A multicenter retrospective evaluation of the prevalence of known and presumed hereditary eye diseases in Lagotto Romagnolo dog breed within a referral population in Italy (2012-2020).

OBJECTIVE: To describe the ophthalmological findings of Lagotto Romagnolo dog breed and to report the prevalence of Known and Presumed Hereditary Eye Diseases (KP-HED). ANIMALS STUDIED: Two hundred sixteen dogs were examined and included in this retrospective study. PROCEDURES: Medical records of Lagotto Romagnolo dogs between 2012 and 2020 were included. Data about the ocular status were collected through ocular screening examinations (OSE) or clinical ophthalmic examinations (COE). The prevalence of each KP-HED was expressed as a function of the total number of the KP-HED in this referral population. RESULTS: A total of 85 dogs (39.35%) were ophthalmologically healthy, ocular diseases presumably not hereditary were found in 43 dogs (19.91%), and 88 dogs (40.74%) were affected by one KP-HED. The most common KP-HEDs diagnosed were cataract (28/88; 31.82%), corneal endothelial dystrophy (17/88; 19.32%), retinal dysplasia (9/88; 10.23%), lens instability (7/88; 7.95%), progressive retinal atrophy (6/88, 6.82%), and keratoconjunctivitis sicca (6/88, 6.82%). Most of dogs with a KP-HED (77.27%, 68/88) were identified within COE group. CONCLUSIONS: To the authors' knowledge, this is the first report of the prevalence of ocular disease in the Lagotto Romagnolo dog breed within a referral population in Italy. This study suggests a relatively high prevalence of KP-HED, with a characteristic late-onset presentation in some diseases. Many of these KP-HED's, lead to ocular pain and irreversible blindness, for this reason, the authors highlight the importance of aiming for an early diagnosis. Breeder's efforts and breeding programs should be directed at limiting such disorders.

Whole-genome sequencing identifies missense mutation in GRM6 as the likely cause of congenital stationary night blindness in a Tennessee Walking Horse.

BACKGROUND: The only known genetic cause of congenital stationary night blindness (CSNB) in horses is a 1378 bp insertion in TRPM1. However, an affected Tennessee Walking Horse was found to have no copies of this variant. OBJECTIVES: To identify the genetic cause for CSNB in an affected Tennessee Walking Horse. STUDY DESIGN: Case report detailing a whole-genome sequencing (WGS) approach to identify a causal variant. METHODS: A complete ophthalmic exam, including an electroretinogram (ERG), was performed on suspected CSNB-affected horse. WGS data were generated from the case and compared with data from seven other breeds (n = 29). One hundred candidate genes were evaluated for coding variants homozygous in the case and absent in all other horses. Protein modelling was used to assess the functional effects of the identified variant. A random cohort of 90 unrelated Tennessee Walking Horses and 273 horses from additional breeds were screened to estimate allele frequency of the GRM6 variant. RESULTS: ERG results were consistent with CSNB. WGS analysis identified a missense mutation in metabotropic glutamate receptor 6 (GRM6) (c.533C>T p.Thr178Met). This single nucleotide polymorphism (SNP) is predicted to be deleterious and protein modelling supports impaired binding of the neurotransmitter glutamate. This variant was not detected in 273 horses from three additional breeds. The estimated allele frequency in Tennessee Walking Horses is 10%. MAIN LIMITATIONS: Limited phenotype information for controls and no additional cases with which to replicate this finding. CONCLUSIONS: We identified a likely causal recessive missense variant in GRM6. Based on protein modelling, this variant alters GRM6 binding, and thus signalling from the retinal rod cell to the ON-bipolar cell, impairing vision in low light conditions. Given the 10% population allele frequency, it is likely that additional affected horses exist in this breed and further work is needed to identify and examine these animals.

Genome-wide association study and whole-genome sequencing identify a deletion in LRIT3 associated with canine congenital stationary night blindness.

