Retinal Architecture in ​RGS9- and ​R9AP-Associated Retinal Dysfunction (Bradyopsia)

Abstract

Purpose: To characterize photoreceptor structure and mosaic integrity in subjects with ​RGS9- and R9AP-associated retinal dysfunction (bradyopsia) and compare to previous observations in other cone dysfunction disorders such as oligocone trichromacy.

Design: Observational case series.

Methods: setting: Moorfields Eye Hospital (United Kingdom) and Medical College Wisconsin (USA).

Study population: Six eyes of 3 subjects with disease-causing variants in ​RGS9 or R9AP.

Main outcome measures: Detailed retinal imaging using spectral-domain optical coherence tomography and confocal adaptive-optics scanning light ophthalmoscopy.

Results: Cone density at 100 μm from foveal center ranged from 123 132 cones/mm(2) to 140 013 cones/mm(2). Cone density ranged from 30 573 to 34 876 cones/mm(2) by 600 μm from center and from 15 987 to 16,253 cones/mm(2) by 1400 μm from center, in keeping with data from normal subjects. Adaptive-optics imaging identified a small, focal hyporeflective lesion at the foveal center in both eyes of the subject with RGS9-associated disease, corresponding to a discrete outer retinal defect also observed on spectral-domain optical coherence tomography; however, the photoreceptor mosaic remained intact at all other observed eccentricities.

Conclusions: Bradyopsia and oligocone trichromacy share common clinical symptoms and cannot be discerned on standard clinical findings alone. Adaptive-optics imaging previously demonstrated a sparse mosaic of normal wave-guiding cones remaining at the fovea, with no visible structure outside the central fovea in oligocone trichromacy. In contrast, the subjects presented in this study with molecularly confirmed bradyopsia had a relatively intact and structurally normal photoreceptor mosaic, allowing the distinction between these disorders based on the cellular phenotype and suggesting different pathomechanisms.

Figure 1

Spectral-domain optical coherence tomography B-scans in 3 subjects with bradyopsia. Top left: A representative macular line scan is shown with designated layer thickness measurements. Bottom left: Total retinal thickness was normal in all subjects compared to a normative database. Normative average thickness is shown as a black line ± 2 standard deviations (gray shaded region). Inner retinal thickness (Top right) and outer nuclear layer thickness (Bottom right) was within the normal range for all subjects compared to a normative database. Subject JC_0759 is represented by a triangle, MM_0032 as a square, and MM_0033 as a circle throughout.

Figure 2

Horizontal spectral-domain optical coherence tomography images through the fovea of all 3 bradyopsia subjects. Qualitative spectral-domain optical coherence tomography analysis shows a focal disruption in the inner segment ellipsoid and interdigitation zone in JC_0759 (Top). This contrasts to the intact outer retinal lamination present in MM_0032 (Middle) and MM_0033 (Bottom). The arrows on JC_0759 and MM_0033 indicate the location of the adaptive-optics scanning light ophthalmoscopy montage shown in Figure 3.

Figure 3

Foveal montages derived from adaptive-optics scanning light ophthalmoscopy for the RGS9 subject JC_0759 and R9AP subject MM_0033. The foveal montage for JC_0759 (Top) shows a hyporeflective lesion that corresponds to the disruption seen on spectral-domain optical coherence tomography in Figure 2. Conversely, the foveal montage from MM_0033 (Bottom) shows a qualitatively normal cone mosaic across the foveal region. Scale bar is 100 μm.

Figure 4

Photoreceptor images from multiple eccentricities obtained with adaptive-optics scanning light ophthalmoscopy in 2 bradyopsia patients. Photoreceptor images are shown at the center of peak density (lesion: JC_0759, Top row, and MM_0033, Bottom row), and 200, 400, 800, and 1200 μm away from center of peak density. Cone photoreceptors were readily identifiable at all locations except the center of JC_0759. Scale bar is 20 μm.

Figure 5

Cone photoreceptor density in relation to eccentricity in 3 subjects with bradyopsia. Normal cone density established by histologic analysis (Curcio and associates²⁰) is shown as the gray shaded region. Subject JC_0759 is represented by a triangle, MM_0032 as a square, and MM_0033 as a circle. The 3 subjects with bradyopsia have very similar cone densities from 0.3 mm from peak density and thereby their respective symbols overlap.

Figure 6

Comparison of foveal cone mosaics as imaged by adaptive-optics light ophthaloscopy in normal subjects and subjects with oligocone trichromacy and RGS9/R9AP-associated retinopathy. Normal (Left) and RGS9/R9AP-associated retinopathy (Right) subjects have a continuous cone mosaic across the foveal region. In contrast, a decreased cone mosaic is observed in oligocone trichromacy (Middle). Scale bar is 25 μm.