Canine leukoencephalomyelopathy (LEMP) is a juvenile-onset neurodegenerative disorder of the CNS white matter currently described in Rottweiler and Leonberger dogs. Genome-wide association study (GWAS) allowed us to map LEMP in a Leonberger cohort to dog chromosome 18. Subsequent whole genome re-sequencing of a Leonberger case enabled the identification of a single private homozygous non-synonymous missense variant located in the highly conserved metallo-beta-lactamase domain of the N-acyl phosphatidylethanolamine phospholipase D ( NAPEPLD ) gene, encoding an enzyme of the endocannabinoid system. We then sequenced this gene in LEMP-affected Rottweilers and identified a different frameshift variant, which is predicted to replace the C-terminal metallo-beta-lactamase domain of the wild type protein. Haplotype analysis of SNP array genotypes revealed that the frameshift variant was present in diverse haplotypes in Rottweilers, and also in Great Danes, indicating an old origin of this second NAPEPLD variant. The identification of different NAPEPLD variants in dog breeds affected by leukoencephalopathies with heterogeneous pathological features, implicates the NAPEPLD enzyme as important in myelin homeostasis, and suggests a novel candidate gene for myelination disorders in people.

Background: Hypercalciuria and hyperoxaluria are risk factors for calcium oxalate ( CaOx) urolithiasis, but breed- specific reports of urinary metabolites and their relationship with stone status are lacking. Objective: To compare urinary metabolites ( calcium and oxalate) and blood ionized calcium ( iCa) concentrations between CaOx stone formers and breed- matched stone- free controls for the Miniature Schnauzer, Bichon Frise, and Shih Tzu breeds. Animals: Forty- seven Miniature Schnauzers ( 23 cases and 24 controls), 27 Bichons Frise ( 14 cases and 13 controls), and 15 Shih Tzus ( 7 cases and 8 controls). Methods: Prospective study. Fasting spot urinary calcium- to- creatinine and oxalate- to- creatinine ratios ( UCa/ Cr and UOx/ Cr, respectively) and blood iCa concentrations were measured and compared between cases and controls within and across breeds. Regression models were used to test the effect of patient and environmental factors on these variables. Results: UCa/ Cr was higher in cases than controls for each of the 3 breeds. In addition to stone status, being on a therapeutic food designed to prevent CaOx stone recurrence was associated with higher UCa/ Cr. UOx/ Cr did not differ between cases and controls for any of the breeds. Blood iCa was higher in cases than controls in the Miniature Schnauzer and Bichon Frise breeds and had a moderate correlation with UCa/ Cr.Conclusions and Clinical Importance: Hypercalciuria is associated with CaOx stone status in the Miniature Schnauzer, Bichon Frise, and Shih Tzu breeds. UOx/ Cr did not correlate with stone status in these 3 breeds. These findings may influence breed- specific stone prevention recommendations.

BACKGROUND:Variants in the serine protease inhibitor Kazal type 1 (SPINK1) gene have been associated with pancreatitis in Miniature Schnauzers. Replication of the association in an independent population is necessary to determine if genetic screening for SPINK1 variants should be considered in clinical practice.HYPOTHESIS:An association between the SPINK1 exonic variant c.74A > C and pancreatitis exists in Miniature Schnauzers. In addition, the variant is absent or rare in Standard Schnauzers, a related breed that is not reported to have an increased risk for pancreatitis.ANIMALS:Case-control study. Seventeen Miniature Schnauzers with pancreatitis (cases), 60 mature Miniature Schnauzers with no substantial history of gastrointestinal signs in their lifetime (controls), and 31 Standard Schnauzers of unknown pancreatitis status.METHODS:A PCR-RFLP assay was used to genotype dogs for the c.74A > C SPINK1 variant. Allele and genotype frequencies were reported for Schnauzers and compared between case and control Miniature Schnauzers.RESULTS:The c.74A > C variant was the major allele in both Schnauzer breeds with a frequency of 0.77 in Miniatures and 0.55 in Standards. The allele and genotype frequencies were similar between Miniature Schnauzers with and without a history of pancreatitis and did not impart an increased risk for pancreatitis.CONCLUSIONS AND CLINICAL IMPORTANCE:Genotyping a larger population of the Miniature Schnauzer breed than a previous study, along with a Standard Schnauzer cohort, demonstrated that the SPINK1 c.74A > C variant is a common polymorphism in the Schnauzer lineage. Furthermore, we were unable to confirm a relationship between the variant and clinically detectable pancreatitis in Miniature Schnauzers.

