Natural History Study of Inherited Retinal Diseases

Overview

This prospective, observational investigation seeks to delineate the interplay between chromatic vision deficits and both functional visual outcomes and anatomical retinal biomarkers in individuals affected by Inherited Retinal Dystrophies (IRDs). The study will recruit approximately 200 subjects, encompassing a heterogeneous population of IRD patients-spanning a range of genotypes and clinical severities-as well as control participants devoid of retinal pathology. All enrolled individuals will undergo a standardized battery of evaluations, including quantitative color vision assessment, best-corrected visual acuity (BCVA) determination, and advanced multimodal retinal imaging. The principal aim is to characterize the relationship between impairments in color discrimination and morphologic disruptions within the outer retinal layers, with particular emphasis on the continuity and reflectivity of the ellipsoid zone (EZ)-historically referred to as the inner segment/outer segment (IS/OS) junction-assessed through spectral-domain optical coherence tomography (SD-OCT). Further, the study will explore associations between chromatic perceptual deficits and underlying genetic mutations, mutation patterns specific to IRD subtypes, and the influence of patient age on the severity and progression of color vision loss. A key secondary objective is the clinical appraisal and validation of a novel diagnostic modality, the Moji Low-Vision Color Discrimination Test (Moji Test), which is specifically engineered to quantify residual color perception in individuals with advanced central visual impairment. The test's discriminatory capacity will be benchmarked against established color vision testing paradigms to assess its reliability, clinical sensitivity, and suitability for implementation in populations with severe visual acuity reduction. By incorporating a genetically and phenotypically diverse IRD cohort, the study is designed to enable granular, stratified analyses that will refine the understanding of structural-functional correlations in hereditary retinal disease. The inclusion of a control group with preserved retinal architecture and normal color vision function will provide essential normative baselines for comparative evaluation and statistical inference.

Inherited retinal dystrophies (IRDs) encompass a broad and genetically diverse class of monogenic disorders marked by progressive degeneration of retinal photoreceptors-namely, rods and cones-which ultimately culminates in irreversible visual dysfunction. As the degenerative process advances, patients frequently develop a combination of central and peripheral visual loss alongside progressive impairments in color discrimination. Among retinal structural biomarkers, the ellipsoid zone (EZ)-a hyperreflective band corresponding to the mitochondria-dense segment of the photoreceptor inner segments, historically denoted as the IS/OS junction in spectral-domain optical coherence tomography (SD-OCT)-has emerged as a key indicator of residual photoreceptor viability and visual function. Prior studies, particularly those focusing on retinitis pigmentosa (RP), have demonstrated a compelling association between EZ integrity and chromatic discrimination ability, reinforcing the critical relationship between anatomical preservation and functional outcomes in retinal dystrophies. This prospective investigation is designed to quantitatively characterize color vision performance in individuals with IRDs and to evaluate its association with retinal microstructural features as revealed by multimodal imaging modalities, including SD-OCT-derived EZ measurements, total retinal thickness, and best-corrected visual acuity (BCVA). By integrating these anatomical measures with genotypic data, the study will further examine the influence of specific mutation types, allelic patterns, and patient age on chromatic function, thereby offering a comprehensive analysis of genotype-phenotype relationships in IRD-associated dyschromatopsia. A persistent challenge in the evaluation of color vision among IRD patients-particularly those with advanced vision loss-is the limited applicability of conventional color vision assessments. Standard psychophysical tests, such as the Ishihara pseudoisochromatic plates and the Farnsworth-Munsell 100 Hue Test, are fundamentally dependent on preserved spatial resolution and pattern recognition, thereby rendering them ineffective in individuals with substantial visual acuity deficits. Although the Low Vision Cambridge Color Test (lvCCT) offers a more accessible alternative for patients with moderate acuity impairment, those with BCVA at or below the level of Counting Fingers (logMAR ≥ 1.6) are frequently unable to complete the test, resulting in inconclusive or misleading data regarding true chromatic capability. In such cases, performance failure often reflects the constraints of visual resolution rather than an authentic deficit in color discrimination, complicating both diagnosis and longitudinal monitoring. To address these limitations, the present study incorporates the Moji Low-Vision Color Discrimination Test (Moji LVCDT)-a novel chromatic assessment tool specifically developed for individuals with profound visual impairment. This test employs high-contrast, large-format color stimuli, enabling the assessment of chromatic discrimination thresholds independent of fine spatial vision. Preliminary validation data indicate that the Moji LVCDT can successfully detect residual color perception in patients who are unable to engage with standard color vision testing paradigms, thereby providing clinically meaningful results even in the most advanced stages of IRD. As part of the study protocol, the Moji LVCDT will be administered in parallel with established color vision tests, including the Ishihara plates and the low-vision-adapted Cambridge Color Test, to evaluate its diagnostic sensitivity, specificity, and correlation with both functional vision and structural retinal metrics. Through comparative analysis, the study aims to validate the Moji LVCDT as a reliable and scalable tool for quantifying color vision in populations historically excluded from color function assessments due to visual acuity constraints. By integrating structural, functional, and genetic data, this investigation seeks to advance current understanding of the pathophysiological basis of color vision loss in inherited retinal diseases. Moreover, the validation of the Moji LVCDT may lay the foundation for the establishment of a standardized, clinically applicable method for tracking chromatic function in low-vision populations. The outcomes of this study have the potential to enhance diagnostic precision, inform clinical management strategies, and provide a sensitive outcome measure for use in future interventional trials targeting retinal preservation and visual function restoration in IRD patients.