Canis ISSN: 2398-2942

Degenerative myelopathy (DM)

Contributor(s): Kyle Braund, Simon Platt, Joan R Coates

Introduction

  • Canine degenerative myelopathy (DM) is a slowly, progressive adult-onset neurodegenerative disease causing paralysis similar to human amylotrophic lateral sclerosis (ALS).
  • Cause: DM is an inherited disease. Mutations in the superoxide dismutase 1 gene (SOD1)  underlie the risk of developing canine DM.
  • Signs: early disease - general proprioceptive ataxia and upper motor neuron (UMN) paraparesis.
  • Diagnosis: diagnosis of exclusion. Genetic testing will complement other antemortem diagnostics for DM. Most DM-affected dogs are homozygous for the SOD1:c.118G>A allele. 
  • Treatment: no effective treatment. Physiotherapy may improve quality of life (all unproven).
  • Prognosis: long-term poor; most dogs are nonambulatory by 10-12 months after onset of signs.
    Print off the owner factsheet on Degenerative myelopathy Degenerative myelopathy to give to your client.

Pathogenesis

Etiology

  • Inherited disease and genetic predisposition.
  • A  c.118G>A transition in Exon 2 of SOD1 that predicts an E40K missense mutation in SOD1, which underlies most cases of canine DM, has been identified.
  • Not all SOD1:c.118A homozygotes develop clinical signs. Initially DM appeared to be an autosomal recessive disease with incomplete penetrance; whereas most human SOD1 mutations are autosomal dominant. Thus, homozygosity for the E40K mutation in SOD1 is a major risk factor for canine DM.  More recently, DM has also been histopathologically confirmed in few heterozygous dogs.
  • A second SOD1 mutation (c.52 A> T) that predicts a T18S missense mutation in SOD1 has been identified in the Bernese Mountain Dog. This mutant c.52T allele appears to be restricted to the Bernese Mountain Dog breed where it is less common than the c.118A allele.

Pathophysiology

  • The etiology of degenerative myelopathy is a genetic mutation in SOD1, resulting in a toxic gain of function (the mutation results in misfolding of SOD1, causing abnormal accumulations of aggregates in the neuron).
  • The multifactorial pathogenesis of canine DM continues to be explored similarly as in ALS.
    • Excitotoxicity related to the reduced expression of GLT-1 may be involved in neuron loss in DM.
    • Abnormalities in the autophagy processes have been shown in the spinal cord of DM affected dogs.
    • Immunohistochemical detection of heat shock protein-70 (hsp70) was significantly increased in the spinal cord ependymal cells suggesting a potential neuroinflammatory signature in progression of canine DM.
  • Chronically affected DM dogs develop muscle atrophy consistent with denervation. Peripheral nerve pathology is consistent with an axonopathy and secondary demyelination.
  • The clinical and pathologic spectrums of DM has now been broadened to involve both the UMN and LMN systems and is considered a multi-system disease involving both central and peripheral axons.

Timecourse

  • Most dogs become nonambulatory within 12 months from time of onset of signs. 
  • If euthanasia is delayed, the signs insidiously progress over 3 to 4 years until death due to respiratory failure.

