DM research: How you can help even if your dog is unaffected!
I was able to attend the DM seminar given by Dr. Joan Coates 10/10/10 in Seattle, hosted by the Cascade Pembroke Welsh Corgi Club. Dr. Coates, if I understand correctly, was not paid by CPWCC and flew in from Missouri and gave this presentation on her own time.
Much of the information she covered can be found in the DM discussions on MyCorgi and elsewhere, but here are some of my notes:
The Coates lab continues their research. They are now looking for "modifier" genes which may determine why some A/A dogs develop DM and most do not.
They need CONTROL SAMPLES FROM OLDER, UNAFFECTED DOGS. If you have an PWC 12 years or older showing no signs of DM, your dog's DNA can benefit this research. This requires a blood sample (a cheek swab doesn't give enough DNA for this purpose), thus a vet visit, but this is a big way you could help. You can't do research without healthy controls. Please, I hope some MyCorgi people will come forward and help this way, it would be a significant contribution.
Remember, your UNAFFECTED dog may very well be A/A AT-RISK. They'll be looking for "modifier" genes your dog has that may be preventing it from developing the disease. This information might help design breeding programs to reduce the incidence of DM by including these protective genes.
Also, they continue to collect postmortem spinal cord and muscle tissue from both affected and unaffected dogs euthanized for other reasons. This is a much more complicated, time-sensitive process involving a $200 kit (provided) and a vet willing to donate the considerable time required to dissect out the spinal cord (funding to pay for this is scarce, as usual).
Contact: Ms. Liz Hansen HansenL@missouri.edu or CoatesJ@missouri.edu.
http://www.caninegeneticdiseases.net/
Notes:
I think the terms "at risk" and "affected" are often confused:
G/G genotype is "clear".
A/G gentoype is "carrier".
A/A genotype is "at risk" -- would not be called "affected" until actual symptoms appear (often, they never do).
In Pembrokes,
G/G clear 6%
A/G carrier 29%
A/A at-risk 64%
The A allele is an ancient, widespread mutation, 79% in Pembrokes and occurs in many other breeds (interestingly, it is 52% in mixed-breeds). Because it's so prevalent, decreasing the incidence of DM in Pems is not simply a matter of breeding only clears. This could introduce a new genetic bottleneck, create new problems, and damage the breed. It's important to "breed the whole dog, not a single trait". This disease is a Mendelian recessive (with incomplete penetrance), so it's important to know how those Punnett squares work.
This is the same gene that causes ALS in humans: SOD1, superoxide dismutase, a free-radical detoxifier, but DM is apparently not a result of loss of this protective anti-oxidant activity (ALS researchers have made "knockout" mice with the SOD1 gene removed, and they don't get ALS). Rather than a "loss of function", it's a "toxic gain-of-function"; the change of one amino acid alters the structure/solubility of the SOD1 protein, and insoluble aggregates of this junk accumulate in the nerve cells, bunging-up the system and presumably causing eventual cell death. The same sort of thing happens in other neurologic diseases.
A/G "carrier" dogs sometimes show pre-clinical signs of this pathology. Microscope sections of their spinal cords stained with antibodies to the SOD1 protein do show some of the protein aggregates seen in affected animals. The age-of-onset for carrier dogs may simply be longer than their lifespan. The mean age-of-onset in PWC is about 11 years.
There may be other, much rarer mutations (not detected by the current test) that could cause the same disease. This is the case in human neurology as well.
It is apparently not an autoimmune disorder.
"There are no treatments that have been clearly shown to stop or slow the progression of DM".
Dr. Coates showed video of affected dogs in various stages of the disease. I'd never seen this. It was unexpectedly moving.
If you have an affected friend, check out http://pets.groups.yahoo.com/group/wheelcorgis/
There are over 400 members!
Hope this helps and I've got it mostly right.
Much of the information she covered can be found in the DM discussions on MyCorgi and elsewhere, but here are some of my notes:
The Coates lab continues their research. They are now looking for "modifier" genes which may determine why some A/A dogs develop DM and most do not.
They need CONTROL SAMPLES FROM OLDER, UNAFFECTED DOGS. If you have an PWC 12 years or older showing no signs of DM, your dog's DNA can benefit this research. This requires a blood sample (a cheek swab doesn't give enough DNA for this purpose), thus a vet visit, but this is a big way you could help. You can't do research without healthy controls. Please, I hope some MyCorgi people will come forward and help this way, it would be a significant contribution.
Remember, your UNAFFECTED dog may very well be A/A AT-RISK. They'll be looking for "modifier" genes your dog has that may be preventing it from developing the disease. This information might help design breeding programs to reduce the incidence of DM by including these protective genes.
