Congenital idiopathic megaesophagus in the German shepherd dog is a sex-differentiated trait and is associated with an intronic variable number tandem repeat in Melanin-Concentrating Hormone Receptor 2.

Congenital idiopathic megaesophagus (CIM) is a gastrointestinal (GI) motility disorder of dogs in which reduced peristaltic activity and dilation of the esophagus prevent the normal transport of food into the stomach. Affected puppies regurgitate meals and water, fail to thrive, and experience complications such as aspiration pneumonia that may necessitate euthanasia. The German shepherd dog (GSD) has the highest disease incidence, indicative of a genetic predisposition. Here, we discover that male GSDs are twice as likely to be affected as females and show that the sex bias is independent of body size. We propose that female endogenous factors (e.g., estrogen) are protective via their role in promoting relaxation of the sphincter between the esophagus and stomach, facilitating food passage. A genome-wide association study for CIM revealed an association on canine chromosome 12 (P-val = 3.12x10-13), with the lead SNPs located upstream or within Melanin-Concentrating Hormone Receptor 2 (MCHR2), a compelling positional candidate gene having a role in appetite, weight, and GI motility. Within the first intron of MCHR2, we identified a 33 bp variable number tandem repeat (VNTR) containing a consensus binding sequence for the T-box family of transcription factors. Across dogs and wolves, the major allele includes two copies of the repeat, whereas the predominant alleles in GSDs have one or three copies. The single-copy allele is strongly associated with CIM (P-val = 1.32x10-17), with homozygosity for this allele posing the most significant risk. Our findings suggest that the number of T-box protein binding motifs may correlate with MCHR2 expression and that an imbalance of melanin-concentrating hormone plays a role in CIM. We describe herein the first genetic factors identified in CIM: sex and a major locus on chromosome 12, which together predict disease state in the GSD with greater than 75% accuracy.

Retinal structural and microvascular abnormalities in retinal dysplasia imaged by OCT and OCT angiography.

OBJECTIVE: To describe the in vivo structural characteristics of multifocal and geographic retinal dysplasia visualized with advanced retinal imaging including confocal scanning laser ophthalmoscopy (cSLO), optical coherence tomography (OCT), en face OCT, and the novel vascular imaging technique OCT angiography (OCTA). DOGS STUDIED AND PROCEDURES: Two dogs were diagnosed with unilateral multifocal or geographic retinal dysplasia and underwent advanced retinal imaging under general anesthesia at the Retinal Disease Studies Facility of the University of Pennsylvania. RESULTS: In both cases, the morphological pattern of the lesions was similar including outer retinal folds that invaginated and formed tubular retinal rosettes, surrounding a central inner retinal thickening (multifocal) or plaque (geographic). The two dogs had multiple vascular anomalies in the lesions such as increased tortuosity, abnormal change of vessel diameter including aneurysms and capillary network disruption. We also identified increased autofluorescence by AF cSLO with short wavelength light source (488 nm and barrier filter at 500 nm), and several areas of photoreceptor loss associated with the lesions. CONCLUSION: The use of OCTA allowed the identification of microvascular abnormalities associated with multifocal and geographic retinal dysplasia in two dogs. To our knowledge, this is the first report where the dye-free OCTA technique is used to study vascular lesions in canine retinas.

Optic nerve colobomas associated with unilateral focal serous retinal detachment in a dog - In-vivo imaging and outcome following laser retinopexy.

PURPOSE: To describe the ophthalmoscopic, in-vivo imaging, fluorescein angiography, and therapeutic photocoagulation outcome in a case of bilateral optic nerve colobomas associated with focal unilateral retinal detachment in a dog. METHODS: Pretraining eye examination of a 1.6-year-old female German shepherd service dog showed a focal juxta-papillary bullous retinal separation in the right eye. In vivo imaging and angiography were performed under general anesthesia using optical coherence tomography. Nonoverlapping diode laser burns were applied through an operating microscope adapter to selected areas along the leading margins of the detachment. RESULTS: The funduscopic examination and in-vivo imaging revealed bilateral optic nerve colobomas associated with a focal bullous detachment in the right eye. Fluorescein angiography showed absence of blood vessel leakage and absence of staining inside of the retinal elevation. Photocoagulation induced immediate changes in retinal layer reflectivity. Three months post-photocoagulation, the retinal detachment had improved and scarring of the burns was visible. One and two years post-procedure, the retinal detachment resolved. CONCLUSIONS: Optical coherence tomography (OCT) imaging provides a detailed analysis of the retinal abnormalities associated with the clinical lesion. Laser retinopexy is a valid therapeutic option to limit the extension of the detachment.

