Imaging Cone Structure in Autosomal Dominant Cone Rod Dystrophy Caused by GUCY2D Mutations

Abstract

 

Purpose

 

Mutations in the GUCY2D gene are known to cause autosomal dominant cone rod dystrophy. Here we examined four subjects with GUCY2D gene mutations using a multi-modal imaging approach to characterize residual cone structure.

 

Methods

 

Three family members spanning three generations and a single unrelated subject, who were all found to harbor the Arg838His substitution in GUCY2D and diagnosed with autosomal dominant cone rod dystrophy, were recruited for imaging. Spectral domain optical coherence tomography (SD-OCT) was used to assess outer retinal lamination. Adaptive optics scanning light ophthalmoscopy (AOSLO) was performed in three of the four subjects using confocal detection, while two of the subjects were also imaged using AOSLO split-detection.

 

Results

 

SD-OCT findings were variable across subjects and included macular atrophy, the presence of a large hyporeflective zone, and subtle mottling of the ellipsoid zone. Confocal AOSLO revealed altered reflectivity of the perifoveal cone mosaic, showing sporadic "dark" cones throughout the perifovea, which were aided in visualization by the presence of neighboring rod photoreceptors. Confocal AOSLO near the fovea showed irregular reflective structure, precluding analysis of residual cone structure (see Figure). However, using AOSLO split-detection, we were able to clearly visualize cone inner segments. At 0.65° from the fovea, cone density was significantly reduced from normal (approximately 17,000 cones/mm² in the two subjects compared to 72,500 cones/mm² expected for normals), while residual cone inner segments were found to be enlarged.

 

Conclusions

 

Interpretation of confocal AOSLO images of degenerative retinal disease can be challenging. AOSLO split-detection allows direct quantification of residual inner segment cone structure and is complementary to the confocal signal from the cone outer segments. These techniques should prove to be a powerful clinical tool to aid in the examination of cone rod dystrophies and other retinal disorders.

 

 

Left: Confocal AOSLO image of the parafoveal photoreceptor mosaic displayed on a logarithmic scale. Irregular reflective structure is visible throughout the image. Right: Corresponding AOSLO split-detection image, revealing enlarged residual inner segment cone structure. Scalebar = 50 μm.

 

Keywords: 550 imaging/image analysis: clinical • 648 photoreceptors • 696 retinal degenerations: hereditary