Congenital stationary night blindness (CSNB), in the complete form, is caused by dysfunctions in ON-bipolar cells (ON-BCs) which are secondary neurons of the retina. We describe the first disease causative variant associated with CSNB in the dog. A genome-wide association study using 12 cases and 11 controls from a research colony determined a 4.6 Mb locus on canine chromosome 32. Subsequent whole-genome sequencing identified a 1 bp deletion in LRIT3 segregating with CSNB. The canine mutant LRIT3 gives rise to a truncated protein with unaltered subcellular expression in vitro. Genetic variants in LRIT3 have been associated with CSNB in patients although there is limited evidence regarding its apparently critical function in the mGluR6 pathway in ON-BCs. We determine that in the canine CSNB retina, the mutant LRIT3 is correctly localized to the region correlating with the ON-BC dendritic tips, albeit with reduced immunolabelling. The LRIT3-CSNB canine model has direct translational potential enabling studies to help understand the CSNB pathogenesis as well as to develop new therapies targeting the secondary neurons of the retina.

BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure.

Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachment remains not well-understood. Our studies of molecular pathology in the canine BEST1 disease model revealed retina-wide abnormalities at the RPE-PR interface associated with defects in the RPE microvillar ensheathment and a cone PR-associated insoluble interphotoreceptor matrix. In vivo imaging demonstrated a retina-wide RPE-PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light. Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments. Immunohistochemical analyses showed correction of the structural alterations at the RPE-PR interface in areas with BEST1 transgene expression. Successful treatment effects were demonstrated in three different canine BEST1 genotypes with vector titers in the 0.1-to-5E11 vector genomes per mL range. Patients with biallelic BEST1 mutations exhibited large regions of retinal lamination defects, severe PR sensitivity loss, and slowing of the retinoid cycle. Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE-PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies.

The effect of repeated eye examinations and breeding advice on the prevalence and incidence of cataracts and progressive retinal atrophy in German dachshunds over a 13-year period.

OBJECTIVE: To analyze the change in prevalence and incidence of hereditary eye diseases (HED) in dachshunds due to breeding regulations based on biennial examinations performed by the German panel of veterinary ophthalmologists (DOK) from 1998 to 2011. ANIMALS INCLUDED: A total of 12 242 dachshunds examined by the DOK and pedigree data of 318 852 dachshunds provided by the German Dachshund Club (DTK). PROCEDURES: The prevalence of congenital cataract (CC), distichiasis (DIST), hereditary cataract (HC), persistent pupillary membranes (PPMs), persistent hyperplastic tunica vasculosa lentis / persistent hyperplastic primary vitreous (PHTVL/PHPV), progressive retinal atrophy (PRA), retinal dysplasia (RD), and findings such as fiberglass-like cataract (FGC) and prominent suture lines (PSLs) was analyzed. The significance (P), confidence interval (CI), odds ratio (OR), relative risk (RR) and inbreeding coefficients (F) were calculated and P < 0.05 was considered significant. The incidence was evaluated based on affected dogs within birth cohorts from 1993 to 2006. RESULTS: The prevalent conditions studied were as follows: CC 0.5%, DIST 6.7%, HC 3.9%, PPMs 8.4%, PHTVL/PHPV 0.4%, PRA 1.5%, RD 0.2%, FGC 2.2%, and PSL 1.5%. The incidence of PRA decreased significantly from 6.0% to 0.6% for dogs born from 1993 to 2006, while HC showed a decreasing trend from 8.7% to 3.1%. More males than females were diagnosed with HC and PRA. Dachshunds with HEDs had an F that was not significantly higher than that of healthy dachshunds. CONCLUSIONS: The decreasing incidence of PRA and HC in dachshunds supports the use of frequent HED examinations in combination with breeding control.

Redundant contribution of a Transient Receptor Potential cation channel Member 1 exon 11 single nucleotide polymorphism to equine congenital stationary night blindness.

