Degenerative Myelopathy in the Rough Collie
© Stephen Webb BSc(Hons), BA, BSc, BSc, MSc.
THIS INFORMATION IS FACTUAL BASED ON SCIENTIFIC RESEARCH,
Degenerative Myelopathy was first investigated in 1973, DM is an autosomal recessive gene with incomplete penetrance and was always thought of as the German Shepherd disease, with corgi’s a close second. It is a progressive neurological disease starting with unsteadiness and weakness in the hind limbs with muscle atrophy, eventually leading to paralysis, incontinence and progressing eventually up the spine to the fore limbs. Usually affecting dogs of 8 years and older but it can appear in dogs as young as 5 years of age.
In 2009 a mutation in the gene for superoxide dimutase 1 (SOD1) was found on chromosome 31, with much research done on both breeds by Missouri University and many others around the world working on various aspects of this disease particularly
because it also has a very similar human version, motor neurone disease - ALS. This mutation quickly became associated with increased chance of developing DM. Early signs are unsteadiness, difficulty in getting up and knuckling over as above.
The SOD 1 gene encodes for a protein that neutralises radical oxygen molecules which are a by-product of normal cell processes and must be broken down quickly if damage to other cells is to be avoided. A missense mutation in the SOD1 gene causes the protein to mis-fold and as a consequence they start to form what is in effect a toxic build up in the nerve cells. The damage causes cell death, loss of muscle control leading to DM and paralysis.
The SOD1 gene provides instructions for the production of Cu/Zn superoxide dismutase an antioxidant to break down toxic charged oxygen molecules called superoxide radicals. Within the gene a change from G to A causes a misfolding of the superoxide dismutase as GAA Glutamate is changed to AAA Lysine.
The SOD1 enzyme is part of the defence mechanism, a faulty gene gives a faulty defence, as the enzyme now misfolds these molecules, they accumulate in the nerve cells and instead of helping to protect them, the build up causing the death of these cells.
However it is a mistake to think the just because there is now a DNA test, that everything is straightforward. The disease itself is not fully understood or its effects on the body in area’s not even explored yet and it is likely to be much more complex than was ever imagined. The DNA test must be thought of at this present time as a work in progress, while it is a very good indicator at the moment it does not give a definitive answer and cannot be used to diagnose for DM. There seems to be a disconnect of information between research and the grass-roots of the various affected breeds, probably due to the complexity of the problem in that the results of the current DNA test actually only give a level of risk in developing DM.
“A DNA test based on the SOD1 mutation is commercially available. Dogs homozygous for the mutation are at risk of developing DM and will contribute one chromosome with the mutant allele to all of their offspring. Heterozygous dogs are DM carriers and are less likely to develop clinical DM, but they can pass on a chromosome with the mutant allele to half of their offspring. Dogs homozygous for the non-mutated (normal) allele are unlikely to develop DM and will provide all of their offspring with a protective normal allele. A test result showing that the dog is at risk can support a presumptive diagnosis of DM in the setting of typical clinical signs and normal findings on neuroimaging and CSF analysis. The SOD1 DNA test is of potential use to dog breeders wishing to reduce the incidence of DM in the breed or line”. - Dr Joan Coates
Nowhere in any scientific literature does it state that the tables used by most breeders are accurate, even clears by DNA test still have an ‘unlikely to develop DM ’ status, clear does not mean 100% clear. There are often complaints that the DM test is not accurate so for many it seems that it is not worth doing. However this is a misunderstanding, it is accurate for the SOD1 gene but its relationship to DM only indicates risk at this stage because research work is on going in fully understanding its mechanism.
The above table represents current understanding but there are a variety of other versions on the internet which are not so good, leading to confusion. Over the years that followed after the development of the test all was not well, results were not always what were expected and rough collies particularly were found to have an added complication in that they had an insertion, exon2 was duplicated at intron2 this gave prior to 2016 in some cases incorrect genotypes for many dogs that had the insertion and the test had to be adapted ensure it gave the correct results.
SOD1 exon2 c.118G. A
The diagram below shows the DNA sequencing of exon 2 of SOD 1, the top sequence shows an affected dog (PC01), the second line is a Clear Dog (PA17) and the third line is a Carrier (PA71). The rectangle shows the point in the gene where the fault lies. The base A in the affected dog (top) should be G as in the clear dog (middle), the lower dog is a carrier which is A/G. Because (G) wild type is replaced by (A) in the faulty gene, DNA tests are usually given the notation G and A;
Clear G/G Carrier G/A Affected A/A (at risk)
What does this mean? This change in just one base where G becomes an A means that the sequence GAA the correct one encodes for the protein Glutamate but GAA now becomes AAA in the affected dog which ultimately encodes for the protein Lysine. That one tiny change creates a big problem, the chemistry is complex but SOD 1 has a job to do and it catalyses the first stage of the neutralisation of superoxide free radicals, most people with no scientific background will have heard at some point that free radicals are harmful to everyone’s health and not just dogs, they are highly reactive, short lived and produced not only by normal cellular metabolic processes but also are generated by toxins in the environment such as air pollution for example but there are also many other forms of harmful substances in everyday life and because they are so reactive they can damage DNA, cells, proteins and lipids thereby causing disease. Yes, SOD1 is strongly linked to DM but it is far from the end of the story.
