Multimodal imaging in patients with MYO7A-related Usher syndrome

Abstract

Purpose : Usher syndrome type1B (USH1B) is associated with variants in the MYO7A gene, which is expressed in retinal pigment epithelium (RPE) and photoreceptor (PR) cells. Most information about cell survival has come from imaging affected patients because mice with MYO7A variants do not develop photoreceptor degeneration. We characterized RPE and PR structure in eyes with USH1B with high-resolution retinal imaging modalities.

Methods : Confocal and non-confocal adaptive optics scanning laser ophthalmoscopy (AOSLO) were used to observe the cone PR mosaic in this cross-sectional study of patients with variants in MYO7A. Regions of interest (ROI) were selected at 1 degree intervals in the central 5° where mosaics of at least 50 cones were seen. Cone spacing was calculated as the average nearest neighbor distance using a density recovery profile analysis, and converted to Z-scores (standard deviations from the mean) to account for changes in cone spacing with eccentricity from the fovea. Fibroblasts were isolated from a skin biopsy from the oldest patient and converted to induced pluripotent stem cells (iPSC), then differentiated to RPE cells to study RPE morphology in cell culture.

Results : 4 USH1B patients (4 eyes) ranged in age from 8-37 (mean 19+14) years, with duration of visual symptoms ranging from 5-27 (mean 11+11) years. AOSLO imaging showed cone mosaics in 3 of the subjects; the oldest subject had severe PR degeneration and cystoid macular edema. All patients imaged with AOSLO had ROI with cone spacing Z-scores greater than 2, but the fraction of ROIs with normal cone spacing was large (over 84% in all cases). iPSC cultures differentiated into well-polarized RPE cells, forming an epithelial-like “cobblestone” appearance. Western blot data showed no evidence of myosin-7a protein, and the cultures were found to be amenable to mutant phenotype analysis (described elsewhere).

Conclusions : In eyes with USH1B, PR were well-preserved in the macula with increased cone spacing in a fraction of regions. Since ROIs were selected at locations where measurable cones were visible, the results are a best-estimate of retinal health. Multimodal imaging of patients with USH1B demonstrates the importance of MYO7A in PR and RPE cell structure. Investigations of iPSC-RPE cell cultures, derived from USH1B patients, are expected to provide further insight into the pathogenesis of USH1B-retinal degeneration.

This is a 2020 ARVO Annual Meeting abstract.