Clinical and genetic spectrum of patients with GUCY2D-associated retinal dystrophies

Abstract

Purpose : To describe the spectrum of retinal dystrophies associated with GUCY2D, and to identify potential clinical endpoints and optimal patient selection for future (gene) therapy.

Methods : This multicenter retrospective study reviewed medical records of 52 affected patients from 30 unrelated families for medical history, symptoms, best-corrected visual acuity (BCVA), ophthalmoscopy, visual field, full-field electroretinography and retinal imaging (fundus photography, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence).

Results : Patients had autosomal dominant cone-rod dystrophy (CORD; n=39; 75%) and autosomal recessive Leber congenital amaurosis (LCA; n=13; 25%). The mean follow-up time was 11.4±11.8 years for CORD and 5.7±4.4 years for LCA. The mean age at onset was 21.5±18.7 years and 0.4±1.0 years, respectively. For CORD, the mean Snellen BCVA at first visit was 0.25±0.22 (0.60±0.65 logMAR), and on average decreased with 0.07 (1.15 logMAR) per 10 years (p<0.003). In LCA patients, Snellen BCVA ranged from no light perception to 0.10 (1.00 logMAR). In CORD patients, the integrity of the ellipsoid zone (EZ) and external limiting membrane (ELM) on SD-OCT were significantly correlated with BCVA (Spearman’s r=-0.685 p=0.001 and r=-0.61 p=0.004, respectively).

Conclusions : LCA associated with GUCY2D mutations resulted in severe congenital visual impairment. GUCY2D-associated CORD showed a later onset and a relatively slow decrease of visual acuity, possibly suggesting a relatively large window of opportunity for future (gene) therapy. Severe visual impairment in the CORD group was generally reached in the 5^th decade of life. The integrity of ELM and EZ may be suitable structural endpoints for future gene therapeutic studies in CORD.

This is a 2021 ARVO Annual Meeting abstract.