Impaired NDRG1 functions in Schwann cells cause demyelinating neuropathy in a dog model of Charcot-Marie-Tooth type 4D.

Mutations in the N-myc downstream-regulated gene 1 (NDRG1) cause degenerative polyneuropathy in ways that are poorly understood. We have investigated Alaskan Malamute dogs with neuropathy caused by a missense mutation in NDRG1. In affected animals, nerve levels of NDRG1 protein were reduced by more than 70% (p< 0.03). Nerve fibers were thinly myelinated, loss of large myelinated fibers was pronounced and teased fiber preparations showed both demyelination and remyelination. Inclusions of filamentous material containing actin were present in adaxonal Schwann cell cytoplasm and Schmidt-Lanterman clefts. This condition strongly resembles the human Charcot-Marie-Tooth type 4D. However, the focally folded myelin with adaxonal infoldings segregating the axon found in this study are ultrastructural changes not described in the human disease. Furthermore, lipidomic analysis revealed a profound loss of peripheral nerve lipids. Our data suggest that the low levels of mutant NDRG1 is insufficient to support Schwann cells in maintaining myelin homeostasis.

Calcification of extruded intervertebral discs in dachshunds: a radiographic, computed tomographic and histopathological study of 25 cases.

BACKGROUND: Three Nordic countries have national breeding programs to reduce the frequency of intervertebral disc disease in dachshunds. The programs include a radiographic examination of the vertebral column and dachshunds with more than four calcified discs visible on radiographs (CDVR) are discouraged from use in breeding. However, disc extrusion is also diagnosed in dachshunds without CDVR. The utility of the breeding programs is therefore questioned. RESULTS: A prospective study of 25 dachshunds surgically treated for disc extrusion was conducted. For all the dogs, preoperative radiographs were evaluated for detectable disc calcifications and preoperative computed tomography (CT) scans were evaluated for presence of calcified material in the vertebral canal. Postoperatively, extruded disc material was examined for degeneration and calcification by histology. Diagnostic imaging and histology were done independently. Radiographically visible calcification was identified in 17 (68.0%) of 25 extruded discs. Calcification was seen in the disc space for all these 17 discs, and for eight of the 17, there was also calcified material visible in the vertebral canal. Extruded material from all the 25 discs was found to be calcified, both by CT and histopathology. CONCLUSIONS: In dachshunds with acute disc extrusion, radiographically visible calcification will frequently be found in the affected disc space, but not all affected disc spaces contain radiographically visible calcification. Using histopathology as the gold standard, a sensitivity of 0.3 (8/25) for radiography and 1.0 (25/25) for CT was found for detecting calcified disc material in the vertebral canal. Further, a sensitivity of 0.7 (17/25) was found for radiography for detecting remaining calcified material in the disc space. Thus, extruded disc material should be considered to be calcified, even in the absence of radiographically visible calcification.

Re-emergence of hereditary polyneuropathy in Scandinavian Alaskan malamute dogs-old enemy or new entity? A case series.

A homozygous mutation has been identified in the N-myc downstream-regulated gene 1 (NDRG1) in recent cases of polyneuropathy in Alaskan malamute dogs from the Nordic countries and USA. The objective of the present study was to determine if cases diagnosed 30-40 years ago with polyneuropathy in the Alaskan malamute breed in Norway had the same hereditary disease as the recent cases. Fourteen historical cases and 12 recently diagnosed Alaskan malamute dogs with hereditary polyneuropathy, and their parents and littermates (n = 88) were included in this study (total n = 114). After phenotyping of historical and recent cases, NDRG1 genotyping was performed using DNA extracted from archived material from five Norwegian dogs affected by the disease in the late 1970s and 1980s. In addition, pedigrees were analysed. Our study concluded that historical and recent phenotypic polyneuropathy cases were carrying the same NDRG1-mutation. The pedigree analysis showed that all affected Alaskan malamute cases with polyneuropathy could be traced back to one common ancestor of North American origin. By this study, a well-documented example of the silent transmission of recessive disease-causing alleles through many generations is provided, demonstrated by the re-emergence of a phenotypically and genetically uniform entity in the Scandinavian Alaskan malamute population.

Acute non-ambulatory tetraparesis with absence of the dens in two large breed dogs: case reports with a radiographic study of relatives.