How many other genes are involved? At this point it is difficult to say, at present SP110 a nuclear body protein involved in gene transcription on chromosome 25 is a modifier locus and plays a role to some extent as it has been found to be present in 40% of affected dogs but in unaffected it is only present in 4% (Ivansson et al. 2016) this seems to govern the timing of the onset of the disease. There are reports of more possible loci on Chromosomes 10, 6, and 20 that may be involved, but again more research needs to be done.
There is enough scientific evidence from around the world to say that rough collies are pre-disposed to DM and through research results its occurrence is comparable to the German Shepherd which should give cause for concern. Despite not knowing the true extent of DM in the UK, it would be difficult to argue that it is not uncommon. The numbers affected can seem misleading as German Shepherd KC registrations per year, run at more than 10 times the level of rough collies which have declined considerably over recent years (GSDs 7-8000 registrations vs Rough collies 5-600 per year) because of the numbers involved it would seem that GSDs are more affected due to their popularity and sheer volume of numbers means increased visibility. However, proportionately the rough collie is equally prone to DM as the GSD and while it is now standard practice to test for DM in the German Shepherd it is not given the same importance in the Rough Collie, yes, many do test but there does not seem to have a breed wide strategy for dealing with this genetic defect despite the KC scheme. It is very much left to individual breeders interpreting results they have and dealing with it within the limits of their own understanding which may or may not always be correct.
The issue goes much deeper than individual kennels, the wrong breeding decisions can have a direct impact on the breed as a whole for future generations. The number of effective founders (Ne ) in rough collies published in 2015 by using the Kennel Club database and was 39.4, in German Shepherds it was 147, but what does this mean? The viability of any animal species is 50 and any numbers below this would normally put on the at risk list, this is not good news for the rough collie and of course some other breeds alongside the rough collie for their long term prospects in terms of risk to health. The fewer the number of effective founders, the more susceptible the dogs within a breed are to the risk of hereditary diseases, in contrast the smooth collie was 90, a better position that the rough collie and although not the subject of this paper but is in itself genetically a strong argument for allowing roughs and smooths to once again be bred together. The rate of loss of genetic diversity within a breed or population increases dramatically when Ne <100, while a population with Ne <50 is considered to be at high risk of detrimental hereditary effects.
The protection of the breed for its long term viability is first and foremost the top priority. There are other implications which affect breeders directly and the precedent has now been set regarding inherited diseases making the Breeder liable if a DNA test is available and a breeder chooses not to use it. Under the UK Animal Welfare Act which as many know is becoming stricter with every passing year and now includes hereditary diseases Breeders need to ensure that they can demonstrate that they have done everything they can to avoid the most serious hereditary diseases that are prevalent within a breed. Doing nothing and leaving it to chance is unwise, the legal precedent has now been set in the UK (2021) and coincidently involving DM under the Animal Welfare Act, where the parents were untested and a subsequent pup was DNA tested and found to carry both copies of the faulty SOD1 gene and therefore at risk, compensation through the courts was awarded to the owner.
There is no easy answer to this inherited disease and a solution is far from straight forward. But testing and then making the wrong breeding decisions based on those tests is equally damaging to the breed. It is clear from my own investigations that further guidance is necessary as some faced with this problem seem to automatically think that carriers need to be excluded or that those affected (at risk) cannot be used it is clear there is some confusion. It cannot be assumed that everyone in the breed knows how to handle this issue.
But what of the future, there is much research into DM in dogs because of its human equivalent and which gene therapy is a front runner in an attempt to reduce the effects of the SOD1 gene. This is being trialled using Adeno-Associated Virus 9 (AAV9) to carry a modified piece of DNA directly into the parts of the dogs body that has defective cells. Stem cell therapy is another attempt and a great deal of research is being carried out to regenerate spinal nerve damage. However even if successful the cost of these treatments would be prohibitive for most owners so are unlikely to have any real impact on dogs suffering with DM in the foreseeable future, DM is not going to go away anytime soon.
© Stephen Webb BSc(Hons), BA, BSc, BSc, MSc.
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