Autosomal Dominant RP1 c.2613dupA (p.Arg872Thrfs*2) Variant Retinitis Pigmentosa Shows Linear Loss of the Ellipsoid Zone over Time with Highly Variable Phenotype

Abstract

Introduction: The aim of the study was to report the phenotype and progression pattern of RP1 retinitis pigmentosa carrying the variant c.2613dupA (p.Arg872Thrfs*2).

Methods: This is a retrospective cohort study from 13 families with confirmed RP1 c.2613dupA (p.Arg872Thrfs*2) variant. Analysis was performed on clinical data including multimodal imaging and visual function tests. Progression rate (PR) was defined as the length of ellipsoid zone (EZ) lost per year and was calculated for all patients. Linear mixed model to predict the diameter of EZ loss as a function of age was applied.

Results: Twenty-one patients were included in the study. EZ loss in all patients ranged from 3.8 to 576.0 µm/year (median PR 76.5, IQR 97.6) in right eyes and from 26.6 to 340.7 µm/year (median PR 96.6, IQR 70.3), in left eyes, respectively, with a linear slope of progression for both eyes. The linear mixed model using age as an explanatory variable explained 25% of the variability in PR and showed that male patients had on average a statistically significant smaller EZ diameter at baseline.

Conclusion: The rate of progression of RP1 as measured by loss of EZ appears to be linear, independent of the age of onset. Furthermore, it appears that male subjects may present with earlier onset of disease as they showed a statistically significant smaller EZ diameter at baseline. Monitoring of EZ loss could be a valid clinical surrogate marker for clinical trials, but possibly sex differences and high variability of phenotypes need to be considered.

Keywords: Cone-rod dystrophy; Ellipsoid zone loss; Genotype-phenotype correlation; Inherited retinal disease; Phenotype variability; RP1 gene; Retinitis pigmentosa.