Degenerative Myelopathy and genetic testing
Ok, as per a request, this is being started as a new discussion. :-) The question, of course, is if this relatively new test should be part of the screening tests we expect (or at least expect to see) when we are choosing a puppy.
First, my initial post, then I'll put in a new response:
I have been puzzling over the DM test, and it makes me uncomfortable. Apparently there is a fair amount of controversy over it. So far all dogs with DM have a certain genetic marker, but it is not clear what percent of dogs with this marker develop the disease. Nor is it clear that there are not other genetic markers involved.
This is something I know a fair amount about. I have an autoimmune condition called ankylosing spondylitis, which is an inflammatory and progressive arthritis of the spine. There is a genetic marker for the disease which is present in roughly 92% of people with AS. I lack this marker. However, over 90% of people who have this genetic marker will NEVER, I repeat NEVER get AS.
Moreover, more recent long-term studies have uncovered at least 2 other genes implicated in the disease, or expression of it.
I would have zero confidence that a test for DM, which is an auto-immune disease, would at this early stage of research give any real indication of how likely an "affected" dog is of coming down with the disease. I would also have virtually no confidence that a dog that that tested clear would not come down with a disease that is symptomatically so similar to DM as to be indistinguishable in its end result. Why is that? Because I highly doubt that research in the field of autoimmune disease in dogs is so far ahead of that in humans that they can say definitively what genes cause this very sad condition.
It leaves more questions than answers. If indeed a relatively large portion of the population tests positive, but it turns out that as in humans the huge majority of "positive" animals will never, ever develop the disease, what would we do by screening them out of the gene pool?
I think the testing should be done for research, but to offer it as a breeder screening as a means of somehow insuring that a pup won't be affected is perhaps getting a little ahead of the current status of the research.
These auto-immune conditions are very complicated, are likely caused by several sets of genes causing expression or suppression of symptoms, and moreover more than likely have an environmental component that "triggers" the onset of disease activity.
Edit: This is from the very website that is conducting the research and testing for DM:
http://www.caninegeneticdiseases.net/DM/testDM.htm
"The “A” allele is very common in some breeds. In these breeds, an overly aggressive breeding program to eliminate the dogs testing A/A or A/G might be devastating to the breed as a whole because it would eliminate a large fraction of the high quality dogs that would otherwise contribute desirable qualities to the breed."
The Pembroke Welsh Corgi is one of the breeds with a very high incidence of Positive or Carrier dogs. Don't count on a flood of breeders offering up the results of their dogs tests any time soon.
Indeed, from the same site:
"Summary: We recommend that dog breeders take into consideration the DM test results as they plan their breeding programs; however, they should not over-emphasize this test result. Instead, the test result is one factor among many in a balanced breeding program. "
First, my initial post, then I'll put in a new response:
I have been puzzling over the DM test, and it makes me uncomfortable. Apparently there is a fair amount of controversy over it. So far all dogs with DM have a certain genetic marker, but it is not clear what percent of dogs with this marker develop the disease. Nor is it clear that there are not other genetic markers involved.
This is something I know a fair amount about. I have an autoimmune condition called ankylosing spondylitis, which is an inflammatory and progressive arthritis of the spine. There is a genetic marker for the disease which is present in roughly 92% of people with AS. I lack this marker. However, over 90% of people who have this genetic marker will NEVER, I repeat NEVER get AS.
Moreover, more recent long-term studies have uncovered at least 2 other genes implicated in the disease, or expression of it.
I would have zero confidence that a test for DM, which is an auto-immune disease, would at this early stage of research give any real indication of how likely an "affected" dog is of coming down with the disease. I would also have virtually no confidence that a dog that that tested clear would not come down with a disease that is symptomatically so similar to DM as to be indistinguishable in its end result. Why is that? Because I highly doubt that research in the field of autoimmune disease in dogs is so far ahead of that in humans that they can say definitively what genes cause this very sad condition.
It leaves more questions than answers. If indeed a relatively large portion of the population tests positive, but it turns out that as in humans the huge majority of "positive" animals will never, ever develop the disease, what would we do by screening them out of the gene pool?
I think the testing should be done for research, but to offer it as a breeder screening as a means of somehow insuring that a pup won't be affected is perhaps getting a little ahead of the current status of the research.
These auto-immune conditions are very complicated, are likely caused by several sets of genes causing expression or suppression of symptoms, and moreover more than likely have an environmental component that "triggers" the onset of disease activity.
Edit: This is from the very website that is conducting the research and testing for DM:
http://www.caninegeneticdiseases.net/DM/testDM.htm
"The “A” allele is very common in some breeds. In these breeds, an overly aggressive breeding program to eliminate the dogs testing A/A or A/G might be devastating to the breed as a whole because it would eliminate a large fraction of the high quality dogs that would otherwise contribute desirable qualities to the breed."
The Pembroke Welsh Corgi is one of the breeds with a very high incidence of Positive or Carrier dogs. Don't count on a flood of breeders offering up the results of their dogs tests any time soon.
Indeed, from the same site:
"Summary: We recommend that dog breeders take into consideration the DM test results as they plan their breeding programs; however, they should not over-emphasize this test result. Instead, the test result is one factor among many in a balanced breeding program. "
Replies are closed for this discussion.
Replies to This Discussion
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Permalink Reply by Beth on
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Now for my follow-up.