Focal/multifocal and geographic retinal dysplasia in the dog-In vivo retinal microanatomy analyses.

PURPOSE: To examine the in vivo microanatomy of retinal folds and geographic lesions in dogs with acquired or inherited retinal dysplasia. MATERIAL AND METHODS: Thirteen dogs had retinal microanatomy evaluation under general anesthesia using cSLO/sdOCT; two eyes had noninherited multifocal retinal folds, five had inherited multifocal retinal folds (drd1 or drd2), and 10 geographic retinal dysplasia. Retinas from two drd2 carrier dogs were examined by histology and immunohistochemistry (IHC) after in vivo imaging. RESULTS: Retinal folds are the common feature of acquired focal/multifocal or geographic retinal dysplasia, are indistinguishable structurally from those associated with syndromic oculoskeletal dysplasia, and represent outer nuclear layer invaginations and rosettes visible by sdOCT. In dogs heterozygous for oculoskeletal dysplasia, the folds form clusters in a perivascular distribution along superior central vessels. IHC confirmed photoreceptor identity in the retinal folds. The geographic dysplasia plaques are not focally detached, but have inner retinal disorganization and intense autofluorescence in cSLO autofluorescence mode that is mainly limited to the geographic lesion, but is not uniform and in some extends beyond the plaques. CONCLUSION: We propose that the autofluorescent characteristic of the geographic lesions is associated with an inner retinal disruption associated with perivascular or infiltrating macrophages and phagocytosis of cellular debris. As well, we suggest restructuring the examination forms to distinguish the folds that are sporadically distributed from those that have a perivascular distribution as the latter likely represent carriers for drd. In this latter group, DNA testing would be a helpful tool to provide specific breeding advice.

Genetic improvement of hip-extended scores in 3 breeds of guide dogs using estimated breeding values: Notable progress but more improvement is needed.

Two hip quality phenotypes-a hip-extended score assigned by a board certified radiologist and the PennHIP distraction index-were analyzed to estimate genetic parameters and to calculate estimated breeding values used for selecting replacement breeders. Radiographs obtained at 12-18 months of age were available on 5,201 German Shepherd Dogs, 4,987 Labrador Retrievers and 2,308 Golden Retrievers. Obtained by fitting a two-trait model using Bayesian techniques, estimates of heritability for the hip-extended score were 0.76, 0.72, and 0.41 in German Shepherd Dogs, Labrador Retrievers, and Golden Retrievers, respectively, while estimated heritabilities for distraction index were 0.60, 0.66 and 0.59, respectively. Genetic correlations between the two hip quality measures were -0.28 in German Shepherd Dogs, -0.21 in Labrador Retrievers, and -0.29 in Golden Retrievers. Genetic selection for improved hip quality based upon the hip extended score phenotype began in 1980. Among first generation puppies, 34% of 273 German Shepherd Dogs, 55% of 323 Labrador Retrievers, and 43% of 51 Golden Retrievers had an Excellent hip extended score. After 8 generations of selection, mostly based on estimated breeding values derived from the hip extended score, over 93% of 695 German Shepherd Dogs, 94% of 528 Labrador Retrievers, and 87% of 116 Golden Retrievers received an Excellent hip extended score. With respect to PennHIP distraction index values among these same dogs, median values were at or above 0.30 for all 3 breeds meaning that half or more of dogs possessing the Excellent hip-extended-score phenotype remained susceptible to developing the osteoarthritis of canine hip dysplasia. Genetic improvement of the hip-extended-view phenotype to its desired biological endpoint left a surprising proportion of dogs expressing sufficient joint laxity to place them in an osteoarthritis at-risk state as they age. Only by directly applying selection pressure to reduce distraction index was marked reduction in joint laxity noted.