Degenerative myelopathy (DM) is a chronic, progressive neurologic condition that typically develops in the latter third of a dog’s life. DM starts in the central portion of the spinal cord then gradually progresses to involve all spinal cord segments. 1 Although DM is unique to the dog, it is a natural-occurring model of human amyotrophic lateral sclerosis (ALS) also known as Lou Gehrig’s Disease.3,4 In dogs, the common form of DM results from a DNA change (mutation) in the SOD1 gene. This is a recessive condition, meaning that dogs with two copies of the mutation are at risk for developing DM. For most affected dogs this condition develops late in life, however a change in the DNA at a different gene than the SOD1 gene has been identified in some dogs that modifies the risk for DM in the Pembroke Welsh corgi. In dogs that have two copies of the at-risk DM mutation and have one or two copies of a mutation found in the SP110 gene, will reduce the age of onset for DM.
Typical DM presents with dysfunctional and abnormal movements of the pelvic limbs around 8 years of age or later. Dogs may show stumbling and disorganized pelvic limb movement. The presenting abnormalities indicate the disease starts in the distal third of the spinal cord.1-3 A physical and neurologic exam may show different signs between the right and left hindlimbs. Dogs may have difficulty flipping their paws to the appropriate position although reflexes may be normal to increased.9,10 The gait of dogs affected with DM can be difficult to distinguish from the gait of dogs with hip dysplasia, arthritis of other joints of the hind limbs, or intervertebral disc disease. As DM progresses, muscle weakness, muscle atrophy, and marked instability result in the inability to walk. Eventually, the muscles will become increasingly flaccid with the loss of more and more motor function. 10 Affected dogs may lose fecal and urinary continence and may completely lose the ability to walk 6 months to 2 years after the onset of signs. This condition does not appear painful during its progression.10
While the SOD1 mutation is considered the main cause of DM, additional environmental and/or genetic factors may contribute to the presence or absence (penetrance) of the disease and also the age of onset (variable expressivity) because not all dogs homozygous for the trait develop clinical disease.6 This is particularly true in Pembroke Welsh corgis (PWC).5
Unique to the PWC, a DNA change has been identified that seems to modify the occurrence of DM in the PWC. The degenerative myelopathy risk modifier (Pembroke Welsh corgi type) is a genetic mutation affecting the onset of disease in a PWC already “at-risk” (having two copies of the SOD1 mutation) for the disease. In an at-risk PWC, a mutation in the SP110 gene increases the chance of developing clinical DM at an earlier age of disease onset. Meaning, PWC’s that have two copies of the SOD1 mutation and at least one copy of the SP110 mutation, are at greater risk for presenting with DM earlier in life. If a PWC does not have the common SOD1 DM mutation, the SP110 variant does not have any effect on a dog’s health.
Genetic testing of the SP110 gene in Pembroke Welsh corgis will determine whether a dog is a genetic carrier of degenerative myelopathy risk modifier (Pembroke Welsh corgi type). Unlike the common SOD1 mutation for DM, the Degenerative Myelopathy modifier (Pembroke Welsh corgi type) is inherited in an autosomal dominant manner. This means at-risk dogs, with two copies of the SOD1 gene mutation, only need to inherit one copy of the SP110 gene mutation to have increased risk of developing degenerative myelopathy earlier in life.
While this SP110 mutation has been identified in breeds other than the PWC, it is unknown if this mutation causes increased risk for DM in these breeds when also present with two copies of the SOD1 common DM mutation. Another way to state this is, dogs identified with one or two copies of the SP110 variant and no disease-causing mutation in SOD1 are not at an increased risk of DM.
Testing for the degenerative myelopathy risk modifier (Pembroke Welsh Corgi Type) is recommended for all PWC that are also “at-risk” for degenerative myelopathy (already known to have two copies of the common SOD1 mutation). Therefore, efforts to prevent puppies from being born with degenerative myelopathy should focus on preventing puppies from being born with two copies of the SOD1 gene mutation rather than selection against the SP110 mutation. Ideally, only dogs clear of the SOD1 mutation would be bred, however, to prevent loss of genetic diversity within a breed, dogs that have one copy of the SOD1 mutation can be bred to a dog that has been tested by a reputable laboratory and shown to be clear of the mutation. This pairing will not produce any at-risk dogs for DM. In a clear x carrier breeding, about half of the pups will be carriers and about half of the pups will be clear. None of the pups will be at risk for DM due to this known, causative mutation.
Paw Print Genetics has veterinarians and geneticists on staff, in our offices, that can help answer your questions. Any questions about DM, the PWC DM modifier, or any other tests that we offer can be discussed by contacting us. Genetic counseling is an important part of the genetic testing process and Paw Print Genetics always offers genetic counseling at no charge to its customers. We are available by phone Mon-Fri 8am-5pm PST and through email seven days a week. We look forward to helping you with your genetic testing that can enhance your breeding program to produce the healthiest puppies possible.
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2) Awanoa 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 2009 Vol 106 (8) pp. 2794-99.
3) 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 Vol 318 (1-2) pp. 55-64.
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6) 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 Vol 113 (22) pp. E3091-100.
7) Nakamae S, Kobatake Y, Suzuki R, et al: Accumulation and aggregate formation of mutant superoxide dismutase 1 in canine degenerative myelopathy. Neuroscience 2015 Vol 303 (0) pp. 229-40.
8) March PA, Coates JR, Abyad RJ, et al: Degenerative myelopathy in 18 Pembroke Welsh Corgi dogs. Vet Pathol 2009 Vol 46 (2) pp. 241-50.
9) Kanazono S, Pithua P, Johnson GC, et al: Clinical Progression of Canine Degenerative Myelopathy. ACVIM Proceedings 2013.
10) Griffiths IR, Duncan ID: Chronic degenerative radiculomyelopathy in the dog. J Small Anim Pract 1975 Vol 16 (8) pp. 461-71.