A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy.

A juvenile form of paroxysmal dyskinesia segregated in the Markiesje dog breed. Affected pups exhibited clinical signs of a severe tetraparesis, dystonia, cramping and falling over when trying to walk. In most cases, the presentation deteriorated within weeks and elective euthanasia was performed. Pedigree analysis indicated autosomal recessive inheritance. Genome-wide association and homozygosity mapping of 5 affected dogs from 3 litters identified the associated locus on chromosome 31 in the region of SOD1. The DNA sequence analysis of SOD1 showed that the patients were homozygous for a frameshift mutation in the fourth codon. None of the other analyzed dogs of the breed was homozygous for the mutation, indicating full penetrance of the genetic defect. Mutations in SOD1 are known to cause recessive degenerative myelopathy in middle-aged dogs with low penetrance and dominant amyotrophic lateral sclerosis in humans with variable age of onset. Our findings are similar to recent observations in human patients that a loss of function mutation in SOD1 leads to a juvenile neurologic disease distinct from amyotrophic lateral sclerosis.

Canine NAPEPLD-associated models of human myelin disorders.

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.

Gastric carcinoma in canines and humans, a review.

Gastric carcinoma (GC) is the most common neoplasm in the stomach of dogs. Although incidence in the general population is reported to be low, breed-specific GC has a high incidence. Median age at presentation ranges from 8 to approximately 10 years. The disease is mostly located in the lesser curvature and antropyloric region of the stomach. Unfortunately, diagnosis is usually made when the disease is at an advanced stage and, therefore, prognosis is poor. Due to similarities in clinical presentation, diagnosis, histology and prognosis, canine GC may serve as a valuable model for human GC. Extensive pedigrees of canine gastric carcinoma cases could reveal insights for human gastric carcinoma. Putative species differences include the role of Helicobacter in pathogenesis, the wide array of genetic data and screening available for humans, and treatment protocols that are available for human GC.

A randomized, open-label, positively-controlled field trial of a hydrolyzed protein diet in dogs with chronic small bowel enteropathy.

BACKGROUND: Hydrolyzed protein diets are commonly used to manage canine chronic enteropathies (CE), but their efficacy has not yet been critically evaluated. HYPOTHESIS: A hydrolyzed protein diet is superior to that of a highly digestible (control) diet in the management of CE in dogs. ANIMALS: Twenty-six dogs (18 test diet, 8 control diet) referred for investigation and management of naturally occurring chronic small intestinal disease. METHODS: Randomized, open-label, positively controlled trial. After a full diagnostic investigation, which included endoscopy, dogs were assigned either to the test diet or control diet on a 2:1 basis (test:control). Cases were re-evaluated 3 times (at approximately 3, 6-12 months, and 3 years). Outcome measures included response of clinical signs (complete, partial, none), change in severity of signs (based upon clinical disease activity index; canine inflammatory bowel disease activity index [CIBDAI]), change in body weight, and need for other therapy. RESULTS: There were no significant differences in baseline characteristics (eg, signalment, body weight, and duration of clinical signs), and histopathologic severity between test and control diet groups. However, despite randomization, CIBDAI was significantly higher in the test diet group (P=.013). Most dogs had responded by first evaluation, with no difference between groups (P=.87). However, significantly more dogs on the test diet remained asymptomatic at both the second (P=.0012) and third (P<.001) re-evaluation, and the decrease in CIBDAI was significantly greater (P=.010). CONCLUSIONS AND CLINICAL IMPORTANCE: A hydrolyzed protein diet can be highly effective for long-term management of canine chronic small bowel enteropathy.

Morbidity and mortality in 928 Dobermanns born in the Netherlands between 1993 and 1999.

The morbidity and mortality among 928 dobermann dogs born between 1993 and 1999 were investigated by sending questionnaires to their owners; 340 (37 per cent) responded. Eighty-one of the dogs had died. Proportional mortality was high for heart failure (14.8 to 22.2 per cent), behavioural problems (19.8 per cent) and cancer (13.6 per cent), but low for hepatitis (3.7 per cent) and cervical spondylomyelopathy (2.5 per cent). Of the 259 surviving dogs, 132 were suffering from various disorders, with a high prevalence of skin problems (22.4 per cent) and urinary incontinence (15.8 per cent).

