Bright-light Vision Is Maintained In Older RPE65-deficient Dogs Despite Progressive Decrease in Photoreceptor Number And Reduction In Residual Electroretinographic Function

Abstract

 

Purpose:

 

The RPE65-deficient dog is a valuable large animal model of Leber congenital amaurosis type 2. While the phenotype of the young RPE65-deficient dog is well described, there is a paucity of information on the natural progression of disease with age. Here we characterize and correlate vision testing, electroretinographic (ERG) and histopathologic features of the phenotype over a wide age range.

 

Methods:

 

Data was collected from 47 RPE65-deficient dogs between 2 months and 8 years of age. Visual function was evaluated using a previously described vision testing apparatus. Dark and light adapted ERG intensity series and flicker responses were recorded. On histologic sections retinal layer thickness and photoreceptor nuclei numbers were evaluated, and retinal pigment epithelial inclusions counted and measured.

 

Results:

 

Vision assessment showed maintenance of vision in bright light at all ages tested. At lower light intensities the dogs were functionally blind. ERG testing showed raised response thresholds at all ages and a decline of ~50% in both light and dark-adapted a- and b-wave amplitudes over the ages investigated. There was a progressive thinning of the outer nuclear layer and corresponding reduction in photoreceptor nuclei numbers with age. By 3 years of age mean photoreceptor nuclei numbers were ~35% of that of the youngest individuals. The central superior retina (overlying the tapetum) had greatest preservation of photoreceptors. Lipid droplets accumulated in the retinal pigment epithelium with the most dramatic increase in size and number observed between 6 and 12 months of age.

 

Conclusions:

 

RPE65-deficient dogs had sufficient retinal function to allow them to negotiate a vision testing apparatus under bright lighting conditions but as the lighting levels decreased they were unable to negotiate the device. This parallels the markedly raised ERG response thresholds. The residual bright light vision was maintained until at least 8 years of age. Photoreceptor numbers declined progressively with age and this loss was reflected by a reduction in ERG amplitudes.

 

Keywords: retinal pigment epithelium