Degenerative Myelopathy in the Rough Collie

© Stephen Webb BSc (Hons), BA, BSc, BSc, MSc
June 2021

Degenerative myelopathy was first investigated in 1973. DM is associated with an autosomal recessive gene with incomplete penetrance and was traditionally thought of as a German Shepherd Dog disease, with the Corgi also strongly represented.

It is a progressive neurological disease which usually begins with unsteadiness and weakness in the hind limbs, followed by muscle loss. It can eventually lead to paralysis and incontinence and may progress up the spine to affect the forelimbs.

DM usually affects dogs aged eight years and older, although it can appear in dogs as young as five.

The SOD1 mutation

In 2009, a mutation in the gene for superoxide dismutase 1, known as SOD1, was identified on chromosome 31. Research has been carried out by the University of Missouri and researchers around the world.

The disease has similarities to amyotrophic lateral sclerosis, also known as ALS or motor neurone disease, in humans. The SOD1 mutation became associated with an increased risk of developing DM.

Early signs can include unsteadiness, difficulty getting up, dragging the hind feet and knuckling over.

The SOD1 gene provides instructions for producing an enzyme that helps neutralise superoxide radicals produced during normal cell processes.

With the mutation associated with DM, the SOD1 protein can misfold and accumulate within nerve cells. This abnormal accumulation is believed to contribute to nerve-cell damage and loss of muscle control.

The SOD1 gene provides instructions for the production of copper-zinc superoxide dismutase, an antioxidant enzyme that helps break down highly reactive oxygen molecules known as superoxide radicals.

Within the gene, a change from G to A alters the amino acid produced at that point, changing glutamate to lysine.

The SOD1 enzyme is part of the body’s defence mechanism. When the protein misfolds, it can accumulate within nerve cells and contribute to their degeneration rather than performing its normal protective function.

Understanding the DNA test

Although a DNA test is available, this does not mean that the disease is completely straightforward or fully understood.

The test accurately identifies the particular SOD1 variant, but the result indicates genetic risk rather than providing a definite clinical diagnosis. Not every dog with two copies of the risk variant will develop symptoms during its lifetime.

A dog showing neurological symptoms cannot be diagnosed with DM solely from a DNA result. Other causes of weakness and paralysis must first be investigated and excluded by a veterinary surgeon or veterinary neurologist.

A DNA test based on the SOD1 mutation is commercially available. Dogs with two copies of the mutation are considered at risk of developing DM and will pass one copy of the variant to all their offspring.

Dogs with one copy are carriers and can pass the variant to approximately half their offspring. Dogs with two normal copies are unlikely to develop SOD1-associated DM and pass a normal copy to their offspring.

An at-risk result can support a presumptive diagnosis when the dog has typical clinical signs and other possible causes have been excluded. The test can also help breeders reduce the risk of producing dogs with two copies of the variant.

“Clear” does not mean that a dog is guaranteed never to develop any neurological condition. It means that the dog does not have the tested SOD1 variant in the form assessed by that particular test.

The Rough Collie complication

After the development of the original test, an additional complication was identified in Rough Collies. Some had a duplicated section involving exon 2, which could interfere with interpretation using earlier testing methods.

Testing methods were adapted to account for this duplication and provide the correct genotype.

SOD1 exon 2 c.118G>A

The diagram below shows DNA sequencing of exon 2 of SOD1. The top sequence represents a dog with two copies of the risk variant, the middle sequence represents a dog with two normal copies and the lower sequence represents a carrier.

The marked area shows the point where the base differs:

Clear G/G     Carrier G/A     At risk A/A

A change in one base from G to A alters the encoded amino acid. The normal GAA sequence encodes glutamate, while the altered AAA sequence encodes lysine.

SOD1 helps catalyse the first stage in neutralising superoxide free radicals. These reactive molecules are produced during normal cellular metabolism and can also be increased by certain environmental exposures.

SOD1 is strongly associated with DM, but it is unlikely to be the whole explanation.

Other possible genetic influences

It remains uncertain how many other genes may influence whether and when DM develops.

Research has identified SP110, a gene on chromosome 25 involved in gene transcription, as a possible modifier. Other possible areas on chromosomes 6, 10 and 20 have also been investigated, but further research is required.

This may help explain why some dogs with two copies of the SOD1 risk variant develop clinical signs while others do not.

DM in Rough Collies

A University of Missouri survey involving many breeds examined the frequency of the tested SOD1 variant. The reported gene frequency in the Rough Collie population studied was similar to that found in German Shepherd Dogs.

The precise frequency within the current UK Rough Collie population is not known. Results from one country or group of dogs should not automatically be assumed to represent every Rough Collie population.

Nevertheless, the presence of the variant within the breed supports the value of informed testing and responsible breeding decisions.

Protecting genetic diversity

Degenerative myelopathy testing should be considered alongside all the other health, temperament, conformation and genetic-diversity factors relevant to a breeding decision.

Automatically excluding every carrier from breeding could unnecessarily reduce the gene pool. A carrier can be mated to a clear dog without producing puppies with two copies of the tested variant, provided the parentage and test results are correct.

Where an at-risk dog is considered for breeding, specialist breed and genetic advice should be obtained. Breeding decisions should aim to reduce risk gradually while protecting the breed’s wider genetic diversity.

The future

Research into DM continues, partly because of its similarities to human motor neurone disease.

Areas of investigation have included gene therapy using viral vectors and the possible use of stem cells to repair or protect damaged nerve tissue. These approaches remain areas of research and are not established cures for clinical DM.

There is currently no cure for degenerative myelopathy.

© Stephen Webb BSc (Hons), BA, BSc, BSc, MSc
June 2021

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