BACKGROUND Paroxysmal dyskinesias are episodes of abnormal, involuntary movement or muscle tone, distinguished from seizures by the character of the episode and lack of seizure activity on ictal EEG. HYPOTHESIS Paroxysmal dyskinesia is an inherited, autosomal recessive disorder in Chinook dogs. ANIMALS Families of Chinook dogs with paroxysmal dyskinesia. METHODS Pedigrees and medical histories were reviewed for 299 Chinook dogs. A family of 51 dogs was used for analysis. Episodes were classified as seizures, paroxysmal dyskinesia, or unknown, and segregation analysis was performed. RESULTS Paroxysmal dyskinesia was identified in 16 of 51 dogs and characterized by an inability to stand or ambulate, head tremors, and involuntary flexion of 1 or multiple limbs, without autonomic signs or loss of consciousness. Episode duration varied from minutes to an hour. Inter-ictal EEGs recorded on 2 dogs with dyskinesia were normal. Three dogs with dyskinesia also had generalized tonic-clonic seizures. One of 51 dogs had episodes of undetermined type. Phenotype was unknown for 6 of 51 dogs, and 28 dogs were unaffected. Segregation was consistent with an autosomal recessive trait. CONCLUSIONS AND CLINICAL IMPORTANCE This movement disorder is prevalent in the Chinook breed, and consistent with a partially penetrant autosomal recessive or polygenic trait. Insufficient evidence exists for definitive localization; episodes may be of basal nuclear origin, but atypical seizures and muscle membrane disorders remain possible etiologies. The generalized seizures may be a variant phenotype of the same mutation that results in dyskinesia, or the 2 syndromes may be independent.

BackgroundThe placebo effect is a well-recognized phenomenon in human medicine; in contrast, little information exists on the effect of placebo administration in veterinary patients.HypothesisNonpharmacologic therapeutic effects play a role in response rates identified in canine epilepsy trials.AnimalsThirty-four dogs with epilepsy.MethodsMeta-analysis of the 3 known prospective, placebo-controlled canine epilepsy trials. The number of seizures per week was compiled for each dog throughout their participation in the trial. Log-linear models were developed to evaluate seizure frequency during treatment and placebo relative to baseline.ResultsTwenty-two of 28 (79%) dogs in the study that received placebo demonstrated a decrease in seizure frequency compared with baseline, and 8 (29%) could be considered responders, with a 50% or greater reduction in seizures. For the 3 trials evaluated, the average reduction in seizures during placebo administration relative to baseline was 26% (P = .0018), 29% (P = .17), and 46% (P = .01).Conclusions and Clinical ImportanceA positive response to placebo administration, manifesting as a decrease in seizure frequency, can be observed in epileptic dogs. This is of importance when evaluating open label studies in dogs that aim to assess efficacy of antiepileptic drugs, as the reported results might be overstated. Findings from this study highlight the need for more placebo-controlled trials in veterinary medicine.

Clinical and metabolic variables were evaluated in 14 Labrador retrievers with exerciseinduced 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.

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.