Double-blind, placebo-controlled study of the efficacy of nandrolone laurate in the treatment of dobermanns with subclinical hepatitis.

Twenty-one three-year-old dobermanns with subclinical hepatitis were treated with nandrolone laurate or a placebo in a double-blind trial. The dogs were scored clinically before and after four months of treatment and they were evaluated by clinical biochemistry and liver biopsies. After the treatment no significant differences were observed between the two groups in any of the clinical biochemistry values; eight of the 21 dogs had no histological evidence of hepatitis and five other dogs had improved, but there was no significant difference between the responses of the two groups.

Improvement in liver pathology after 4 months of D-penicillamine in 5 doberman pinschers with subclinical hepatitis.

Five female Doberman Pinschers with increased hepatic copper concentrations and persistent (3-4 years) subclinical hepatitis were treated with D-penicillamine for 4 months. Before and after treatment, the dogs underwent clinical, hematologic (red blood cell, white blood cell, and differential and thrombocyte counts), and clinical chemistry (creatinine, alkaline phosphatase, alanine aminotransferase, and total bile acid concentrations) examinations, and liver biopsies were examined histologically and their copper content measured quantitatively. No adverse effects were observed during treatment, and CBC and serum chemistry test results did not change. The mean liver copper concentration was 1,036 mg/kg dry matter before treatment and decreased to 407 mg/kg after treatment (P = .03). The copper concentrations had decreased (by between 134 and 1,135 mg/kg dry matter) in all of the dogs. The histopathologic appearance had improved or returned to normal in all 5 dogs. We conclude that D-penicillamine effectively reduced copper retention in these dogs and improved the histopathologic appearance of the lesions. However, because D-penicillamine has both copper-chelating and anti-inflammatory properties, it is not possible to draw conclusions on the etiology of this disease.

Chronic hepatitis in Doberman pinschers. A review.

Chronic hepatitis in Doberman pinschers is predominantly seen in female dogs, usually between 4 and 7 years of age and was first recognized in the early eighties. The histopathological characteristics of Doberman hepatitis are those of micronodular cirrhosis with histological features of fibrosis, piece meal necrosis and progressive lymphocyte and plasma cell infiltration of the portal triads. Currently there are two hypotheses on the pathogenesis although neither of them has been elucidated. The first hypothesis is that of a copper toxicosis. The second is that of autoimmunity. Similarities and differences with other breeds and studies on both hypotheses are reviewed, as well as results of recent research of our group. Based on recent findings chronic hepatitis in Doberman pinschers is most likely to be a form of copper toxicosis. Although there are several indications that suggest autoimmunity as well, this still remains unclear.

Association between liver copper concentration and subclinical hepatitis in Doberman Pinschers.

The prevalence of subclinical hepatitis was investigated in a group of 106 randomly selected 3-year-old Doberman Pinschers. Histopathologic examination of liver samples from 65 dogs (52 dogs with high bile acids, alkaline phosphatase activity, or alanine aminotransferase activity or with copper granules in hepatocytes in a liver aspirate and 13 normal dogs) revealed subclinical hepatitis in 22 dogs (19 females and 3 males). Liver copper concentrations measured by instrumental neutron activation analysis was significantly higher (mean +/- SD; 419 +/- 414 microg/g dry matter) in dogs with hepatitis than those without liver disease (197 +/- 113 microg/g; P = .0008). At 2.6 +/- 0.6 years hepatitis persisted in 5 of 16 dogs available for examination. One dog with a high copper concentration but normal liver subsequently developed subclinical hepatitis after 3 years. During the follow-up period, the average copper concentration of the 6 dogs with persistent subclinical hepatitis was 939 +/- 299 microg/g and had continued to rise significantly (P = .02). The hepatitis in these dogs was associated with apoptotic hepatocytes and copper-laden Kupffer cells in centrolobular regions. The results of this study suggest that there is a relationship among copper storage, hepatocellular damage, and hepatitis in Doberman Pinschers.