Susan M. Taylor

MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers.

Mutations in the MTM1 gene encoding myotubularin cause X-linked myotubular myopathy (XLMTM), a well-defined subtype of human centronuclear myopathy. Seven male Labrador Retrievers, age 14–26 wk, were clinically evaluated for generalized weakness and muscle atrophy. Muscle biopsies showed variability in fiber size, centrally placed nuclei resembling fetal myotubes, and subsarcolemmal ringed and central dense areas highlighted with mitochondrial specific reactions. Ultrastructural studies confirmed the centrally located nuclei, abnormal perinuclear structure, and mitochondrial accumulations. Wild-type triads were infrequent, with most exhibiting an abnormal orientation of T tubules. MTM1 gene sequencing revealed a unique exon 7 variant in all seven affected males, causing a nonconservative missense change, p.N155K, which haplotype data suggest derives from a recent founder in the local population. Analysis of a worldwide panel of 237 unaffected Labrador Retrievers and 59 additional control dogs from 25 other breeds failed to identify this variant, supporting it as the pathogenic mutation. Myotubularin protein levels and localization were abnormal in muscles from affected dogs, and expression of GFP-MTM1 p.N155K in COS-1 cells showed that the mutant protein was sequestered in proteasomes, where it was presumably misfolded and prematurely degraded. These data demonstrate that XLMTM in Labrador Retrievers is a faithful genetic model of the human condition.

A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse

Labrador retrievers are the most common dog breed in the world, with over 200,000 new kennel club registrations per year. The syndrome of exercise-induced collapse (EIC) in this breed is manifested by muscle weakness, incoordination and life-threatening collapse after intense exercise. Using a genome-wide microsatellite marker scan for linkage in pedigrees, we mapped the EIC locus to canine chromosome 9. We then used SNP association and haplotype analysis to fine map the locus, and identified a mutation in the dynamin 1 gene (DNM1) that causes an R256L substitution in a highly conserved region of the protein. This first documented mammalian DNM1 mutation is present at a high frequency in the breed and is a compelling candidate causal mutation for EIC, as the dynamin 1 protein has an essential role in neurotransmission and synaptic vesicle endocytosis.

Focal myasthenia gravis as a paraneoplastic syndrome of canine thymoma: improvement following thymectomy

A 10-year-old, neutered male cocker spaniel-cross experienced regurgitation, dry retching, and weight loss. A large, mediastinal mass and dilatation of the esophagus were seen on thoracic radiographs. Cytological, histopathological, immunohistochemical, and serological findings were consistent with a lymphoepithelial thymoma and focal, esophageal myasthenia gravis. Surgical removal of the mass resulted in rapid resolution of the megaesophagus and a decrease in serum acetylcholine-receptor antibody concentration. The dog was clinically normal until the thymoma recurred six months postoperatively. Clinical signs, diagnostic evaluation, management, and treatment of a dog with thymoma and megaesophagus are described.

Steroid‐Responsive Meningitis‐Arteritis in Dogs with Noninfectious, Nonerosive, Idiopathic, Immune‐Mediated Polyarthritis

Signs related to spinal pain are commonly reported in dogs with noninfectious, nonerosive, idiopathic immune-mediated polyarthritis (IMPA). This study examined the prevalence and etiology of spinal pain in these dogs through a retrospective review of 62 case records of dogs with IMPA. All dogs with IMPA and signs suggestive of spinal pain were described with regard to age, gender, breed, physical stature, location of vertebral pain, rectal temperature, and clinical laboratory findings. The prevalence of spinal pain in these dogs was 29% (18 of 62). Fourteen of the 18 dogs with spinal pain and IMPA were male. Cerebrospinal fluid (CSF) from 11 dogs with signs of spinal pain was analyzed. Five of these (46%) had concurrent steroid-responsive meningitis-arteritis (SRMA). We concluded that SRMA does occur concurrently in some dogs having IMPA. Meningeal involvement may explain the origin of spinal pain observed in some of these dogs.

Prospective Evaluation of Laparoscopic Pancreatic Biopsies in 11 Healthy Cats

BACKGROUND Definitive diagnosis of feline pancreatic disease is dependent on histologic examination of biopsies. HYPOTHESIS Laparoscopic punch biopsy of the pancreas does not significantly affect pancreatic health or clinical status of healthy cats, and provides an adequate biopsy sample for histopathology. ANIMALS Eleven healthy female domestic shorthair cats. METHODS Effects of laparoscopic pancreatic visualization alone in 5 cats compared with laparoscopic pancreatic visualization and punch biopsy in 6 cats were studied. Temperature, pulse, and respiratory rate, physical examination, and daily caloric intake were evaluated for 1 week before and 1 week after the procedure. Pain scores (simple descriptive score and dynamic interactive visual assessment score) were evaluated hourly during the 1st 6 hours postprocedure. Complete blood cell counts, serum biochemical profiles, serum feline pancreatic lipase immunoreactivity, and urine specific gravity were evaluated before the procedure and at 6, 24, and 72 hours postprocedure. One month postprocedure, during sterilization, the pancreas was reassessed visually in all cats, and microscopically in the biopsy group. RESULTS For all variables evaluated, there were no significant differences between biopsy and control cats. Re-evaluation of the pancreatic biopsy site 1 month later documented a normal tissue response to biopsy. The laparoscopic punch biopsy forceps provided high-quality pancreatic biopsy samples with an average size of 5 mm x 4 mm on 2-dimensional cut section. CONCLUSIONS AND CLINICAL IMPORTANCE Laparoscopic pancreatic biopsy is a useful and safe technique in healthy cats.

