Cone contrast sensitivity testing in X-linked retinal diseases: Insights into genotype, sex and disease severity

To evaluate cone contrast sensitivity (CS) in X-linked inherited retinal diseases (IRDs), specifically RPGR-associated retinitis pigmentosa (RPGR) and choroideremia (CHM) using the Konan ColorDx Cone Contrast Threshold (CCT) test, and to explore associations with clinical measures of visual function.

Eighty-five participants were assessed, including affected males, female carriers and healthy controls. Clinical assessments included best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), fundus-tracked perimetry and fundus autofluorescence (FAF) imaging. Linear mixed models were used to evaluate cone CS differences by diagnosis and sex, adjusting for age and BCVA.

Affected males with RPGR (n = 10) and CHM (n = 5) had significantly reduced L-, M- and S-cone sensitivity compared to controls and carriers. Female CHM carriers (n = 10), who predominantly had mild disease, showed no significant differences in cone CS relative to controls. In contrast, female RPGR carriers (n = 16) had significantly reduced sensitivity for all cone types. Compared to CHM, both males and female carriers of RPGR-associated disease had lower M-cone CS, after adjusting for age and BCVA. Subgroup analysis revealed further reductions in cone CS in carriers with more advanced CHM (S-cone CS: 0.37 vs. 0.75) and RPGR (S-cone CS: -0.3 vs. 0.48; M-cone CS: 0.87 vs. 1.55), compared to those with milder disease. Reduced BCVA and LLVA were strongly correlated with lower CS across all cone types in both affected males (r < -0.70, p < 0.05) and female carriers (r < -0.64, p < 0.05).

Cone dysfunction is evident in both males and female carriers of X-linked IRDs, with cone subtypes affected differentially based on genotype and disease severity. M-cone sensitivity appears particularly vulnerable in RPGR-associated disease. The ColorDx CCT test may serve as a valuable tool for detecting subclinical cone dysfunction and monitoring disease progression in female carriers, with potential utility as a functional biomarker in clinical care and future therapeutic trials.