BACKGROUND: Non-ambulatory tetraparesis with an absence of the dens of C2 (axis) has not previously been reported in large breed dogs. An absence or hypoplasia of the dens has been reported in both small, medium and large breed dogs, but not in closely related animals. METHODS: Two young large-breed dogs (a German shepherd and a Standard poodle) both with an acute onset of non-ambulatory tetraparesis were subjected to physical, neurological and radiographic examinations. Both dogs were euthanased and submitted for postmortem examination within one week of onset of clinical signs. To investigate possible heritability of dens abnormalities, oblique radiographs of the cranial cervical vertebrae were taken of nine and eighteen dogs related to the German shepherd and the Standard poodle, respectively. RESULTS: Absence of the dens, atlantoaxial instability and extensive spinal cord injury was found in both case dogs. Radiographs revealed a normal dens in both parents and in the seven littermates of the German shepherd. An absence or hypoplasia of the dens was diagnosed in six relatives of the Standard poodle. CONCLUSIONS: Atlantoaxial subluxation with cervical spinal cord injury should be considered as a differential diagnosis in non-ambulatory tetraparetic young large breed dogs. Absence of the dens and no history of external trauma increase the likelihood for this diagnosis. This study provides evidence to suggest that absence or hypoplasia of the dens is inherited in an autosomal way in Standard poodle dogs.

A Gly98Val mutation in the N-Myc downstream regulated gene 1 (NDRG1) in Alaskan Malamutes with polyneuropathy.

The first cases of early-onset progressive polyneuropathy appeared in the Alaskan Malamute population in Norway in the late 1970s. Affected dogs were of both sexes and were ambulatory paraparetic, progressing to non-ambulatory tetraparesis. On neurologic examination, affected dogs displayed predominantly laryngeal paresis, decreased postural reactions, decreased spinal reflexes and muscle atrophy. The disease was considered eradicated through breeding programmes but recently new cases have occurred in the Nordic countries and the USA. The N-myc downstream-regulated gene (NDRG1) is implicated in neuropathies with comparable symptoms or clinical signs both in humans and in Greyhound dogs. This gene was therefore considered a candidate gene for the polyneuropathy in Alaskan Malamutes. The coding sequence of the NDRG1 gene derived from one healthy and one affected Alaskan Malamute revealed a non-synonymous G>T mutation in exon 4 in the affected dog that causes a Gly98Val amino acid substitution. This substitution was categorized to be "probably damaging" to the protein function by PolyPhen2 (score: 1.000). Subsequently, 102 Alaskan Malamutes from the Nordic countries and the USA known to be either affected (n = 22), obligate carriers (n = 7) or healthy (n = 73) were genotyped for the SNP using TaqMan. All affected dogs had the T/T genotype, the obligate carriers had the G/T genotype and the healthy dogs had the G/G genotype except for 13 who had the G/T genotype. A protein alignment showed that residue 98 is conserved in mammals and also that the entire NDRG1 protein is highly conserved (94.7%) in mammals. We conclude that the G>T substitution is most likely the mutation that causes polyneuropathy in Alaskan Malamutes. Our characterization of a novel candidate causative mutation for polyneuropathy offers a new canine model that can provide further insight into pathobiology and therapy of human polyneuropathy. Furthermore, selection against this mutation can now be used to eliminate the disease in Alaskan Malamutes.

Gold Bead Implantation in Acupoints for Coxofemoral Arthrosis in Dogs: Method Description and Adverse Effects.

Gold bead implantation has been used for years as an alternative method to improve function in chronic joint disease both in humans and dogs. The aims of the present study were to describe the technique of implanting 24-karat gold beads around the hip joints of dogs with chronic hip dysplasia, and to record any side effects or complications of such treatment. A prospective placebo-controlled double-blinded clinical trial was performed. Eighty dogs were randomly allocated to treatment or placebo, with 38 in the gold implantation group and 42 in the placebo group, and followed intensely for six months. The implantation technique was simple to perform, using fluoroscopy and with the dogs under inhalation anesthesia for about 30 minutes. Adverse effects, measured as pain or discomfort, were seen for a period of up to four weeks in 15 of the dogs in the gold implantation group, compared to six dogs in the placebo group. During implantation, a technical difficulty occurred as 82% of the dogs showed leakage of blood and/or synovia from the needles. The dogs in the gold implantation group were radiographed 18 months later. Of the 30 dogs that were radiographed at both inclusion and 24 months, 80% (24 dogs) showed a deterioration of the coxofemoral arthrosis, the other six had stable disease evaluated by radiography. Migration of gold beads was only observed in one dog.

