Abstract
Purpose :
The gene GUCY2D encodes the photoreceptor guanylate cyclase a key phototransduction enzyme involved in the restoration of cytoplasmic cGMP and return to the dark state of the photoreceptor. GUCY2D is associated with inherited retinal diseases including autosomal dominant cone-rod dystrophy (CRD). We performed a retrospective, observational cohort study to describe the natural history and progression of GUCY2D-associated CRD. In addition, the study aimed to investigate structural and functional biomarkers and their correlation with GUCY2D-associated CRD.
Methods :
Retrospective analysis was conducted on data from 16 patients with GUCY2D-associated CRD across two sites. Assessments included central macular thickness (CMT) and length of disruption to the ellipsoid zone (EZ) via optical coherence tomography (OCT), electroretinography (ERG) parameters, best corrected visual acuity (BCVA), and fundus autofluorescence.
Results :
At first visit, with a mean age of 30 years (range 5 – 70 years), 11 patients had a BCVA below the medical standards for holding an Australian Driver’s licence (LogMAR > 0.3 in both eyes), and 1 patient met the Australian definition of legal blindness (LogMAR ≥ 1 in both eyes). Analysis over the observation period (mean = 7 years, range 0 – 17 years) demonstrated a deterioration of LogMAR by -0.019 per year (SE = 0.003, p < 0.0001), during which 3 patients crossed the threshold of legal blindness. This study also demonstrated a significant reduction in CMT of -1.3 µm per year (standard error (SE) = 0.4 µm; p = 0.005) and lengthened disruption of the EZ by 42 µm per year (SE = 5 µm, p = <0.0001). Similarly, cone function as measured by ERG was shown to decrease with increasing age; b-wave amplitude of both the light-adapted 30 Hz flicker and fused flicker decreased by 0.83 µV (SE = 0.30 µV, p = 0.005) and 0.21 µV (SE = 0.09 µV, p = 0.02) per year, respectively. Reduction in CMT and increased EZ disruption on OCT were significantly associated with functional changes including poorer BCVA and decreased cone function on ERG.
Conclusions :
We have described the natural long-term decline in vision and cone function associated with mutations in GUCY2D. We have also identified a set of functional and structural biomarkers that may be useful as outcome parameters for future therapeutic clinical trials.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.