Joan R. Coates,     Columbia, Missouri

Shinichi Kanazono,     Columbia, Missouri

Pathophysiology

Since it was first described by Averill (1973), canine DM, because of its histopathologic features, was termed a nonspecific degeneration of spinal cord tissue of undetermined cause. Awano and colleagues (2009) identified a c.118G>A transition of glutamate to lysine in SOD1 that predicted an E40K missense mutation underlying canine DM. In this initial study there was a highly significant association between homozygosity for the SOD1:c.118A allele and the DM phenotype in Pembroke Welsh corgis and also in four other dog breeds: boxer, Chesapeake Bay retriever, German shepherd dog, and Rhodesian ridgeback. SOD1 is a ubiquitous intracellular protein functioning as a free radical scavenger. Mutations in SOD1 are known to cause some forms of familial ALS in humans. ALS, the most common adult motor neuron disease, is characterized by loss of motor neurons causing stiffness and slowing of muscle movements, difficulty speaking and swallowing, muscle atrophy, and severe weakness. The Greek word amyotrophy means “muscles without nourishment.” Lateral is the location within the spinal cord of axonal disease, and sclerosis refers to replacement of diseased axons by sclerotic or “scar” tissue. In addition, Awano and associates (2009) demonstrated that, as in ALS, cytoplasmic aggregates that bind anti-SOD1 antibodies were present in the spinal cords of dogs with DM that were homozygotic for SOD1:c.118A. The aggregates are thought to form because amino acid substitutions force SOD1 to assume an unstable conformation. It is unclear if the aggregates cause or contribute to the neurodegeneration or are a by-product of other neurodegenerative processes. No similar SOD1 antigen–containing aggregates are found in healthy dogs lacking known SOD1 mutations.

Not all SOD1:c.118A homozygotes develop clinical signs; therefore DM appears to be an incompletely penetrant autosomal-recessive disease, whereas most human SOD1 mutations are autosomal dominant. Thus homozygosity for the E40K mutation is a major risk factor for canine DM. We have detected the DM-associated SOD1:c.118A allele in over 100 different dog breeds. The mutant allele appears to be very common in some breeds. It remains to be seen whether or not homozygosity for the mutation puts dogs of all of these different genetic backgrounds at risk of developing DM. Recently another mutation in SOD1 has been discovered in a DM-affected Bernese mountain dog (Wininger et al, 2011). This finding serves as a reminder that direct DNA tests can indicate the presence or absence of disease-causing alleles but cannot be used to rule out a diagnosis because other sequence variants in the same gene or in a different gene might produce a similar disease phenotype.

Clinical Spectrum

Subsequent to the discovery of the SOD1 mutation underlying canine DM, the clinical spectrum became more clearly defined with identification of the stages of disease progression (Table 234-1). Dogs with DM follow a predictive pattern of clinical signs that begins with UMN pelvic limb paresis and general proprioceptive ataxia, progresses to LMN paraparesis, and then spreads to involve the thoracic limbs and brainstem. The earliest clinical signs appear when dogs are at least 8 years or older, and the mean age of onset is 9 years. There is no sex predilection. The clinical course of DM can vary after the presumptive diagnosis is made; the mean disease duration is 6 to 12 months in larger dog breeds, at which point dogs become nonambulatory paraparetics. Pet owners usually elect euthanasia when their dogs can no longer support weight with their pelvic limbs. Dogs of smaller breeds can be cared for by the pet owner over a longer time; for example, the median disease duration in the Pembroke Welsh corgi was 19 months (Coates et al, 2007). DM-affected Pembroke Welsh corgis often have signs of thoracic limb paresis at the time of euthanasia.

Diagnostic Approach

Accurate antemortem diagnosis is based on recognition of the pattern of progression of clinical signs supported by inclusionary and exclusionary diagnostic testing.