Cervical chondroid chordoma in a standard dachshund: a case report.

A ten-year-old male standard dachshund was presented with a history of neck pain and progressive gait disturbances. Following a neurological examination and diagnostic imaging, including CT, a neoplastic lesion involving the third and fourth cervical vertebrae was suspected. The lesion included an extradural mass on the right side of the spinal canal causing a local compression of the cervical cord. Surgery, using a modified dorsal laminectomy procedure, was performed in order to decompress the cervical spinal cord. Histopathological examination of the extradural mass indicated that the tumour was a chondroid chordoma. Following discharge, the quality of life for the dog was very good for a sustained period, but clinical signs recurred at 22 months. The dog was euthanased 25 months post-surgery. On post-mortem examination, a regrowth of neoplastic tissue was found to have infiltrated the bone and spinal cord at C3-C4. This is the first report to show that palliative surgery can offer successful long-lasting treatment of chondroid chordoma of the cervical spine in the dog.

Early recurrence of thoracolumbar intervertebral disc extrusion after surgical decompression: a report of three cases.

Thoracolumbar disc extrusions were diagnosed in three chondrodystrophic dogs with paraparesis of up to three days duration. All cases were managed by hemilaminectomy and removal of extruded disc material. In one dog, fenestration of the herniated disc space was also performed. Initially neurological function improved or was unchanged, but from two to ten days postoperatively clinical signs of deterioration became apparent. In all the dogs, recurrence of disc extrusion at the same location as the initial extrusion was diagnosed by computer tomography and at a second surgery abundant disc material was found at the hemilaminectomy site between the dura and an implanted graft of autogenous fat.

A retrospective epidemiological study of clinical signs and familial predisposition associated with aseptic meningitis in the Norwegian population of Nova Scotia duck tolling retrievers born 1994-2003.

Aseptic meningitis (AM) is a disease that causes grave clinical signs such as intensive neck pain, fever, and lethargy. The severity of this disease is reflected in the fact that affected animals require long-term, and in chronic cases, lifelong therapy with corticosteroids. A number of dogs must be euthanized because of therapeutic failure. In recent years, the Norwegian population of Nova Scotia duck tolling retrievers has experienced an increase in individuals with AM. The aim of the present study was to investigate the prevalence of AM and to pursue the suspicion of hereditary factors influencing an accumulation of AM cases in the breed. Using the Norwegian Kennel Club registery, a random sample (362 dogs) stratified by year of birth was drawn from the total population born from 1994 to 2003 (1525 individuals). The owners were contacted and questioned about clinical signs of AM in their dogs. Subsequently, the practising veterinarians and the breeders of positive responders were contacted in order to confirm a clinical diagnosis of AM and to identify possible affected family members. Pedigrees of AM positive individuals and affected relatives were investigated. The study estimated a prevalence of AM of 2.5%. For all affected dogs, it was possible to trace the pedigree of both parents of affected dogs back to a specific founder dog. The genealogical investigation strongly indicates that genetic factors are involved in the etiology of the disease.

Calcification of intervertebral discs in the dachshund: a radiographic and histopathologic study of 20 dogs.

BACKGROUND: The purpose of the study was to compare radiographic and histopathologic findings with regard to number and extent of calcified discs in the dachshund. METHODS: The intervertebral discs of 20 dachshunds were subjected to a radiographic and histopathologic examination. The dogs were selected randomly from clinical cases euthanased for reasons unrelated to research at the Norwegian School of Veterinary Science. Lateral radiographs were taken of the vertebral columns after removing them from the carcasses. The histopathologic examination included 5 microm thick sections in the transverse plane, stained with hematoxylin-eosin and von Kossa. Radiographs and histological sections were evaluated independently. RESULTS: A total of 148 (28.5%) calcified discs were identified at the radiographic and 230 (45.7%) at the histopathologic examination. Of 92 discs found to be calcified by histopathology, but not by radiography, the degree of calcification was evaluated as 'slight' in 84 (91.3%). All the intervertebral discs (n = 138) that were found to be calcified by radiography were also found to be calcified by histopathology. CONCLUSION: A sensitivity of 0.6 and specificity of 1.0 for radiography was calculated when using histopathology as the gold standard.