Elucidating early cellular retinal structural changes in GUCA1A-related autosomal dominant cone dystrophy

Abstract

Purpose : Mutations in the guanylate cyclase activator A1A(GUCA1A) gene which encodes guanylate cyclase activating protein, GCAP1, have been associated with both autosomal dominant (AD) cone and cone-rod dystrophies. GCAP1 plays a key role in recovery of photoreceptor to the dark-adapted state after light stimulus and its dysfunction is hypothesized to result in apoptosis of photoreceptors. Here we explore earlier cellular retinal structure changes in GUCA1A-related AD cone dystrophy using adaptive optics scanning light ophthalmoscope (AOSLO).

Methods : An asymptomatic 11 year old subject with a known GUCA1A-mediated AD cone dystrophy mutation(c.464A>G, p.(Glu155Gly)) underwent a comprehensive ophthalmic examination and high resolution imaging. Outer retinal structure was assessed using spectral-domain optical coherence tomography (SD-OCT) and the photoreceptor mosaic was imaged using confocal and split-detector AOSLO. AOSLO images were compared to 2 age-matched controls.

Results : Vision was 20/20 and color vision was normal OU. Clinical exam showed mild pigment mottling in the central maculas OU. SD-OCT showed intact but speckled-appearing ellipsoid band in the perifoveal macula. AOSLO demonstrated a disrupted photoreceptor mosaic with significantly decreased cone density when compared to age matched controls (8000 cells/mm² vs 23,400 cells/mm² at 4 degrees temporal to fovea). Split-detector AOSLO revealed inner segment photoreceptor structure (Figure 1B-arrow) in areas where no waveguiding cones were visualized (Figure 1A-arrow).

Conclusions : Significant cone photoreceptor degeneration occurs before functional loss in GUCA1A-mediated cone dystrophy. Split-detector AOSLO allows for a more precise assessment of retained photoreceptor structure. This highlights the potential utility of AOSLO to increase understanding of retinal degeneration at early asymptomatic stages and to identify ideal candidates with retained photoreceptor structure who may most benefit from emerging gene therapies.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

GUCA1A-mediated cone dystrophy showing disrupted photoreceptor mosaic 4 degrees temporal to fovea. (A) Confocal AOSLO showing dark, non-waveguiding cone photoreceptors (grey arrow) with surrounding rod photoreceptors. (B) Split-detector ALSLO from same location, revealing enlarged cone photoreceptor inner segments (orange arrow), some corresponding with dark, non-waveguiding cones on confocal AOSLO.