Natural History of an Unusual Chorioretinal Phenotype Associated With the RHO p.(Met216Lys) Variant

Purpose: While variants in RHO are a leading cause of autosomal dominant retinitis pigmentosa (RP), the c.647T>A p.(Met216Lys) variant gives rise to a phenotype that can mimic choroideremia. We describe its long-term natural history. Methods: Patients were included from four centers (in France, the United Kingdom, and the United States). Clinical features analyzed included pedigrees, best-corrected visual acuity (BCVA), visual fields, color vision, electroretinography, and multimodal imaging (color fundus photography, short-wavelength and near-infrared fundus autofluorescence [SW- and NIR-AF], and spectral domain optical coherence tomography [SD-OCT]). Results: Seventeen patients (11 women; median age at first examination, 45 years [range, 13-68 years]) from eight unrelated families were included. Follow-up was available for 13 individuals (median, 159 months [range, 24-286 months]). Impaired night vision was the predominant presenting symptom (71%), with BCVA relatively preserved at baseline. Visual fields showed pericentral round scotomas, enlarging and coalescing over time, with relative sparing of the far periphery. On SW-AF, younger patients showed a diffuse granular pattern, whereas older patients showed well-demarcated patches of autofluorescence loss. Serial imaging in seven patients confirmed that these patches enlarged and coalesced within individuals over time. Color fundus photography showed preserved optic disc color and normal retinal vessel caliber. SD-OCT demonstrated outer retinal tubulations, a thinned choroid, and progressive ellipsoid zone (EZ) loss (median rate of EZ width loss, 176 µm per year). Conclusions: The RHO c.647T>A p.(Met216Lys) variant is associated with a slowly progressive, unusual chorioretinal dystrophy phenotype that can closely mimic choroideremia. Our findings suggest pathogenetic mechanisms that differ from typical RHO-associated RP.