BACKGROUND: Congenital stationary night-blindness (CSNB) is a recessive autosomal defect in low-light vision in Appaloosa and other horse breeds. This condition has been mapped by linkage analysis to a gene coding for the Transient Receptor Potential cation channel Member 1 (TRPM1). TRPM1 is normally expressed in the ON-bipolar cells of the inner nuclear layer of the retina. Down-regulation of TRPM1 expression in CSNB results from a transposon-like insertion in intron 1 of the TRPM1 gene. Stop transcription signals in this transposon significantly reduce TRPM1 primary transcript levels in CSNB horses. This study describes additional contributions by a second mutation of the TRPM1 gene, the ECA1 108,249,293 C > T SNP, to down-regulation of transcription of the TRPM1 gene in night-blind horses. This TRPM1 SNP introduces a consensus binding site for neuro-oncological ventral antigen 1 (Nova-1) protein in the primary transcript. Nova-1 binding disrupts normal splicing signals, producing unstable, non-functional mRNA transcripts. RESULTS: Retinal bipolar cells express both TRPM1 and Nova-1 proteins. In vitro addition of Nova-1 protein retards electrophoretic migration of TRPM1 RNA containing the ECA1 108,249,293 C > T SNP. Up-regulating Nova-1 expression in primary cultures of choroidal melanocytes carrying the intron 11 SNP caused an average log 2-fold reduction of ~6 (64-fold) of TRPM1 mRNA expression. CONCLUSIONS: These finding suggest that the equine TRPM1 SNP can act independently to reduce survival of TRPM1 mRNA escaping the intron 1 transcriptional stop signals in CSNB horses. Coexistence and co-inheritance of two independent TRPM1 mutations across 1000 equine generations suggests a selective advantage for the apparently deleterious CSNB trait.

Discrepancy in compliance between the clinical and genetic diagnosis of choroidal hypoplasia in Danish Rough Collies and Shetland Sheepdogs.

Collie eye anomaly (CEA) is a congenital, inherited ocular disorder which is widespread in herding breeds. Clinically, the two major lesions associated with CEA are choroidal hypoplasia (CH) and coloboma, and both lesions are diagnosed based on ophthalmological examination. A 7.8-kb intronic deletion in the gene encoding non-homologous end-joining factor 1 (NHEJ1) has been reported to be the causative mutation underlying CH when present in the homozygous state. In this study, we have investigated the compliance between the clinical and genetic diagnosis of CH in the Danish Rough Collie and Shetland Sheepdog populations. Our results show that the deletion in NHEJ1 is not predictive for CH in the Danish Rough Collie population, whereas the clinical and genetic diagnosis is in accordance with each other in the Shetland Sheepdog population. Based on these results, it can be concluded that the intronic deletion in NHEJ1 is not the causative mutation but, rather, a marker linked to the locus underlying the trait in some populations but linked to both the wild-type and CH-causing locus in most dogs in the Danish Rough Collie population.

Twenty-five thousand years of fluctuating selection on leopard complex spotting and congenital night blindness in horses.

Leopard complex spotting is inherited by the incompletely dominant locus, LP, which also causes congenital stationary night blindness in homozygous horses. We investigated an associated single nucleotide polymorphism in the TRPM1 gene in 96 archaeological bones from 31 localities from Late Pleistocene (approx. 17 000 YBP) to medieval times. The first genetic evidence of LP spotting in Europe dates back to the Pleistocene. We tested for temporal changes in the LP associated allele frequency and estimated coefficients of selection by means of approximate Bayesian computation analyses. Our results show that at least some of the observed frequency changes are congruent with shifts in artificial selection pressure for the leopard complex spotting phenotype. In early domestic horses from Kirklareli-Kanligecit (Turkey) dating to 2700-2200 BC, a remarkably high number of leopard spotted horses (six of 10 individuals) was detected including one adult homozygote. However, LP seems to have largely disappeared during the late Bronze Age, suggesting selection against this phenotype in early domestic horses. During the Iron Age, LP reappeared, probably by reintroduction into the domestic gene pool from wild animals. This picture of alternating selective regimes might explain how genetic diversity was maintained in domestic animals despite selection for specific traits at different times.

Prevalence of uveal cysts and pigmentary uveitis in Golden Retrievers in three Midwestern states.

OBJECTIVE: To determine the prevalence of uveal cysts and pigmentary uveitis (PU) in Golden Retrievers in 3 Midwestern states. DESIGN: Prospective cross-sectional study. ANIMALS: 164 American Kennel Club-registered Golden Retrievers in the states of Illinois, Indiana, and Michigan. PROCEDURES: For all dogs, biomicroscopic and binocular indirect ophthalmoscopic examinations of both eyes were performed after pupillary dilation. A finding of pigment deposition in a radial pattern or in zones on the anterior aspect of the lens capsule of 1 or both eyes was required for a diagnosis of PU. RESULTS: Eighty of the 328 (24.4%) eyes and 57 of the 164 (34.8%) dogs had visible uveal cysts. Of those 80 eyes with cysts, 41 (51.3%) had a single cyst located nasally and posterior to the iris, 33 (41.3%) had multiple uveal cysts, and 6 (75%) had a single, free-floating cyst. A diagnosis of PU was made for 9 (5.5%) dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Prevalences of uveal cysts (34.3%) and PU (5.5%) in the examined Golden Retrievers were both higher than prevalences reported previously (5.4% for uveal cysts and 1.5% for PU) in the Canine Eye Registry Foundation's 2009 All-Breeds Report. Study findings have indicated that PU is not a rare condition and should be considered as a differential diagnosis for Golden Retrievers with ocular disease.

