A heterozygous pathogenic RPE65 variant phenocopies a mitochondrial retinopathy

The gene retinoid isomerohydrolase retinal pigment epithelium 65 (RPE65; OMIM# 180069), is abundantly expressed in the RPE and encodes an isomerohydrolase enzyme that catalyzes an essential step in the visual cycle by converting all-trans retinyl ester to 11-cis retinol. Most pathogenic variants in RPE65 are loss-of-function and have been associated with autosomal recessive inherited retinal diseases (IRD) such as Leber congenital amaurosis (LCA; OMIM# 204100) or retinitis pigmentosa (RP) 20 (OMIM# 613794). Both of these biallelic RPE65-associated conditions can be treated with an ocular gene therapy known as Luxturna (Voretigene neparvovec-rzyl) but, owing to different pathomechanisms, autosomal dominant forms of RPE65-associated IRDs do not have an approved therapy. The best characterized autosomal dominant RPE65 variant is of Irish origin, p.(Asp477Gly), but a novel autosomal dominant variant of Belgian origin has recently been identified that causes a macular pattern dystrophy resembling that occurring in maternally inherited diabetes and deafness (MIDD), with chorioretinal atrophy as a hallmark. Here, we describe the case of a 67-year-old Belgian patient presenting with progressive vision loss and macular pattern dystrophy resembling MIDD, which was found to be caused by the same heterozygous variant in RPE65 identified by Van Vooren and colleagues. We emphasize the importance of considering RPE65 heterozygosity in cases resembling MIDD with negative mitochondrial genome sequencing. In addition, we highlight outer retinal tubulations (ORTs) as an optical coherence tomography feature in our patient, like some cases of MIDD, supporting an overlapping clinical phenotype.