Feline Leukemia Virus Detection by ELISA and PCR in Peripheral Blood from 68 Cats with High, Moderate, or Low Suspicion of having FeLV-Related Disease

Clinicopathologic criteria were used to group 68 cats according to high, moderate, or low suspicion of having feline leukemia virus (FeL V)-related disease. Peripheral blood samples were tested for FeL V antigen by enzyme-linked immunosorbent assay (ELISA) and for FeL V DNA by polymerase chain reaction (PCR). There was no significant difference between ELISA and PCR results in the 68 cats. In the high-suspicion group, 46% (11/24) of cytopenic cats were test positive (ELISA and PCR) and 87% (13/15) with hemopoietic neoplasms were test-positive. Also within the high suspicion group, test-positive cats were 2.5 times more likely to die within the 1 year follow-up period than were test-negative (ELISA and PCR) cats. Among cats in the moderate-suspicion group, 15% (2/13) were test-positive, and none (0/16) of the cats in the low suspicion group was test positive. The relative risk of a positive test (ELISA and PCR) in the high suspicion group was 3.7 times that for the moderate-suspicion group and 22.8 times that for the low suspicion group. There was no significant difference in the relative risk of a positive test result between the moderate and low suspicion groups. The results indicate that FeL V detection by PCR can be adapted for diagnostic purposes using peripheral blood samples, however, results do not differ significantly from FeL V ELISA results. Also, a proportion of cats with a high suspicion of having FeL V-related cytopenia and hemopoietic tumors are negative for both circulating FeL V antigen and DNA. These cats may not have FeL V-related disease, or FeL V may exist in a disease-producing but nonreplicating form ultimately detectable by PCR in tissues other than peripheral blood.

Exercise-induced collapse of Labrador retrievers: survey results and preliminary investigation of heritability.

Completed surveys were obtained from owners of 225 Labrador retrievers affected by the syndrome of exercise-induced collapse. Questions addressed signalment, age of onset, description of collapse episodes, and owner perception of activities and factors associated with collapse. Most dogs were young (mean 12 months) when collapse episodes began. Retrieving was the activity most commonly associated with collapse. Owners felt that excitement (187/225; 83%) and high environmental temperatures (71/225; 31%) increased the likelihood of collapse. Analysis of pedigrees collected from 169 affected dogs was most consistent with an autosomal recessive mode of inheritance.

Presence and impact of the exercise-induced collapse associated DNM1 mutation in Labrador retrievers and other breeds

The impact of the mutation causing dynamin 1 (DNM1)-associated exercise-induced collapse (d-EIC) was determined in a retrospective genetic survey. The frequency of DNM1 mutant allele carriers in Labrador retrievers from conformation show, field trial/hunt test, pet or service lines ranged from 17.9% to 38.0% and the frequency of homozygous mutant (EE genotype) individuals ranged from 1.8% to 13.6%; 83.6% of these EE Labradors were reported to have collapsed by 4 years of age. DNM1 mutation carriers and EE dogs with a collapse phenotype were also detected in Chesapeake Bay retrievers, Curly-coated retrievers, Boykin spaniels, Pembroke Welsh corgis and mixed breed dogs thought to be Labrador retriever crosses. The DNM1 mutation was not identified in Golden, Flat-coated, or Nova Scotia duck tolling retrievers, or 15 other non-retrieving breeds. Veterinarians and breeders should be aware that the DNM1 EE genotype is not completely penetrant and that d-EIC is a widespread health concern in several very popular breeds, as well as breeds whose genetic similarity to retrievers is not obvious.

Evaluations of Labrador retrievers with exercise-induced collapse, including response to a standardized strenuous exercise protocol.

Clinical and metabolic variables were evaluated in 14 Labrador retrievers with exercise-induced collapse (EIC) before, during, and following completion of a standardized strenuous exercise protocol. Findings were compared with previously reported variables from 14 normal Labrador retrievers that participated in the same protocol. Ten of 14 dogs with EIC developed an abnormal gait during evaluation, and these dogs were significantly more tachycardic and had a more severe respiratory alkalosis after exercise compared to the normal dogs. Muscle biopsy characteristics and sequential lactate and pyruvate concentrations were normal. Genetic testing and linkage analysis excluded malignant hyperthermia as the cause of EIC. Common causes of exercise intolerance were eliminated, but the cause of collapse in EIC was not determined.

Selected Disorders of Muscle and the Neuromuscular Junction

A variety of disorders affect the muscles or the neuromuscular junction of dogs and cats, most often causing weakness, exercise intolerance, and muscular pain or atrophy. The myopathies are infectious, immune-mediated, inherited or acquired secondary to systemic disease. Acquired myasthenia gravis is a common disorder of the neuromuscular junction, which clinically resembles a myopathy. Reaching a specific diagnosis is essential to determine optimal therapy and prognosis for each of the commonly recognized disorders.