Degenerative Myelopathy – Frequently Asked Questions

DM can occur in over 115 breeds, including: 

  • Most at risk breeds: German Shepherds, Pembroke Welsh Corgis, Boxers, Bernese Mountain Dogs, and Chesapeake Bay retrievers 
  • Many other purebred dogs and crosses such as American Eskimo Dog, Borzoi, Boxer Dog, Cardigan Welsh Corgi, Cavalier King Charles Spaniels Golden Retriever, Great Pyrenean Mountain Dog, Hovawart Dogs, Kerry Blue Terrier, Nova Scotia Duck Tolling Retriever, Poodle, Rhodesian Ridgeback, Rough Collie Shetland Sheepdog, Soft Coated Wheaten Terriers, Tibetan terriers.  

DM is caused by a "gain of function" mutation in the SOD1 gene (E40K). This mutation: 

  • Disrupts protein stability, leading to misfolding and aggregation of the SOD1 protein. 
  • Causes oxidative stress, impaired axonal transport, and mitochondrial dysfunction. 
  • Mimics some aspects of Amyotrophic Lateral Sclerosis (ALS) in humans. 
  • Is an autosomal recessive disorder (two copies of mutant gene) but may manifest in some heterozygous dogs (one copy of mutant genes). 

  • Most dogs are at least eight years of age when they begin to show clinical signs 
  • Initial signs: Subtle, non-painful hindlimb weakness, ataxia, and dragging paws (T3-L3 localisation plus L4 nerve roots). 
  • Progression: Hindquarter paralysis, loss of proprioception, muscle atrophy, and urinary/faecal incontinence. 
  • Advanced stages: Tetraplegia and respiratory failure.

  • Genetic Testing for SOD1 mutation: Detects risk of DM but does not confirm diagnosis. 
  • Exclusion Diagnosis:  
    • Rule out other spinal cord diseases like intervertebral disc disease (IVDD) and spinal tumours. 
    • Rule out co-morbidities that may also cause nerve cell dysfunction including  
      • Hypothyroidism (under-active thyroid gland) especially in susceptible breeds such as the Nova Scotia Duck Tolling Retriever, Boxer dog and Rhodesian ridgeback  
      • B12 and folate especially in breeds such as the German Shepherd that are predisposed to bowel disease with gut microbiome abnormalities. Gut disease should be addressed and Vitamin B12 and folate should be supplemented if deficient.  
  • Definitive Diagnosis: Postmortem and histopathology. 
  • Emerging Techniques: 

Degenerative myelopathy (DM) is primarily caused by mutations in the SOD1 gene, which encodes the enzyme superoxide dismutase 1. This enzyme plays a crucial role in protecting cells from oxidative damage by neutralizing reactive oxygen species. Below are key aspects of the genetics of DM: 

DM is generally inherited in an autosomal recessive manner, meaning that a dog must inherit two copies of the mutated SOD1 gene (one from each parent) to develop the disease. Dogs with one mutated copy and one normal copy are considered carriers and typically do not show clinical signs 

  • High-risk breeds: DM has a higher prevalence in breeds such as: 
    • German Shepherd Dogs 
    • Pembroke Welsh Corgis 
    • Boxers 
    • Chesapeake Bay Retrievers 
    • Rhodesian Ridgebacks 
    • Standard Poodles 
    • Cavalier King Charles spaniels 
  • In these breeds, the mutation frequency is significant, and genetic testing is recommended for breeding programs to reduce the spread of the disease.

Not all dogs with two copies of the mutated gene develop clinical signs of DM. This suggests that incomplete penetrance or other genetic and environmental factors may influence the onset and progression of the disease. 

For example, the SP110-mediated gene transcription affect the probability of getting DM in SOD-1 mutation homozygous Pembroke Welsh Corgi. Ongoing research aims to identify these modifiers and develop therapies targeting the effects of the SOD1 mutation. 

  • Purpose: Genetic testing for the SOD1 mutation helps identify at-risk dogs (homozygous mutants) and carriers (heterozygous). 
  • Procedure: Testing involves a simple cheek swab or blood sample, and results are classified as: 
    • Clear/Normal (no copies of the mutation) 
    • Carrier (one copy of the mutation) 
    • At-Risk (two copies of the mutation) 

  • Breeding two carriers can result in 25% of offspring being at risk for DM, 50% being carriers, and 25% being clear. 
  • Responsible breeding programs aim to minimize the number of carriers while maintaining genetic diversity within the breed. 

DM is progressive and fatal, with most dogs succumbing within months to a few years of diagnosis. Physiotherapy and consistent care can extend mobility and quality of life. 

DM is currently incurable; management focuses on improving quality of life and slowing progression. 

