a 69-year-old man of Scottish ancestry whose clinical presentation and ophthalmologic imaging were consistent with choroideremia, but who was negative for mutation in CHM or other genes, Jauregui et al. (2018) identified heterozygosity for the D477G mutation in the RPE65 gene. The authors amended the patient's diagnosis from choroideremia to adRP, and concluded that RPE65-associated adRP presents with a misleading choroideremia-like phenotype. The proband's affected sister and unaffected mother were not available for evaluation; his deceased father died at age 43 years with no ophthalmic symptoms. The authors noted that the patient stated that his ancestors may have migrated from Scotland to Ireland.