Cats: a gold mine for ophthalmology.

Over 200 hereditary diseases have been identified and reported in the cat, several of which affect the eye, with homology to human hereditary disease. Compared with traditional murine models, the cat demonstrates more features in common with humans, including many anatomic and physiologic similarities, longer life span, increased size, and a genetically more heterogeneous background. The development of genomic resources in the cat has facilitated mapping and further characterization of feline models. During recent years, the wealth of knowledge in feline ophthalmology and neurophysiology has been extended to include new diseases of significant interest for comparative ophthalmology. This makes the cat an extremely valuable animal species to utilize for further research into disease processes affecting both cats and humans. This is especially true in the advancement and study of new treatment regimens and for extended therapeutic trials. Groups of feline eye diseases reviewed in the following are lysosomal storage disorders, congenital glaucoma, and neuroretinal degenerations. Each has important implications for human ophthalmic research.

Five cases of pigmented paravenous retinochoroidal atrophy in dogs.

OBJECTIVE: To describe a funduscopic finding in dogs that is referred to as Pigmented Paravenous Retinochoroidal Atrophy (PPRCA). ANIMALS STUDIED: Over a period of 24 years of ophthalmological practice, five cases of a characteristic paravenous retinal atrophy were observed in dogs. PROCEDURES: A comprehensive clinical ophthalmological examination in all five dogs was complemented by abdominal sonography (cases 1, 3), clinical pathology analysis (cases 1, 3, 4), and a histological examination of both bulbi, kidneys, spleen, and liver in one dog (case 1). RESULTS: Localized hyper-reflectivity in the tapetal fundus was observed in all five dogs and demonstrated a characteristic perivascular distribution along some peripheral retinal blood vessels. In these areas, geographic copper-brown coloration that tended to become darker with time was seen. Ophthalmoscopic signs of inflammation were lacking. The funduscopic abnormalities slowly progressed in size over years. Visual impairment could not be detected. Histopathology in one dog revealed severe retinal atrophy with multifocal perivascular distribution, mainly affecting the tapetal fundus and occasionally expanding into the nontapetal fundus. CONCLUSIONS: The described retinal lesions bear similarities with PPRCA in humans. As in humans, it appears to be an incidental funduscopic finding that is not associated with obvious vision impairment.

[Hereditary eye dieseas in the Entlebucher Mountaindog in Switzerland: a retrospective study from 1999 to 2009]. / Vererbte Augenerkrankungen beim Entlebucher Sennenhund in der Schweiz: Eine Retrospektive Studie von 1999 bis 2009.

The aim of this study was to analyze the prevalence and the incidence of hereditary cataract and progressive retinal atrophy (PRA) in the Entlebucher Mountaindog (EMD) and to evaluate possible changes over time. In addition, the influence of selective breeding programs and DNA-testing for PRA was also investigated. Data of eye certifications for hereditary eye diseases was used. Between 1999 and 2009 a total of 798 ocular examinations were carried out in 285 EMD. 20.4 % had cataracts and 69 % of these were of the posterior polar type. PRA was diagnosed in 6.3 % of the dogs. Cataracts were diagnosed at 5.24 ± 2.71 years (mean ± standard error), while PRA was diagnosed at 4.93 ± 1.32 years of age. The incidence of PRA and cataract showed a decreasing trend (p-value > 0.2) without being significant.

Congenital abnormalities in production animals.

The increase in number of food-producing animals each year implies that even small prevalences of congenital anomalies in these ruminant species are still reflected in a significant number of affected animals born each year. It takes a specific investigation to show the true incidence of such congenital abnormalities. This article discusses recent research into several conditions to demonstrate the opportunities that exist for investigating such conditions both from a genetic and an environmental perspective.

