Description

Canine degenerative myelopathy (DM) is a slowly, progressive adult-onset neurodegenerative disease causing paralysis similar to human amyotrophic lateral sclerosis (ALS – Lou Gehrig’s disease). Canine DM was first described by Averill in 1973 as an insidious, progressive, general proprioceptive (GP) ataxia and upper motor neuron (UMN) spastic paresis of the pelvic limbs ultimately leading to paraplegia and necessitating euthanasia.1 Although initially described in German Shepherd dogs (Averill 1973; Braund 1978), DM is now being recognized as a common neurologic problem in many pure breeds and mixed breeds (Zeng et al., 2014). 

Disease etiology

Hereditary disease and genetic predisposition.

Clinical presentation

Dogs with DM exhibit a predictable pattern of clinical signs that begins with UMN pelvic limb paresis and GP ataxia, progress to LMN paraparesis, and then spreads to involve the thoracic limbs and brainstem (Coates et al., 2007; Coates and Wininger 2010; Johnston et al., 2000).  The clinical course of DM is rather uniform after the presumptive diagnosis but ambulatory (paresis/ataxia) to nonambulatory status occurs within a median time of 10 months (95% CI, 9-12; unpublished data, Kanazono et al., 2012) from onset of signs. Pet owners usually elect euthanasia when their dogs can no longer support weight in their pelvic limbs.  The pet owner can care for smaller dogs over a longer time.  The median disease duration in the Pembroke Welsh Corgi was 19 months (Coates et al., 2007). 

Treatment

Pharmacotherapies including drugs and nutritional supplements for canine DM have been advocated; however, the efficacies of these therapies have not been established.  The long-term prognosis of DM is poor.  Mechanisms for inducing silencing of protein coding genes for SOD1 in ALS like small interfering-RNA, micro-RNA, and antisense oligonucleotides are undergoing clinical trial testing in dogs affected with DM.

Although well-controlled studies are still needed to establish efficacy, physical rehabilitation may have positive effects in early DM.  Kathmann et al. reported survival data from 22 DM affected dogs that received varying degrees of physiotherapy (Kathmann et al., 2006).  Dogs that received intensive physiotherapy had significantly longer survival times (mean = 255 days) compared to dogs that received moderate (mean = 130 days) or no physiotherapy (mean = 55 days).  Study limitations included lack of randomization and definitive diagnosis, small group size, and bias from owner perception; still results warrant further investigation into the efficacy of rehabilitation in DM-affected dogs. 

Recent Publications

Averill DR. Degenerative myelopathy in the aging German Shepherd dog: clinical and pathologic findings. J Am Vet Med Assoc 1973;162:1045-1051, 1973.

Awano T, Johnson GS, Wade CM, et al. Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2009;106:2794-2799.

Braund KG, Vandevelde M: German Shepherd dog myelopathy--a morphologic and morphometric study. American Journal of Veterinary Research, 1978;39(8):1309-1315.

Chang RC, Parakh S, Coates JR, Long S, Atkin JD. Protein disulphide isomerase is associated with mutant SOD1 in canine degenerative myelopathy.  NeuroReport 2019;30:8-13

Coates JR, March PA, Oglesbee M, et al. Clinical characterization of a familial degenerative myelopathy in Pembroke Welsh Corgi dogs. J Vet Intern Med 2007;21:1323-1331.

Coates JR, Wininger FA.: Canine degenerative myelopathy, Vet Clin North Am Small Anim Pract 2010;40:929-950.

Crisp MJ, Beckett J, Coates JR, Miller TM. Canine degenerative myelopathy: biochemical characterization of superoxide dismutase 1 in the first naturally occurring non-human amyotrophic lateral sclerosis model. Exp Neurol 2013;248:1-9.

Fernandez-Trapero M, Espejo-Porras, F, Coates JR, Perez-Diaz C, de Lago E, Fernandez-Ruiz J. Up-regulation of CB2 receptors in reactive astrocytes in canine degenerative myelopathy, a disease model of amyotrophic lateral sclerosis. Disease Models & Mechanisms. 2017;10:551-558. 9 PMID: 28069688; DOI: 10.1242/dmm.028373

Golubczyk D, Malysz-Cymborska I, Kalkowski L, Janowski M, Coates JR, Wojtkiewica J, Maksymowicz W, Walczak P. The role of glia in canine degenerative myelopathy:  Relevance to human amyotrophic lateral sclerosis. Mol Neurobio 2019. https://doi.org/10.1007/s12035-019-1488-3 

Ivansson EL, Megquier K, Kozyrev SV, et al. Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy. Proc Natl Acad Sci U S A 2016;3091-3100.

Johnston PEJ, Barrie JA, McCulloch MC, et al. Central nervous system pathology in 25 dogs with chronic degenerative radiculomyelopathy. Vet Rec 2000;146:629-633.

Kanazono S, Pithua P, Johnson GC, et al. Clinical progression of canine degenerative myelopathy. J Vet Int Med 2013;27:673-674.

