Central Retinal Sensitivity Decline in RPGR-related Retinal Phenotypes

Abstract

Purpose: To characterize the natural history of central retinal sensitivity decline in RPGR-associated retinopathy, and to evaluate and quantify phenotypic differences in disease progression using microperimetry-derived metrics.

Design: A retrospective cohort study SUBJECTS: 50 patients with genetically confirmed RPGR mutations (36 rod-cone, 14 cone-rod dystrophy [CORD]), contributing 357 microperimetry assessments.

Methods: Central retinal function was assessed using the standard 68-point MAIA microperimeter grid pattern after 20 minutes of dark adaptation and without dilation. Mean sensitivity across the central 4 (MS4) and 16 (MS16) loci were extracted and analysed post-hoc. Longitudinal decline rates were modelled using generalized linear mixed models, and survival analyses were conducted using Cox proportional hazards models with random intercepts and robust clustering to account for repeated measures and intra-subject correlation.

Main outcome measures: rate of retinal sensitivity decline RESULTS: CORD patients exhibited significantly faster rates of central retinal sensitivity decline. The annual MS16 decline rate was 10.8% (95% CI: 6.6, 14.8) in CORD versus 5.1% (95% CI: 2.9, 7.1) in rod-cone patients (p=0.02). MS4 declined by 14.9% (95% CI: 10.2, 19.4) annually in CORD compared to 4.1% (95% CI: 1.2, 6.8) in rod-cone (p<0.001). The median survival age to total loss of sensitivity for MS16 was 25.1 years in CORD and 33.1 years in rod-cone (p=0.01); and for MS4, 27.2 years and 33.3 years, respectively (p=0.02). Hazard ratios demonstrated an 8.2-fold (MS16) and 7.2-fold (MS4) increased instantaneous risk of central vision loss in CORD compared to rod-cone patients.

Conclusions: This study reveals significantly different rates of functional decline between RPGR phenotypes, with CORD patients at markedly higher risk of early central vision loss. These findings support the use of microperimetry as a sensitive outcome measure and provide critical survival data for clinical trial design, patient counselling, and therapeutic prioritization. Patients with cone-dominated phenotypes may benefit from earlier intervention.

Keywords: RP; Retinitis Pigmentosa; cox regression; microperimetry; survival analysis.