Also, they continue to collect postmortem spinal cord and muscle tissue from both affected and unaffected dogs euthanized for other reasons. This is a much more complicated, time-sensitive process involving a $200 kit (provided) and a vet willing to donate the considerable time required to dissect out the spinal cord (funding to pay for this is scarce, as usual).
Contact: Ms. Liz Hansen HansenL@missouri.edu or CoatesJ@missouri.edu.
http://www.caninegeneticdiseases.net/
Notes:
I think the terms "at risk" and "affected" are often confused:
G/G genotype is "clear".
A/G gentoype is "carrier".
A/A genotype is "at risk" -- would not be called "affected" until actual symptoms appear (often, they never do).
In Pembrokes,
G/G clear 6%
A/G carrier 29%
A/A at-risk 64%
The A allele is an ancient, widespread mutation, 79% in Pembrokes and occurs in many other breeds (interestingly, it is 52% in mixed-breeds). Because it's so prevalent, decreasing the incidence of DM in Pems is not simply a matter of breeding only clears. This could introduce a new genetic bottleneck, create new problems, and damage the breed. It's important to "breed the whole dog, not a single trait". This disease is a Mendelian recessive (with incomplete penetrance), so it's important to know how those Punnett squares work.
This is the same gene that causes ALS in humans: SOD1, superoxide dismutase, a free-radical detoxifier, but DM is apparently not a result of loss of this protective anti-oxidant activity (ALS researchers have made "knockout" mice with the SOD1 gene removed, and they don't get ALS). Rather than a "loss of function", it's a "toxic gain-of-function"; the change of one amino acid alters the structure/solubility of the SOD1 protein, and insoluble aggregates of this junk accumulate in the nerve cells, bunging-up the system and presumably causing eventual cell death. The same sort of thing happens in other neurologic diseases.
A/G "carrier" dogs sometimes show pre-clinical signs of this pathology. Microscope sections of their spinal cords stained with antibodies to the SOD1 protein do show some of the protein aggregates seen in affected animals. The age-of-onset for carrier dogs may simply be longer than their lifespan. The mean age-of-onset in PWC is about 11 years.
There may be other, much rarer mutations (not detected by the current test) that could cause the same disease. This is the case in human neurology as well.
It is apparently not an autoimmune disorder.
"There are no treatments that have been clearly shown to stop or slow the progression of DM".
Dr. Coates showed video of affected dogs in various stages of the disease. I'd never seen this. It was unexpectedly moving.
If you have an affected friend, check out http://pets.groups.yahoo.com/group/wheelcorgis/
There are over 400 members!
Hope this helps and I've got it mostly right.
Replies to This Discussion
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Permalink Reply by Sam Tsang on
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Thank you John! If everything goes well, Mocha and Vienna will participate in the blood test in 4 years :)
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Permalink Reply by Beth on
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Thank you so much for the report, John. I find the research fascinating. I have participated in genetic research for my own human disease, and I know that after collecting tens of thousands of blood samples for DNA, they have uncovered (in the human disease) several modifier genes and are now moving on to the next stage of research.
These things are complicated. I understand where puppy-buyers would want breeders to test, but then what do the breeders do with the results? With 64% at-risk and only 6% clear, breeding all the at-risks to ONLY clears, or even ONLY carriers, would introduce huge new problems into the breed.
And if a breeder tests and advertises the results, how to explain to a puppy-buyer that yes, I'm selling you an at-risk puppy, but at this point that is the ethical thing to do?
I think if I were breeding I would test for the benefit of the research, but do nothing with the results and not even tell my puppy-buyers I was testing. It's human nature to want a clear or carrier puppy, but at this point breeding for that goal, or even breeding to reduce the incidence, would quite likely introduce other issues into the gene-pool, due to genetic bottle-necking. That, and the fact that there still might be other genes that cause the disease, make this much more complicated than, say, breeding away from vWb in Corgis.
Here is hoping that they find a much-less common modifier gene, soon and learn what actually triggers onset. If I win the Power Ball, I will give a nice contribution to their project. :-)
And yes, I plan on having my dogs tested if they stay healthy to age 12.
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Permalink Reply by John Wolff on
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Let's all recognize that nearly 2/3 of PWC puppies are at-risk now. Admittedly, this is a complicated thing to explain to people unfamiliar with genetics (I hadn't thought much about this aspect myself until just now).