OBJECTIVE:To determine clinical characteristics and mode of inheritance of idiopathic epilepsy (IE) in English Springer Spaniels.DESIGN:Original study.ANIMALS:45 dogs with IE and 74 siblings and their respective parents.PROCEDURE:IE was diagnosed on the basis of age at the time of seizure onset and results of laboratory testing and neurologic examinations. Simple segregation analysis was performed with the Davie method.RESULTS:Median age at the onset of seizures was 3 years; however, 9 (20%) dogs were between 5 and 6 years old at the time of the onset of seizures. Twenty-one dogs (47%) had generalized seizures, and 24 (53%) had focal onset seizures. Results of segregation analysis were consistent with partially penetrant autosomal recessive or polygenic inheritance. Simulated linkage indicated that there was a 58% chance of obtaining suggestive linkage with the available pedigrees.CONCLUSIONS AND CLINICAL RELEVANCE:Results of the present study suggest that in English Springer Spaniels, IE segregates in a manner that is consistent with partially penetrant autosomal recessive inheritance (ie, a single major locus with modifying genes) or polygenic inheritance. Given enough families with accurate phenotypic information and available DNA, it should be possible to use genetic linkage analysis to identify chromosomal segments containing the causative gene or genes.

Medical record, seizure survey, and telephone interview information was obtained for 29 Vizslas with idiopathic epilepsy (IE), 74 unaffected siblings, and 41 parents to determine the common clinical characteristics and most likely mode of inheritance. IE was diagnosed on the basis of the age of seizure onset, laboratory results, and neurologic examination findings. Computerized tomography (CT) or magnetic resonance imaging (MRI) scan with cerebrospinal fluid (CSF) analysis was required for the inclusion of dogs with an age of seizure onset of < 6 months or > 5 years. Simple segregation analysis was performed with an ascertainment correction and chi-square analysis. IE appeared to be familial in these pedigrees, with 79% of affected Vizslas exhibiting partial onset seizures. Partial seizure signs included a combination of limb tremors, staring, pupillary dilatation, or salivation without loss of consciousness in > 50% of the dogs with partial signs. The estimated segregation frequency of P = .22 (95% CI, P = .08 to .36) was consistent with autosomal recessive inheritance; however, polygenic inheritance could not be excluded as a possibility. Simulated linkage with FASTSLINK estimated that the average logarithm of odds (LOD) score would be 3.23 with a 10-centimorgan (cM) whole-genome scan for these families, indicating that these families would be useful for a whole-genome scan to potentially find the chromosomal segment(s) containing the epilepsy gene or genes. We conclude that IE in Vizslas appears to be primarily a partial onset seizure disorder that may be inherited as an autosomal recessive trait.

A neonatal ataxia syndrome was observed in Coton de Tulear dogs. Seven affected pups (32%; 7/22) of both genders came from 5 different litters with phenotypically normal parents. Neurologic examination revealed normal mental status, head titubation, intention tremors, and severe gait, stance, and ocular ataxia beginning at 2 weeks of age. One of the pups was able to walk with assistance, but most of the affected pups were unable to stand and used propulsive movements ("swimming") for goal-oriented activities. They frequently would fall to lateral recumbency with subsequent decerebellate posturing and paddling. Ocular motor abnormalities included fine vertical tremors at rest and saccadic dysmetria. The condition was nonprogressive at least until 4 months of age. No specific abnormalities were identified in routine laboratory screening of blood and urine. Cerebrospinal fluid (CSF) analysis was normal in 1 dog, and a mild increase in protein concentration was observed in a second dog. CSF organic and amino acid concentrations were within normal limits. Magnetic resonance imaging and computed tomography of the brain, electromyography, motor nerve conduction studies, and brain stem auditory-evoked potentials were within normal limits. Postmortem examinations were performed on 5 affected dogs between 2 and 4 months of age. Routine light microscopic and immunocytochemical examination of brain, spinal cord, peripheral nerve, and muscle did not disclose any gross or histologic lesions. Compared with the cerebellum from an age-matched normal dog, the cerebellum from an affected dog showed synaptic abnormalities, including loss of presynaptic terminals and organelles associated with parallel fiber varicosities within the molecular layer and increased numbers of lamellar bodies in Purkinje cells. An autosomal recessive trait affecting development of the cerebellum is suspected.