Background: Some paroxysmal movement disorders remain without an identified genetic cause.Objectives: The aim was to identify the causal genetic variant for a paroxysmal dystonia–ataxia syndrome in Weimaraner dogs.Methods: Clinical and diagnostic investigations were performed. Whole genome sequencing of one affected dog was used to identify private homozygous variants against 921 control genomes.Results: Four Weimaraners were presented for episodes of abnormal gait. Results of examinations and diagnostic investigations were unremarkable. Whole genome sequencing revealed a private frameshift variant in the TNR (tenascin‐R) gene in an affected dog, XM_038542431.1:c.831dupC, which is predicted to truncate more than 75% of the open read frame. Genotypes in a cohort of 4 affected and 70 unaffected Weimaraners showed perfect association with the disease phenotype.Conclusions: We report the association of a TNR variant with a paroxysmal dystonia–ataxia syndrome in Weimaraners. It might be relevant to include sequencing of this gene in diagnosing humans with unexplained paroxysmal movement disorders. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

We investigated a hereditary cerebellar ataxia in Belgian Shepherd dogs. Affected dogs developed uncoordinated movements and intention tremor at two weeks of age. The severity of clinical signs was highly variable. Histopathology demonstrated atrophy of the CNS, particularly in the cerebellum. Combined linkage and homozygosity mapping in a family with four affected puppies delineated a 52 Mb critical interval. The comparison of whole genome sequence data of one affected dog to 735 control genomes revealed a private homozygous structural variant in the critical interval, Chr4:66,946,539_66,963,863del17,325. This deletion includes the entire protein coding sequence of SELENOP and is predicted to result in complete absence of the encoded selenoprotein P required for selenium transport into the CNS. Genotypes at the deletion showed the expected co-segregation with the phenotype in the investigated family. Total selenium levels in the blood of homozygous mutant puppies of the investigated litter were reduced to about 30% of the value of a homozygous wildtype littermate. Genotyping >600 Belgian Shepherd dogs revealed an additional homozygous mutant dog. This dog also suffered from pronounced ataxia, but reached an age of 10 years. Selenop^-/- knock-out mice were reported to develop ataxia, but their histopathological changes were less severe than in the investigated dogs. Our results demonstrate that deletion of the SELENOP gene in dogs cause a defect in selenium transport associated with CNS atrophy and cerebellar ataxia (CACA). The affected dogs represent a valuable spontaneous animal model to gain further insights into the pathophysiological consequences of CNS selenium deficiency.

The main goals of the standard treatment for advanced symptomatic knee osteoarthritis, total knee arthroplasty (TKA), are pain reduction and restoration of knee motion. The aim of this study was to analyse the outcome of the patient-based Knee Injury and Osteoarthritis Outcome Score (KOOS), and the surgeon-based Knee Society Score (KSS) and its Knee Score (KS) and Knee Functional Score (KFS) components after (TKA) using the Journey knee prosthesis, and to assess the correlation of these scores with range of motion (ROM). In a prospective case series study between August 1st 2008 and May 31st 2011, 99 patients, all operated by a single surgeon, received Journey bicruciate stabilized total knee prostheses. The female/male ratio was 53/34, the mean patient age at surgery was 68 years (range 41–83 years), and the left/right knee ratio was 55/44. The KOOS, range of motion, and KS and KFS were obtained preoperatively and at 1-year follow-up. The pre- and postoperative levels of the outcome measures were compared using the Wilcoxon signed-rank test. Correlation between ROM and patient outcomes was analysed with the Spearman coefficient. All KOOS subscores improved significantly. Ninety percent of patients improved by at least the minimum clinically relevant difference of 10 points in stiffness and other symptoms, 94.5% in pain, 94.5% in activities of daily living, 84.9% in sports and recreation, and 90% in knee-related quality of life. The mean passive and active ROM improved from 122.4° (range 90-145°) and 120.4° (range 80-145°) preoperatively to 129.4° (range 90-145°) and 127.1° (range 100-145°) postoperatively. The highest correlation coefficients for ROM and KOOS were observed for the activity and pain subscores. Very low or no correlation was seen for the sport subscore. There was a significant and clinically relevant improvement of KSS (preop/postop 112.2/174.5 points), and its KS (preop/postop 45.6/86.8 points) and KFS (preop/postop 66.6/87.8 points) components. The Journey bicruciate stabilized knee prosthesis showed good 1-year postoperative results in terms of both functional and patient-based outcome. However, higher knee ROM correlates only moderately with patient-based outcome, implying that functionality afforded by the Journey bicruciate TKA is not equivalent to patient satisfaction.