Also note that -- if I've got this right -- the Coates lab needs blood DNA from non-symptomatic 12+ y.o. Pems REGARDLESS of their genotype -- well, I guess clears might be of less use as controls, but most specimens they get will be either at-risk or carriers, needed to discover why some at-risks develop disease and others do not. What they're doing is collecting a lot of dogs' DNA -- affected and unaffected -- feeding it into automated gene-mapping equipment (the Affymetrix canine SNP chip, high magic) -- and have the computer look for what bits of DNA seem to go along with the disease and what bits seem to inhibit the disease.
So if you participate this way, you're not "getting your dog tested" (you can do that with a cheek swab, $65). You're voluntarily donating your dog's blood DNA to science.
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Permalink Reply by christy fry on
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Thats alot of serious info...I read it twice and still went HUH? Mine are not tested and that's ok with me and while I don't have alot of knowledge on this disease, it sounds like a late in life onsetter and with carts and other medicines they can live very comforable for a time. And like Beth said if they were tested by the breeder's and were at risk I would never want to know it's not that I would worry, it's that I would have 12 yrs to worry =) And if mine do come down with DM I would not think any less of their breeders, they did provide me with wonderfull companions =)
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I did not mention that the age-of-onset is earlier in the larger breeds. While DM is most prevalent in PWC, Boxers, GSD, Chesapeake retrievers and Rhodesian Ridgebacks, it does occur in many others, and this research can benefit them, too.
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Permalink Reply by shelley power on
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John,
This is a wonderful summary of the seminar! I would have loved to have been able to go!! So glad you went! We are doing hips on my bitch, Mika, this week and then in the following weeks we will do dna on both male and female... DM and Vwd... anxious for results:)
heres hoping Dr Coates can get somewhere in the midwest sometime soon!
~shelley and the herd
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Permalink Reply by Carol Rea on
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I am so glad you could go and have posted this information!! I have an IVDD dog and therefore am a member of the yahoo group wheelcorgis, most of which are DM. DM is a terrible disease, and the more we know about it the better. I cannot believe what these loving people go through with their pets as the go through this disease, I never thought that I would feel lucky that Lucky had IVDD!! (I realize that he is young enough that DM could strike in a yr or 2, they can have both)
Both of my boys will be tested at the appropriate age (or about, we don't know actual age) Did Dr Coates talk about cost of the spinal cord kit - there has been alot of discussion about the $200 on wheelcorgi. Many members are of course, sending spinal cords after the end of life, but others just cannot manage the cost and there are not any funds to help people out.
You have cleared up a lot of what I did not understand, even after reading about it almost weekly when someone has a question on DM
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I don't see much point in testing a dog for DM unless you're thinking of breeding it. If the animal is showing symptoms, it might help in the diagnosis (an A/G or G/G genotype would rule-out DM). That's all.
Anybody with a 12+ y.o. Pem with no symptoms of DM, please consider contacting the Coates lab and sending a blood specimen! But this is not for "testing" (although they may give you your dog's DM genotype if you ask them; I'm not clear on that). This is just voluntarily donating your normal dog's DNA to science as an unaffected control. They will map your dog's chromosomes, add this info to the database, and let the computer look it over.
Remember, your UNAFFECTED dog may very well be A/A AT-RISK. The computer will be looking for "modifier" genes your dog has that may be preventing it from developing the disease. This information could help design breeding programs to reduce the incidence of DM.
CoatesJ@missouri.edu or HansenL@missouri.edu
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I think you misunderstood, I would not be testing my dogs for DM, but donating the DNA for Dr Coates research
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Permalink Reply by Leo Notenboom on
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"I don't see much point in testing a dog for DM unless you're thinking of breeding it."
Actually you can use testing to rule out DM in a dog that's showing symptoms. That is, a "clear" or "carrier" dog showing hind-end weakness should be examined for other issues. (I do recall Dr. Coates saying as much, though much more clearly than I just did :-).
When Helen started showing symptoms we had her tested, and she came back as "at risk". That, unfortunately, tells us nothing - could be DM, could be something else. (FWIW: we picked up Helen's cart yesterday - short video: http://leospictures.com/5079791462/ )
I was there as well, and this is a good write-up, John. Thanks. I'll probably point some wheelcorgi people here.
Leo
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Permalink Reply by shelby geisler on
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I lost a dog to "probable" DM which is the reason I follow this disease so closely. I say probable because I never sent the spinal cord in. Casey passed in Dec 2005. Would I want to care for another dog going through this NO!. Would I do it for the ones sharing my life now YES.
The reason I feel it's important to test all the dogs is to get a more acurate figure how many are actually AT RISK. If we continue to just test the ones showing symptoms of course the affected figures will be high and no doubt discounted as an unimportant fact.
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