Longitudinal phenotypic characterization of type II Usher syndrome caused by mutations in USH2A

Abstract

Purpose : Mutations in USH2A are the leading cause of Usher syndrome and a major contributor of non-syndromic RP. Recent advances in gene therapy have increased attention to inherited eye disease. However, the size of the USH2A gene makes it a poor candidate for conventional viral gene therapy, and alternative approaches are being developed including small molecule drugs and non-viral gene therapy. Therefore, detailed longitudinal data is required to accurately predict progression and identify potential outcome measures.

Methods : Patients were identified from the Moorfields Eye Hospital genetic eye disease database. Subjects with molecularly confirmed biallelic USH2A variants, at least 3 visits with gradable OCT and AF data were selected. OCT images were graded for central retinal thickness (CRT), photoreceptor layer thickness and residual ellipsoid zone (EZ) length. AF images were graded for ring appearance, hyper-autofluorescent (hyperAF) ring area and horizontal/vertical diameter.

Results : Fifty-six patients had longitudinal OCT, and 55 patients had AF. The average age was 40 years (range 15-66) and average duration between visits was 15 mths (range 9-51mths). EZ length and AF parameters were highly correlated between eyes (r²=0.92 and 0.97, respectively), while CRT was less correlated (r²=0.61). Rate of decline for EZ was 159 µm/yr for the whole cohort (412µm/yr for those <20 yrs old; 114µm/yr for age 50-60 yrs). Decline in AF area was 0.78mm²/yr for the whole cohort (2.9mm²/yr for <20yrs; 0.4mm²/yr for 50-60 yrs). EZ length was the most predictive OCT feature with r²=0.12 baseline to time point 1 compared to time point 1 & 2. Conversely, hyperAF area was much more predictive r²=0.79 between the same points. EZ length was weakly, but statistically significantly correlated with hyperAF horizontal diameter (p <0.0001; r²=0.48). There were no statistically significant differences in OCT or AF parameters by mutation type.

Conclusions : CRT and acuity were not good predictors of change, likely due to factors such as retinal edema. Measures of OCT photoreceptor thickness, EZ size and hyper AF were both repeatable and could serve as trial endpoints. There was a significant correlation between rates of change and age, with younger subjects degenerating more quickly. Therefore, in trials designed to detect lack of degeneration younger subjects present the greatest probability of detecting treatment effect.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.