Abnormal Appearance of the Area Centralis in Labrador Retrievers With an ABCA4 Loss-of-function Mutation

PURPOSE: To study retinal appearance and morphology in Labrador retrievers (LRs) heterozygous and homozygous for an ABCA4 loss-of-function mutation. METHODS: Ophthalmic examination, including ophthalmoscopy and simple testing of vision, was performed in five ABCA4(wt/wt), four ABCA4(wt/InsC), and six ABCA4(InsC/InsC) LRs. Retinas were also examined with confocal scanning laser ophthalmoscopy (cSLO) and optical coherence tomography (OCT). Infrared and fundus autofluorescence (FAF) images were studied, and outer nuclear layer (ONL) and neuroretinal thickness were measured in the central and peripheral area centralis. RESULTS: Clinical signs in young ABCA4(InsC/InsC) LRs were subtle, whereas ophthalmoscopic findings and signs of visual impairment were obvious in old ABCA4(InsC/InsC) LRs. Retinal appearance and vision testing was unremarkable in heterozygous LRs regardless of age. The cSLO/OCT showed abnormal morphology including ONL thinning, abnormal outer retinal layer segmentation, and focal loss of retinal pigment epithelium in the fovea equivalent in juvenile ABCA4(InsC/InsC) LRs. The abnormal appearance extended into the area centralis and visual streak in middle-aged ABCA4(InsC/InsC) and then spread more peripherally. A mild phenotype was seen on cSLO/OCT and FAF in middle-aged to old ABCA4(wt/InsC) LRs. CONCLUSIONS: Abnormal appearance and morphology in the fovea equivalent are present in juvenile ABCA4(InsC/InsC). In the older affected LRs, the visual streak and then the peripheral retina also develop an abnormal appearance. Vision deteriorates slowly, but some vision is retained throughout life. Older heterozygotes may show a mild retinal phenotype but no obvious visual impairment. The ABCA4(InsC/InsC) LR is a potential model for ABCA4-mediated retinopathies/juvenile-onset Stargardt disease in a species with human-sized eyes. TRANSLATIONAL RELEVANCE: The ABCA4(InsC) mutation causes juvenile-onset abnormal appearance of the fovea equivalent in affected dogs that slowly spreads in the retina, while only a mild phenotype is seen in older carriers. This is the first non-primate, large-animal model for ABCA4-related/STGD1 retinopathies in a species with a fovea equivalent.