  • Nutritional supplementation for example with L-carnitine and omega three fatty acids (EPA, DHA).  
  • Curcumin shows promise for prolonging survival, although its effects require further study. 

  • Harnesses can be helpful to support a weak but ambulatory dog.  
  • Dogs that are unable to stand and walk on their hindquarters may benefit from using a cart (wheelchair).  
  • A “toe up sciatic sling” may assist dogs preventing paw knuckling; and “toe grips” can help limit toenail wear.   
  • Clients are encouraged to monitor quality of life using structured surveys (e.g., the AWAG)  
  • Useful links  

Mechanism of Action: 

  • Riluzole is an FDA-approved drug for Amyotrophic Lateral Sclerosis (ALS) in humans. 
  • It inhibits glutamate release, reducing glutamate excitotoxicity, which is implicated in motor neuron degeneration in DM. 

Rationale for Use in DM: 

  • DM shares pathological similarities with ALS, including motor neuron degeneration and glutamate toxicity. 
  • By mitigating neuronal damage, Riluzole is hypothesized to slow DM progression. 

Current Research: 

  • Clinical trials are ongoing to assess the safety and efficacy of Riluzole in dogs with DM. 
  • A multi-institutional study funded by the AKC Canine Health Foundation is evaluating its therapeutic potential and impact on quality of life. (AKCCHF, CVM NCSU)  

Study Design: 

  • Randomized, double-blind, placebo-controlled trials. 
  • Dogs are administered Riluzole or a placebo over a one-year period. 
  • Biomarkers, such as neurofilament light chain in cerebrospinal fluid and plasma, are used to monitor disease progression. 

Preliminary Findings: 

  • Initial phases confirm safety in canine subjects. 
  • Results regarding efficacy are pending as of December 2024. 

Dosage: 

  • A standardized dosing protocol has not been officially established. 
  • Dosing in trials is carefully monitored, and veterinarians are advised to await trial results before prescribing. 

Limitations: 

  • Long-term effects and efficacy in dogs remain unconfirmed. 
  • Expensive treatment and not yet widely available for veterinary use. 

Potential Benefits: 

  • Could delay progression of DM. 
  • May improve quality of life by protecting motor neurons. 

Advisory: 

  • Riluzole use outside clinical trials is not currently recommended until trials provide definitive evidence. 

Intensive Neurorehabilitation and Mesenchymal Stem Cell (MSC) Transplantation Protocol (INSCP): 

Study Design: A prospective controlled blinded cohort involving 13 dogs. 

  • INSCP group (n=8): Intensive rehabilitation and MSC transplantation. 
  • Ambulatory Rehabilitation Protocol (ARP) group (n=5): Less intensive rehabilitation without MSC transplantation. 

Study outcomes: 

  • Longer survival (438 days in INSCP vs. 274 days in ARP). 
  • Greater improvements in ambulation and neurological function in INSCP. 

Limitations: 

  • Small sample size and owner-driven treatment selection, and a lack of post-discharge intensive rehabilitation 
  • Inability to distinguish if MSC made any difference compared to intensive neurorehabilitation alone  
  • Uncontrolled Variables: The study does not account for confounding factors like variability in home care or prior treatments. Survival benefits may reflect broader care practices rather than INSCP direct effect 

PBMt may reduce inflammation, modulate astrocyte activity, and protect motor neurons through enhanced cellular energetics and reduced oxidative stress.  

Study Design:  retrospective analysis two PBMt protocols (PTCL-A: 6 dogs, PTCL-B: 14 dogs) to determine their effects on disease progression and survival in DM-affected dogs.  

  • PTCL-B (980 nm wavelength, continuous grid application, higher irradiance)  
  • PTCL-A (904 nm wavelength, point-to-point application). 
  • Both groups received intensive physical rehabilitation, including underwater treadmill exercises and at-home programs, which contributed to overall care. 

Study outcomes: 

  • Dogs in the higher irradiance, longer treatment group (PTCL-B) had significantly longer survival (38.2 months vs. 11.09 months). 
  • Improved time to non-ambulatory paresis in PTCL-B group (31.76 months vs. 8.79 months). 

Limitations: 

  • small sample size. 
  • Retrospective design lacks randomization and controls, increasing the risk of bias. 
  • Differences in baseline characteristics between PTCL-A and PTCL-B groups could confound results, even though statistical adjustments were made. 

 

Doses: 

  • DHA: 40 mg/kg/day. 
  • EPA: 25 mg/kg/day. 
  • L-Carnitine: 100 mg/kg/day. 
  • Coenzyme Q10: 100 mg/day. 