Diagnosis

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Treatment

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Prevention

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Outcomes

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Ivansson E L, Megquier K, Kozyrev S V et al (2016) Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy.  Proceedings of the National Academy of Sciences of the United States of America. Early Ed. April 15, 1-10 PubMed
  • Oyake K, Kobatake Y, Shibata S, Sakai H, Saito M, Yamato O, Kushida K, Maeda S, Kamishina H (2016) Changes in respiratory function in Pembroke Welsh Corgi dogs with degenerative myelopathy. J Vet Med Sci 78 (8), 1323-1327 PubMed.
  • Nakamae S, Kobatake Y, Suzuki R et al (2015) Accumulation and aggregate formation of mutant superoxide dismutase 1 in canine degenerative myelopathy. Neuroscience 303, 229-240 PubMed.
  • Ogawa M, Uchida K, Yamato O., Mizukami K, Chambers J K, Nakayama H (2015) Expression of autophagy-related proteins in the spinal cord of Pembroke Welsh Corgi dogs with canine degenerative myelopathy. Vet Pathol 52, 1099-1107 PubMed.
  • Lovett M C, Coates J R, Oglesbee M, Fenner W, Moore S A (2014) Quantitative assessment of HSP70, IL-1β and TNF-α in the spinal cord of dogs with E40K SOD1-associated degenerative myelopathy.  Vet J 200 (2), 312-317 PubMed.
  • Ogawa M, Uchida K, Yamato O, Inaba M, Uddin M M, Nakayama H (2014) Neuronal loss and decreased GLT-1 expression observed in the spinal cord of Pembroke Welsh Corgi dogs with canine degenerative myelopathy. Vet Pathol 51, 591-602 PubMed.
  • Pfahler S, Bachmann N, Fechler C et al (2014) Degenerative myelopathy in a SOD1 compound heterozygous Bernese Mountain dog. Animal Genetics 1-2 PubMed.
  • Zeng R, Coates J R, Johnson G C, Hansen L, Awano T, Kolicheski A, Ivansson E, Perloski M, Lindblad-Toh K, O’Brien DP, Guo J, Katz M L, Johnson G S (2014) Breed distribution of SOD1 alleles previously associated with canine degenerative myelopathy.  J Vet Int Med 28, 515-521 PubMed.
  • Shelton G D, Johnson G C, O’Brien D P et al (2012) Degenerative myelopathy associated with a missense mutation in the superoxide dismutase 1 (SOD1) gene progresses to peripheral neuropathy in Pembroke Welsh Corgis and Boxers.  J Neurol Sci 318, 55-64 PubMed.
  • Wininger F A, Zeng R, Johnson G S, Katz M L, Johnson G C, Bush W W, Jarboe J M, Coates J R (2011) Degenerative myelopathy in a Bernese Mountain Dog with a novel SOD1 missense mutation.  J Vet Int Med 25 (5), 1166-1170 PubMed.
  • Coates J R, Wininger F A (2010) Canine degenerative myelopathy.  Vet Clin N Am Sm Anim Pract 40 (5), 929-950 PubMed.
  • Awano T, Johnson G S, Wade C, Katz M L, Johnson G C, Taylor J F, Perloski M, Long S, March P A, Olby N J, Khan S, O’Brien D P, Lindblad-Toh K, Coates J R (2009) Genome-wide association analysis reveals a SOD1 missense mutation canine degenerative myelopathy that resembles amyotrophic lateral sclerosis.  Proceedings of the National Academy of Sciences of the United States of America 106 (8), 2794-2799 PubMed.
  • March P A, Coates J R, Abyad R, Williams D A, O’Brien D P, Olby N J, Keating J H, Oglesbee M (2009) Degenerative myelopathy in 18 Pembroke Welsh Corgi dogs.  Vet Pathol 46, 241-250 PubMed.
  • Polizopoulou Z S, Koutinas A F, Patsikas M N, Soubasis N (2008) Evaluation of a proposed therapeutic protocol in 12 dogs with tentative degenerative myelopathy. Acta Vet Hung 56 (3), 293-301 PubMed.
  • Coates J R, March P A, Oglesbee M, Ruaux C G, Olby N J, Berghaus R D, O'Brien D P, Keating J H, Johnson G S, Williams D A (2007) Clinical characterization of a familial degenerative myelopathy in Pembroke Welsh Corgi dogs. J Vet Intern Med 21 (6), 1323-1331 PubMed.
  • Kathmann I, Cizinauskas S, Doherr M G et al (2006) Daily controlled physiotherapy increases survival time in dogs with suspected degenerative myelopathy. J Vet Int Med 20, 927-932 PubMed.
  • Johnston P E J, Barrie J A, McCulloch M C, Anderson T J, Griffiths I R (2000) Central nervous system pathology in 25 dogs with chronic degenerative radiculomyelopathy. Vet Rec 146 (22), 629-633 PubMed.
  • Matthews N S & deLahunta A (1985) Degenerative myelopathy in an adult miniature poodle. JAVMA 186 (11), 1213-1215 PubMed.
  • Braund K G, Vandevelde M (1978) German Shepherd dog myelopathy - a morphologic and morphometric study. Am J Vet Res 39 (8), 1309-1315 PubMed.
  • Griffiths I R, Duncan I D (1975) Chronic degenerative radiculomyelopathy in the dog. Journal of Small Animal Practice 16 (8), 461-471 PubMed.
  • Averill D R (1973) Degenerative myelopathy in the aging German Shepherd dog: Clinical and pathologic findings. J Am Vet Med Assoc 162 (12), 1045-1051 PubMed.

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