Mild RPE65-Associated Inherited Retinal Dystrophies: A Multimodal Clinical and Genetic Evaluation

RPE65 is a key enzyme in the visual cycle, converting all-trans retinyl esters into 11-cis retinol, a crucial step in regenerating the photopigment necessary for vision. Mutations cause a spectrum of inherited retinal diseases (IRDs), from severe generalized early-onset dystrophies, such as Leber congenital amaurosis, to classical retinitis pigmentosa or mild phenotypes, including congenital stationary night blindness, such as fundus albipunctatus.

We analyzed two independent patients with mild RPE65-associated IRDs using multimodal diagnostics, including best-corrected visual acuity; Goldman visual field; dark-adapted testing, including scotopic perimetry; full-field electroretinography; and multimodal retinal imaging. Phenotypes were evaluated based on existing literature and predicted variant impact.

Both patients exhibited overall mild IRDs with only slightly impaired rod function and largely preserved cone function. Identified RPE65 missense variants likely allow partial enzyme function, consistent with comparatively mild and slowly progressive disease. Superior rod scotomas and mid-peripheral morphologic changes were identified despite normal or near-normal full-field function.

Functional rod changes in the inferior mid-periphery of the retina, which may be followed by metabolic stress and structural retinal changes, seem to be the hallmark of mild RPE65-associated IRDs and may represent early site-specific pathology. These changes may be linked to an increased susceptibility to UV-induced retinal damage associated with RPE65 mutations. Local rod function assessment is critical for proper disease monitoring and guiding therapeutic decisions.

Localized multimodal diagnostics help detect early changes in mild RPE65-associated IRDs, supporting precise monitoring and gene therapy counseling.