Ophthalmology of South american camelids.

In the past 10 years, information about South American camelid anatomy, physiology, medicine, and surgery has increased exponentially, including information about the eye. Although trauma-related diseases are the most common eye problems for which camelids are presented to veterinarians, there have recently been many anecdotal reports and published case reports of camelids having ocular malignancies and potentially hereditary ocular abnormalities. The increased number of ocular diseases being reported may be because of increased recognition of camelid diseases or an increase in these diseases as a result of restricted gene pools as a consequence of inbreeding. As the popularity of camelids is steadily increasing, owners are becoming more knowledgeable about their animals, and there is more need for veterinarians who understand their ocular anatomy, physiology, disease susceptibility, and recommended treatments. This article provides the relevant information about the eye.

Functional and structural changes in a canine model of hereditary primary angle-closure glaucoma.

PURPOSE: To characterize functional and structural changes in a canine model of hereditary primary angle-closure glaucoma. METHODS: Intraocular pressure (IOP) was evaluated with tonometry in a colony of glaucomatous dogs at 8, 15, 18, 20, and 30 months of age. Retinal function was evaluated using electroretinography (scotopic, photopic, and pattern). Examination of anterior segment structures was performed using gonioscopy and high-frequency ultrasonography (HFU). RESULTS: A gradual rise in IOP was observed with an increase in age: 8 months, 14 mm Hg (median value); 15 months, 15.5 mm Hg; 18 months, 17.5 mm Hg; 20 months, 24 mm Hg; 30 months, 36 mm Hg. Provocative testing with mydriatic agents (tropicamide and atropine 1%) caused significant increases in IOP (35% and 50%, respectively). HFU analysis showed complete collapse of iridocorneal angles by 20 months of age. Scotopic and photopic ERG analysis did not reveal significant deficits, but pattern ERG analysis showed significantly reduced amplitudes in glaucomatous dogs (glaucoma, 3.5 +/- 0.4 muV; control, 6.2 +/- 0.3 muV; P = 0.004; Student's t-test). Histologic analysis revealed collapse of the iridocorneal angle, posterior bowing of the lamina cribrosa, swelling and loss of large retinal ganglion cells, increased glial reactivity, and increased thickening of the lamina cribrosa. CONCLUSIONS: Canine hereditary angle-closure glaucoma is characterized by a progressive increase in intraocular pressure, loss of optic nerve function, and retinal ganglion cell loss.

The electroretinogram components in Abyssinian cats with hereditary retinal degeneration.

PURPOSE: To examine phototransduction using the a-wave and other aspects of retinal function with the intraretinal b- and c-waves at different stages of an inherited photoreceptor degeneration in Abyssinian cats. METHODS: Vitreal and intraretinal ERGs were recorded from eight dark-adapted, anesthetized Abyssinian cats. Brief bright flashes were used to elicit vitreal a- and b-waves. Longer, weaker flashes were used to elicit intraretinal b- and c-waves. Stages 1 through 4 of the disease were characterized ophthalmoscopically. Parameters of the Lamb and Pugh a-wave model (a(max), A, and t(eff)) for the Abyssinian cats were compared with those for normal cats. Light microscopy was used to count photoreceptor nuclei. RESULTS: The maximum a-wave amplitude, a(max), was significantly smaller in stage 1, and continued to decrease (stage 1: 50% of normal, stage 2: 28%, stage 3: 27%; and stage 4: unrecordable). There was a small, but not significant, decrease in the amplification constant A from 0.24 +/- 0.11 s(-2) in normal cats to 0.16 +/- 0.08 s(-2) in Abyssinian cats. The intraretinal b- and c-wave amplitudes decreased most dramatically during the early stage of the disease. Affected animals had fewer photoreceptors than unaffected Abyssinians or control animals. The number of photoreceptors declined most rapidly in the inferior periphery. CONCLUSIONS: The amplitudes of all ERG components were already reduced significantly by stage 1 and progressively declined. The lack of major changes in a-wave model parameters indicates that the degeneration is probably not due to a mutation in transduction proteins. Losses of photoreceptor function were larger than losses of photoreceptor nuclei.