Canine Multifocal Retinopathy (cmr1) Model of Human Best Macular Dystrophy: Imaging Earliest Retinal Lesions

Abstract

Purpose: : Canine multifocal retinopathy 1 (cmr1) is a recessive disease caused by a homozygous C73T stop mutation in the canine VMD2 gene and is a large animal model for retinopathies in humans caused by mutations in the human bestrophin (BEST1) gene. Histological and molecular findings in cmr1 recapitulate the features of Best disease. The mechanism of disease and causes for phenotypic variation in dogs and humans, remain largely unknown. In this work, specialized imaging methods were used to examine the early retinal/RPE changes in cmr1.

Methods: : Dogs from a breeding colony known to harbor the cmr1 mutation were genotyped, and three litter-mates homozygous for the mutation were selected for routine clinical examination and/or specialized imaging procedures to detect potential lesions in the RPE and/or retina. Imaging included confocal scanning laser ophthalmoscopy (cSLO) using HRA2 (Heidelberg Engineering) and spectral domain optical coherence tomography (SD-OCT) using RTVue-100 (Optovue Inc).

Results: : At 7 months, all three cmr1 homozygous mutant dogs showed no evidence of retinal abnormalities by routine clinical exam. By 12 months, both eyes of dog #1 showed multiple tan-pink lesions characteristic of the disease. Two mutant siblings (dogs #2 and #3), however, continued to show no retinal abnormalities by routine fundus exam. Near-infrared reflectance imaging using cSLO in dog #2, however, showed a single small (~0.6 mm diameter) lesion in each eye. Bilateral symmetric lesions were located in the area centralis ~6 mm temporal-superior to the optic nerve head within the visual streak of the tapetal retina. Lesions corresponded to a detachment by SD-OCT. At 13 months, dog #3 did not show retinal abnormalities by cSLO or SD-OCT.

Conclusions: : The earliest retinal changes in cmr1 are evident with cSLO or SD-OCT imaging even when not detectable by indirect ophthalmoscopy. The localization and appearance of the earliest lesions at the area centralis in one dog suggest a disease expression like the macular involvement in human Best disease. The apparent differences in age of onset of retinal lesions among homozygous mutant siblings suggest other genetic, developmental and environmental factors may play a role in the disease.

Keywords: imaging methods (CT, FA, ICG, MRI, OCT, RTA, SLO, ultrasound) • macula/fovea • retinal pigment epithelium