Independent Degeneration of Photoreceptors and Retinal Pigment Epithelium: Multimodal Imaging Evidence From Choroideremia Carriers

Purpose: To characterize retinal structural alterations and elucidate underlying pathogenesis in female carriers of choroideremia (CHM) using multimodal imaging. Methods: This single-center retrospective study analyzed 100 eyes of 50 genetically confirmed female CHM carriers. Clinical evaluation comprised genotype, age, visual acuity, color fundus photography, fundus autofluorescence (FAF), infrared reflectance, and optical coherence tomography (OCT). Retinal lesions were identified and classified using point-to-point co-localization analysis across modalities. Results: The mean age of carriers was 39.6 ± 17.8 years (range 3.2-80.3 years). All eyes exhibited varying degrees of retinal abnormalities. Most common findings included yellowish changes on color photographs, mottled areas of hyper- and hypo-autofluorescence on FAF, and isolated interdigitation zone (IZ) loss on OCT. Chorioretinal atrophy beyond the peripapillary region, indicating a severe phenotype, was observed in 18% of eyes. Five characteristic degenerative lesions were identified: Type A, isolated IZ loss; Type B, hyper-autofluorescent spots corresponding to presumed photoreceptor loss; Type C, drusen-like deposits; Type D, degeneration of the retinal pigment epithelium (RPE) and RPE-photoreceptor interface; and Type E, outer retinal degeneration. Type B lesions suggest that photoreceptor loss may precede RPE loss at specific loci. Type A lesions were the earliest abnormality, significantly associated with milder phenotypes, indicating the RPE-photoreceptor interface is the initial site of pathology. In contrast, Type D and E lesions were associated with severe phenotypes. Conclusions: Identified hyper-autofluorescence lesions corresponding to presumed photoreceptor loss indicate independent degeneration of photoreceptors and RPE. These findings suggest that future therapeutic approaches should concurrently target both cellular components.