Kathmann I, cizinauskas S, Doherr MG, et al. Daily controlled physiotherapy increases survival time in dogs with suspected degenerative myelopathy, J Vet Intern Med 2006;20:927-932.

Katz ML, Jensen CA, Student JT, Johnson GC, Coates JR.  Cervical spinal cord and motor unit pathology in a canine model of SOD1-associated amyotrophic lateral sclerosis. Journal of the Neurological Sciences 2017;378:193-203. http://www.sciencedirect.com/science/article/pii/S0022510X17303052 

Kobatake Y, Sakai H, Tsukui T, Yamato O, Kohyama M, Sasaki J, Kato S, Urushitani M, Maeda S, Kamishina H.  Localization of a mutant SOD1 protein in E40K-heterozygous dogs: Implications for non-cell-autonomous pathogenesis of degenerative myelopathy. J Neurol Sci 2017;372:369-378.

Lovett MC, Coates JR, Shu Y, et al. Quantitative assessment of hsp70, IL-1beta and TNF-alpha in the spinal cord of dogs with E40K SOD1-associated degenerative myelopathy. Vet J 2014;200;312-317.

March PA, Coates JR, Abyad RJ, et al. Degenerative myelopathy in 18 Pembroke Welsh Corgi dogs. Vet Pathol 2009;46:241-250.

Matthews NS, de Lahunta A. Degenerative myelopathy in an adult miniature poodle. J Am Vet Med Assoc 1985;186:1213-1215.

Morgan BR, Coates JR, Johnson GC, et al. Characterization of intercostal muscle pathology in canine degenerative myelopathy: A disease model for amyotrophic lateral sclerosis. J Neurosci Res 2013;91:1639–1650.

Morgan BR, Coates JR,  Johnson GC, Shelton GD, Katz ML. Characterization of thoracic motor and sensory neurons and spinal nerve roots in canine Degenerative myelopathy, a potential disease model of amyotrophic lateral sclerosis. J Neurosci Res 2014;92:531–541.

Nakamae S, Kobatake Y, Suzuki R, et al. Accumulation and aggregate formation of mutant superoxide dismutase 1 in canine degenerative myelopathy. Neurosci 2015;303:229-240.

Ogawa M, Uchida K, Yamato O, et al. neuronal loss and decreased GLT-1 expression observed in the spinal cord of Pembroke Welsh corgi dogs with canine degenerative myelopathy. Vet Path 2013;51(3):591-602. 

Ogawa M, Uchida K, Yamato O, et al. Expression of autophagy-related proteins in the spinal cord of Pembroke Welsh corgi dogs with canine degenerative myelopathy. Vet Pathol 2015;52:1099-1107.

Oyake K, Kobatake Y, Shibata S, et al. Changes in respiratory function in Pembroke Welsh corgi dogs with degenerative myelopathy. J Vet Med Sci 2016;78:1323-1327.

Pfahler S, Bachmann N, Fechler C, et al. Degenerative myelopathy in a SOD1 compound heterozygous Bernese mountain dog. Anim Genet 2014;45:309-310.

Polizopoulou ZS, Koutinas AF, Patsikas MN, et al. Evaluation of a proposed therapeutic protocol in 12 dogs with tentative degenerative myelopathy. Acta Vet Hung 2008;56:293-301.

Shelton GD, Johnson GC, O’Brien DP, et al. 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 2012;318:55-64.

Toedebusch CM, Snyder JC, Jones MR, et al. Arginase-1 expressing microglia in close proximity to motor neurons were increased early in disease progression in canine degenerative myelopathy, a model of amyotrophic lateral sclerosis. Mol Cell Neurosci 2018;88:148-157.

Toedebusch CM*, Bachrach M, Garcia VB, Johnson GC, Shaw GPJ, Coates JR§, Garcia ML.  Cerebrospinal fluid phosphorylated neurofilament heavy as a diagnostic marker of canine degenerative myelopathy.  Journal of Veterinary Internal Medicine 2017;31:513-520. Epublished 2017 Feb 10. doi: 10.1111/jvim.14659.  PMID 28186658 https://www.ncbi.nlm.nih.gov/pubmed/28186658

Wininger FA, Zeng R, Johnson GS, et al. Degenerative myelopathy in a Bernese mountain dog with a novel SOD1 missense mutation. J Vet Intern Med 2011;25:1166-1170.

Yokota S, Kobatake Y, Noda Y, Nakata K, Yamato O, Hara H, et al., Activation of the unfolded protein response in canine degenerative myelopathy.  Neurosci Letters 2018;687:216-222.

Zeng R, Coates JR, Johnson GC, Hansen L, Awano T, Kolicheski A, Ivansson E, Perloski M, Lindblad-Toh K, O’Brien DP, Guo J, Katz ML, Johnson GS. Breed distribution of SOD1 alleles previously associated with canine degenerative myelopathy.  Journal of Veterinary Internal Medicine.  2014;28:515-521.  http://onlinelibrary.wiley.com/doi/10.1111/jvim.12317/abstract; PMID: 24524809