We investigated a hereditary syndrome in Cane Corso dogs. Affected dogs developed dental-skeletal-retinal anomaly (DSRA), clinically characterized by brittle, discolored, translucent teeth, disproportionate growth and progressive retinal degeneration resulting in vision loss. Combined linkage and homozygosity mapping delineated a 5.8 Mb critical interval. The comparison of whole genome sequence data of an affected dog to 789 control genomes revealed a private homozygous splice region variant in the critical interval. It affected the MIA3 gene encoding the MIA SH3 domain ER export factor 3, which has an essential role in the export of collagen and other secreted proteins. The identified variant, XM_005640835.3:c.3822+3_3822+4del, leads to skipping of two exons from the wild type transcript, XM_005640835.3:r.3712_3822del. Genotypes at the variant were consistent with monogenic autosomal recessive mode of inheritance in a complete family and showed perfect genotype-phenotype association in 18 affected and 22 unaffected Cane Corso dogs. MIA3 variants had previously been shown to cause related phenotypes in humans and mice. Our data in dogs together with the existing functional knowledge of MIA3 variants in other mammalian species suggest the MIA3 splice defect and a near complete loss of gene function as causative molecular pathomechanism for the DSRA phenotype in the investigated dogs.

A 1-month-old, female, smooth-haired miniature Dachshund with dilute color and neurological defects was investigated. The aim of this study was to characterize the clinical signs, histopathological changes and underlying genetic defect. The puppy had visible coat color dilution and was unable to hold its head on its own or to remain in a stable prone position for an extended period. Histopathological examination revealed an accumulation of clumped melanin and deposition of accumulated keratin within the hair follicles, accompanied by dermal pigmentary incontinence. These dermatological changes were compatible with the histopathology described in dogs with an MLPH-related dilute coat color. We sequenced the genome of the affected dog and compared the data to 795 control genomes. MYO5A, coding for myosin VA, was investigated as the top functional candidate gene. This search revealed a private homozygous frameshift variant in MYO5A, XM_022412522.1:c.4973_4974insA, predicted to truncate 269 amino acids (13.8%) of the wild type myosin VA protein, XP_022268230.1:p.(Asn1658Lysfs*28). The genotypes of the index family showed the expected co-segregation with the phenotype and the mutant allele was absent from 142 additionally genotyped, unrelated Dachshund dogs. MYO5A loss of function variants cause Griscelli type 1 syndrome in humans, lavender foal in horses and the phenotype of the dilute mouse mutant. Based on the available data, together with current knowledge on other species, we propose the identified MYO5A frameshift insertion as a candidate causative variant for the observed dermatological and neurological signs in the investigated dog.

Muscular dystrophy due to dystrophin deficiency in humans is phenotypically divided into a severe Duchenne and milder Becker type. Dystrophin deficiency has also been described in a few animal species, and few DMD gene variants have been identified in animals. Here, we characterize the clinical, histopathological, and molecular genetic aspects of a family of Maine Coon crossbred cats with clinically mild and slowly progressive muscular dystrophy. Two young adult male littermate cats exhibited abnormal gait and muscular hypertrophy with macroglossia. Serum creatine kinase activities were highly increased. Histopathologically, dystrophic skeletal muscle exhibited marked structural changes including atrophic, hypertrophic, and necrotic muscle fibers. Immunohistochemistry showed irregularly reduced expression of dystrophin but the staining of other muscle proteins such as β- and γ-sarcoglycans as well as desmin was also diminished. Whole genome sequencing of one affected cat and genotyping of the littermate found both to be hemizygous mutant at a single DMD missense variant (c.4186C>T). No other protein-changing variants in candidate genes for muscular dystrophy were detected. In addition, one clinically healthy male littermate was hemizygous wildtype, while the queen and one female littermate were clinically healthy, but heterozygous. The predicted amino acid exchange (p.His1396Tyr) resides in a conserved central rod spectrin domain of dystrophin. Various protein modeling programs did not predict major disruption of the dystrophin protein by this substitution, but the altered charge of the region may still affect protein function. This study represents the first genotype-to-phenotype correlation of Becker-type dystrophin deficiency in companion animals.