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Karina E Guziewicz, Valerie Dufour, Lauren Lew, Brian Thomas Kendrick, Ana Ripolles Garcia, William A Beltran, Artur V Cideciyan, Samuel G Jacobson, Gustavo D Aguirre; A newly recognized canine phenotype of early-onset retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2792.
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Inherited retinal dystrophies (IRD) are a heterogeneous group of neurodegenerative disorders associated with pathogenic variants in 200+ genes identified so far. IRDs are typically characterized and diagnosed by spatio-temporal features of the rod and cone disease across the retina. However, congenital or early-onset IRDs such as LCA, ACHM, early-onset RP or CRD can show overlapping phenotypes that may change with disease progression. We performed clinical and genetic characterization of a newly recognized form of an early-onset IRD segregating in modern dog breeds to define the detailed phenotype at the different severity stages.
Privately owned dogs presented to the UPenn Veterinary clinic with ACHM-like signs. A general physical exam and ophthalmologic assessments were performed, including funduscopy, ERG and in vivo imaging (Heidelberg Spectralis). Additional information was gathered from veterinary ophthalmologists and pet breeders/owners surveys to establish the clinical course (n=10, age: 3-30m). Blood samples were collected and processed for molecular studies.
A novel phenotype of canine IRD manifests as congenital or early-onset disease with cone-mediated ERG dysfunction between 3-4m of age, and initially normal rod-mediated responses that began to decrease at 6m, and severely reduced by 1yr of age. At 4m, the dogs had a normal fundus appearance; hyperreflectivity in the area centralis was seen at 6m of age. cSLO/OCT at 1yr revealed narrowing of retinal arteries, photoreceptor loss, and atrophic changes. At 2.5yr, there was advanced disease with retina-wide degeneration, increased fundus hyperreflectivity, further thinning of retinal vessels, and areas of depigmentation in the non-tapetal region. Based on pedigree analysis, the new form of canine IRD segregates as an autosomal recessive trait. GWAS and homozygosity mapping led to the identification of 5Mb candidate interval on CFA8. Fine-mapping studies are currently ongoing.
The considerable clinical and genetic heterogeneity of human IRDs pose a major diagnostic challenge, which along with the dearth of reliable animal models that parallel the early human phenotypes, hinders development of specific therapies. Here, we describe a newly recognized canine IRD phenotype which presents as an autosomal recessive non-syndromic congenital/early-onset retinal dystrophy with overlapping clinical features of ACHM, MD, and CRD
This is a 2020 ARVO Annual Meeting abstract.
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