Limitations:  

Doses and use  

  • Prednisolone 0.5 mg/kg for 5-7 days, tapering thereafter and withdraw after 2 weeks. 
  • Has been recommended if acute deterioration and may see temporary improvement but not recommended long term. 

Limitations:  

  • Therapeutic protocol where prednisolone was given for the first two weeks and upon worsening of neurological signs and dogs also supplemented with ɛ-aminocaproic acid, N-acetylcysteine, vitamins B, C and E  did not appear to affect the course in 12 dogs  

  • 75mg/Kg divided in 3 doses a day for 2 weeks, then 3 doses every other day 
  • Has antioxidant properties, current (limited) research indicates that NAC does not significantly alter the disease's progression. 

  • 500mg twice a day 
  • An antifibrinolytic agent hypothesized to reduce the endothelial inflammation in the spinal cord associated to the disorder and due to immune-complexes and fibrin deposition. 
  • Therapeutic protocol including ɛ-aminocaproic acid and N-acetylcysteine, supplemented with vitamins B, C and E did not appear to affect the course in 12 dogs (in this protocol prednisolone was given for the first two weeks and upon worsening of neurological signs)

The mechanism of disease is complex, and ongoing research studies have found: 

  • E40K Mutation and Aggregated SOD1 Proteins: These contribute to neurodegeneration by disrupting cellular processes, including inducing endoplasmic reticulum stress, mitochondrial dysfunction, and impaired axonal transport. 
  • E40K Mutation and Aggregation: The E40K mutation disrupts the “salt” bridge between glutamic acid (E40) and lysine (K91), destabilizing the protein and resulting in misfolding and aggregation. This phenomenon does not occur in human SOD1 (hSOD1) with the same mutation, suggesting species-specific structural differences. In canine DM, Met117 (M117) contributes to structural instability due to poor packing in the hydrophobic core of the β-barrel structure. Stabilizing these regions could be a therapeutic strategy for DM. 
  • Disulfide Crosslink Formation: The destabilization of the β-barrel structure increases the exposure and flexibility of the Cys7 residue, enabling it to form disulfide crosslinks with other SOD1 molecules. An in vitro study developed a fragment antibody (22E1) to specifically bind mutant SOD1 at the E40K mutation site and stabilize the β-barrel structure. Although this is an in vitro study, it suggests a potential therapeutic target in DM and ALS. 
  • Prion-like Propagation: In vitro models suggest mutant SOD1 aggregates can induce aggregation in normal SOD1 proteins, potentially explaining the progressive nature of the disease. 
  • Glutamate Excitotoxicity: Studies of spinal cords in Pembroke Welsh Corgi dogs with DM found a marked reduction of glutamate transporter 1 (GLT-1), resulting in glutamate excitotoxicity and nerve cell death. 
  • Neuroinflammation: Mediated by astrocytes and microglia, this contributes to DM progression. DM-affected dogs show significant upregulation of proinflammatory cytokines (IL-1β and TNF-α) and chemokines (e.g., CCL2), along with increased expression of vascular cell adhesion molecule-1 (VCAM-1), suggesting an inflammatory phenotype. Anecdotally, some dogs respond to low doses of glucocorticoids such as prednisolone, but this effect is not sustained, and immunosuppressive treatments like azathioprine or cyclophosphamide show no benefits. 
  • Immunohistochemistry Findings: Activated microglia/macrophages and astrocytes are prominent in DM spinal cords. CCL2 is primarily expressed by astrocytes, while activated macrophages/microglia show increased HLA-DR positivity (a type of Major Histocompatibility Complex (MHC) Class II molecule). 
  • Macrophage Migration Inhibitory Factor (MIF): This multifunctional protein with chaperone-like activity inhibits protein misfolding and aggregation. MIF expression reduces the amount of insoluble SOD1E40K protein, suggesting its role in promoting refolding or degradation of misfolded proteins. Further research is needed to assess its in vivo applicability and safety. 
  • MicroRNA (miRNA) Profiles: Quantification of spinal cord miRNA profiles in DM-affected dogs identified three upregulated miRNAs (miR-23a, miR-142, miR-221) and 18 downregulated miRNAs. Upregulated miRNAs are associated with protein ubiquitination and cellular responses, enhancing aggregation of mutant SOD1 protein in vitro. The roles of the downregulated miRNAs remain unexplored. 
  • Species-Specific Resilience: In dogs, the substitution of glutamic acid (E) with lysine (K) at position 40 on the SOD1 protein disrupts its structure, leading to protein misfolding and aggregation, the hallmark of DM. In horses, however, lysine at the 40th position is naturally occurring and does not cause aggregation. The SOD1 protein in horses has a more negative net charge, which reduces its aggregation tendency, along with potential genetic modifiers or enhanced antioxidant defences. 

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