Structural and Functional Relationships in RDH12-Associated Early-Onset Severe Inherited Retinal Degeneration

Abstract

Purpose : To increase our understanding of the structural and functional relationships in RDH12-associated early-onset and severe inherited retinal degeneration (RDH12-EOSRD) as a premise to the selection of target disease stages and retinal regions, as well as safety and efficacy signals for future clinical trials.

Methods : Patients (n=19, ages 6-21 years) with homozygous or compound heterozygous mutations in RDH12 that could reliably perform on visual field testing had a comprehensive ophthalmic evaluation, retinal imaging with spectral domain optical coherence tomography (SD-OCT), and in two patients, with a custom-built, adaptive optics scanning light ophthalmoscopy (AOSLO) system. Structural parameters were related to co-localized visual thresholds by automated light- and dark-adapted static chromatic perimetry.

Results : There was a narrow spectrum of severity with particularly severe central retinal abnormalities. Visual acuity (VA) ranged from 0.4 to 2.0 logMAR (mean 0.84 logMAR). Foveal sensitivity was reduced by at least 10 dB in all patients and related linearly to VA. Outer retinal thickness (from the outer plexiform layer to Bruch’s membrane) was at least half the normal thickness in all patients and related poorly with VA. The pericentral retina showed severe vision loss with similar losses of cone- and rod-mediated function or had only residual islands of severely abnormal cone function. The outer nuclear layer and photoreceptor inner and outer segments were discernible despite the severe vision loss. The peripapillary retina could be relatively spared even with normal or near normal cone- and rod-mediated sensitivities and retinal structure. Cones in this region were present at normal or near normal densities and exhibited waveguiding properties on AOSLO imaging.

Conclusions : RDH12-EOSRDs show a retina-wide disease with a severe central degeneration and similarly dysfunctional rods and cones. The structural-functional relationships in relatively preserved regions suggest vision loss does not result directly from the RDH12 insufficiency, but rather from resulting outer segment abnormalities and ultimately photoreceptor and RPE degeneration and loss. Regions with profoundly abnormal vision, but with clearly detectable photoreceptors and signals distal to the photoreceptor inner segment, raise hope of functional restoration of these areas by gene augmentation.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.