Clinical Surrogate Endpoints in Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy: Findings From a Two-Year Natural History Study

Purpose: Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy is a rare, inherited retinal dystrophy characterized by drusen formation and early vision loss. Its phenotypical similarities with dry age-related macular degeneration (AMD) make Malattia Leventinese a valuable monogenetic disease model for AMD. Identifying sensitive outcome measures is crucial for clinical trials. This study quantifies retinal pigment epithelium and drusen complex (RPEDC) increase and retinal layer degeneration using fully automated segmentation for multimodal imaging analysis, and investigates structural thresholds associated with functional decline through pointwise correlation. Methods: This multicenter cohort study included 25 patients (15 women and 10 men; median age = 60 years, interquartile range [IQR] = 51-73 years) with genetically confirmed Malattia Leventinese. Participants underwent multimodal imaging, including spectral-domain optical coherence tomography (SD-OCT), ultrawide fundus retinography and fundus autofluorescence (FAF), and mesopic and two-color scotopic microperimetry. Changes in retinal layer thicknesses and retinal sensitivity were assessed over 2 years using linear mixed-effects models, and structure-function breakpoints were estimated with piecewise models. Results: RPEDC thickness increased (+2.24 µm/y), whereas photoreceptor inner segments (-0.70 µm/y) and outer nuclear layer (-1.95 µm/y) thicknesses, in addition to choroidal thickness (-10.83 µm/y), decreased with disease progression. Total retinal thickness remained stable. Scotopic sensitivity declined over time, with -0.40 decibel (dB)/year at 505 nm and -0.37 dB/year at 627 nm, whereas mesopic sensitivity remained stable. Function decreased most in early disease stages, with the onset of drusen accumulation. Conclusions: In Malattia Leventinese, the total retinal thickness remains unchanged because the RPEDC increase offsets the thinning of outer retinal layers. Only scotopic function decreases significantly with progression and before the age of 55 years. Mesopic function may serve to track later stages. These findings support the outer nuclear layer and photoreceptor inner segment thicknesses as key structural endpoints and scotopic sensitivity as an early functional outcome measure for monitoring disease progression in ongoing and future clinical trials.