Degenerative Myelopathy in a Bernese Mountain Dog with a Novel SOD1 Missense Mutation

Abstract

A n 8-year-old female spayed Bernese Mountain Dog (BMD) presented to the Bush Veterinary Neurology Service (BVNS) for paraparesis. The dog had been seen at the BVNS 13 months earlier for evaluation of progressive pelvic limb weakness. At that time, the dog had a short-strided gait in the pelvic limbs, mild postural reaction deficits in the right pelvic limb, normal segmental reflexes, and laxity of the right coxofemoral joint. The dog was treated with meloxicam (0.15 mg/kg PO q24h) for 3 days, amantidine (2 mg/kg PO q24h) for 1 month, and doxycycline (6 mg/kg PO q12h) for 2 weeks with no improvement noted. The dog had a previous history of hypothyroidism that had been treated with 0.3 mg levothyroxine PO q12h.Asymmetric general proprioceptive ataxia and spastic paraparesis were present on neurologic examination. Postural reactions were delayed in both pelvic limbs and segmental reflexes were normal. Initial diagnostic tests included a CBC, serum biochemistry, and thoracic and spinal radiographs. The results of all tests were within normal limits. A DNA test for the SOD1:c.118G 4 A mutation commonly associated with canine degenerative myelopathy (DM) was normal (homozygous for the G allele).1 Physiotherapy was initiated. Sixteen months after the initial presentation, signs had progressed to paraplegia with preservation of pain perception. Decreased patellar and withdrawal reflexes were present in both pelvic limbs and suggested neurodegeneration that had progressed to include the lower motor neurons associated with the femoral and sciatic nerves. Analysis of cerebrospinal fluid obtained by atlantooccipital puncture revealed mild albuminocytologic dissociation with a protein concentration of 30 mg/dL and no nucleated cells. Magnetic resonance imaging of the spinal cord was performed 21 months after the initial presentation with a 1.5 T unit, a T2-weighted (T2W), T1-weighted (T1W), and half Fourier acquisition single-shot turbo spin echo (HASTE) sagittal sequences were acquired from the foramen magnum to the sacrum. Transverse T2W, T1W, and T1W postcontrast b weighted images were acquired from T12 to L4. Spondylosis and a mildly increased signal within the dorsal funiculus of the spinal cord were noted at the T12-13 disc space on T2W images. The T12-13 disc was well hydrated and similar in size to adjacent discs.The dog was euthanized 21 months after the initial presentation because the disease had progressed to include fecal and urinary incontinence. Histopathologic evaluation of formalin-fixed spinal cord was performed at the University of Missouri Veterinary Medical Diagnostic Laboratory. Spinal cord cross sections were stained by standard methods with luxol fast blue (LFB), and periodic acid Schiff (PAS) as a counter stain. Immunostaining was performed to detect phosphorylated neurofilament and glial fibrillary acid protein (GFAP) as a measure of axonal loss and gliosis, respectively. Deparaffinized sections were treated with rabbit anti-GFAP antibody c without pretreatment, and binding was detected with horser...

Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy

“…Homozygosity for the variant allele was associated with risk of developing DM in five dog breeds (17). A separate SOD1 missense mutation has been discovered in Bernese Mountain Dogs, but has only been detected in that specific breed so far (23,24). Biochemical characterization of the two canine SOD1 mutant proteins indicated the increased propensity to form protein aggregates with retained enzymatic activity, supporting a toxic gain-of-function role in canine DM similar to that role in human ALS (25).…”

Accumulation and aggregate formation of mutant superoxide dismutase 1 in canine degenerative myelopathy

“…The resequencing of SOD1 from normal and DM-affected dogs revealed a c.118G >A missense mutation in exon 2 that predicted an E40K substitution (Awano et al, 2009). A homozygous c.52A > T missense mutation was more recently identified in the SOD1 gene in a Bernese Mountain Dog, which predicted a T18S substitution (Wininger et al, 2011) proposed to represent a spontaneous animal model of a SOD1-mediated human neurodegenerative disorder, namely amyotrophic lateral sclerosis (ALS) (Boillee et al, 2006). A recent study characterizing the biochemical properties of canine mutant SOD1 further indicated a strong link between SOD1-mediated diseases in humans and dogs (Crisp et al, 2013).…”

Genotyping Assays for the Canine Degenerative Myelopathy-Associated c.118G>A (p.E40K) Mutation of the <i>SOD1</i> Gene Using Conventional and Real-Time PCR Methods: A High Prevalence in the Pembroke Welsh Corgi Breed in Japan

“…Therefore, it is important to clarify the incidence of DM and identify other factors involved in the onset of DM. More recently, another novel DM-associated mutation was identified as c.52A>T (p.T18S) in a Bernese Mountain Dog [9], which is also known as a breed predisposed to DM [3,4]. Based on these observations, veterinarians should know that the genotyping assays for the c.118G>A mutation have application limits.…”