Ocular Histopathology and Immunohistochemical Analysis in the Oldest Known Individual with Autosomal Dominant Vitreoretinochoroidopathy

Purpose: To assess the immunohistochemical and histopathologic changes in a subject with autosomal dominant vitreoretinochoroidopathy (ADVIRC). Design: Research manuscript. Participant: A 92-year-old white man with ADVIRC. Methods: The subject was documented clinically for 54 years. The retina/choroid complex of the right eye was evaluated with cryosections stained with hematoxylin–eosin or periodic acid–Schiff (PAS) reagent. Cryosections also were evaluated with immunofluorescence or alkaline phosphatase (APase) immunohistochemistry (IHC) using primary antibodies against bestrophin 1 (BEST1), glial fibrillary acidic protein (GFAP), pigment epithelium–derived factor (PEDF), RPE65, transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF), and vimentin. The left retina and choroid were evaluated as flatmounts using immunofluorescence. Ulex europaeus agglutinin (UEA) lectin was used to stain viable vasculature. Main Outcome Measures: The immunohistochemical and histopathologic changes in retina and choroid from a subject with ADVIRC. Results: The subject had a heterozygous c.248G>A variant in exon 4 of the BEST1 gene. There was widespread chorioretinal degeneration and atrophy except for an island of spared retinal pigment epithelium (RPE) monolayer in the perimacula/macula in both eyes. In this region, some photoreceptors were present, choriocapillaris (CC) was spared, and RPE cells were in their normal disposition. There was a Müller cell periretinal membrane throughout much of the fundus. Bestrophin-1 was not detected or only minimally present by IHC in the ADVIRC RPE, even in the spared RPE area. Beyond the island of retained RPE monolayer on Bruch's membrane (BrMb), there was migration of RPE into the neuroretina, often ensheathing blood vessels and producing excessive matrix within their perivascular aggregations. Conclusions: The primary defect in ADVIRC is in the RPE, the only cells in the eye that express the BEST1 gene. The dysfunctional RPE cells may go through epithelial/mesenchymal transition as they migrate from BrMb to form papillary aggregations in the neuroretina, often ensheathing blood vessels. This may be the reason for retinal blood vessel nonperfusion. Migration of RPE from BrMb also was associated with attenuation of the CC.