This is from the site doing DM testing:
"In the seven breeds we studied so far (Boxer, Chesapeake Bay Retriever, German Shepherd Dog, Pembroke Welsh Corgi, Cardigan Welsh Corgi, Rhodesian Ridgeback, and Standard Poodle), dogs with test results of A/G and G/G have never been confirmed to have DM. Essentially all dogs with DM have the A/A test result. Nonetheless, many of the dogs with an A/A test result have not shown clinical symptoms of DM. Dogs with DM can begin showing signs of disease at 8 years of age, but some do not show symptoms until they are as old as 15 years of age. Thus, some of the dogs who have tested A/A and are now normal may still develop signs of DM as they age. We have, however, found a few 15-year-old dogs that tested A/A and are not showing the clinical symptoms of DM. Unfortunately, at this point we do not have a good estimate of what percent of the dogs with the A/A test result will develop DM within their lifespan."
Ok, so now we have a test that shows that all dogs with DM show the genetic marker A/A. We do not know what percent of dogs with the A/A gene will develop disease. Moreover, we don't know how many "Clears" are out there to cross-breed to. On another site, I saw it estimated that 60% of all Corgis test "positive" for the gene, but unclear whether by positive they meant carriers or double-positives.
Herein lies the problem. First, is it helpful to the breed to only breed carriers to clears, if clears only make up roughly 40% of the gene pool? With the already high prevalence of line-breeding in many kennels, how much further can we reduce the gene pool without negatively impacting other health aspects of the breed?
Second: If you breed a carrier to a carrier, theoretically you get a 25 clear/ 50 carrier/ 25 "affected" split. However, DM as an autoimmune disease is NOT a disease where 100%, or even close to it, of "affected" animals get ill. What percent do? We have no idea, as the testing is still new. The limited testing they have done has found a number of 15-year-old dogs who are still asymptomatic. 15 is ancient for a dog.
So, in a litter of 8 with two carriers being bred, in theory (but not in practice) you would get 2 clear pups, 4 carrier pups, and 2 "affected" pups. But what is the rate at which affected pups will exhibit the disease? And at what age of onset? If expression rate is, say, 20%, you would get .4 pups out of a litter of 8 (or 5% of all dogs) expressing symptoms. If expression rate is 10% you would get .2 pups out of a litter of 8, or 2.5 pups out of 100, exhibiting symptoms.
Which is where we then move to age of onset. In the GSD, average age of onset is around 8. But in Pembrokes, it is older. I think I saw somewhere it's around 11 in Corgis. So now what if we have a disease with a 20% expression rate, that hits dogs with an average age of onset old enough that to be fair a significant percentage of dogs would already have passed from other causes long before they would have started showing symptoms? So now you are taking that 5 possible dogs out of a hundred, and reducing it significantly by the dogs that were either already deceased before they would have genetically started exhibiting symptoms, or would already be seriously ill from other symptoms of age.
I don't know what the incidence of expression is. No one does. I do know that in human auto-immune diseases where a genetic marker is found, only a very small percent of people every get the disease. And if indeed 60% of all Corgis carry the genetic marker for DM, but something less than 5% of Corgis get DM, then that is likely also true of dogs.
So what damage do we do to the gene pool by aggressively breeding carriers only to clears, and not breeding affected dogs at all? Genetic testing is a pandora's box. Weeding out DM completely would still not get rid of nearly all the spinal column injuries that could make a dog go down behind. We had a lab who went down behind that was due most likely to arthritis, for example. As another example, I read a report online that showed that most Corgis that have serious bleeding disorders actually test negative for VwB, the bleeding disorder that is screened for.
For myself, at this stage I don't think we know enough about this disease or the genetics involved. I think as many people as practical should volunteer their dogs for testing, for the sake of research. But when the testing site itself does not recommend not breeding positive or carrier dogs, I don't think we as consumers can fairly insist that we know more than the scientists, and demand that breeders share the results of their dogs with us. More testing might very well find the subset of genes that is responsible for expression, suppression, or age of onset in double positive dogs. It may find an environmental "trigger" that is easily treated or avoided in double positive dogs.
For now, I will stick with the tests recommended by the PWCCA, which don't include the DM test. From the research site:
"Thus, a realistic approach when considering which dogs to select for breeding would be to consider dogs with the A/A or A/G test result to have a fault, just as a poor top-line or imperfect gait would be considered faults. Dogs that test A/A should be considered to have a worse fault than those that test A/G. Dog breeders could then continue to do what conscientious breeders have always done: make their selections for breeding stock in light of all of the dogs’ good points and all of the dogs’ faults. Using this approach over many generations should substantially reduce the prevalence of DM while continuing to maintain or improve those qualities that have contributed to the various dog breeds." -
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Ok, poking around further online and I found at least one breeder site that said that 60% of Corgis tested are shown to be at risk for developing DM, which would mean double positives not carriers. However, I don't think the numbers tested are yet high enough to be accurate. But if the numbers are even half that high, again it is not something that we can selectively breed out in the near term without doing substantial damage to the gene pool, IMO.
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Permalink Reply by John Wolff on
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From my reading of that paper, I couldn't tell if they'd actually established the gene frequency in PWC by testing a wide random sample, but I gathered that maybe 2/3 of PWC are AA. A small proportion of these will develop symptoms of DM, so AA is necessary but not sufficient for the disease.
I was a bit surprised that their genome-wide association study couldn't pick out another gene which, combined with AA, is implicated in DM. Look for further data on this. People are really interested because DM in dogs is ALS in humans. There is motivation for further study.
I was surprised that the A allele is so frequent. Smacks of selection. I wouldn't be surprised if that this DM locus (the place where the DM gene is physically located) is tightly linked (physically close on the chromosome) to some other locus with a trait coveted by corgi breeders (let's call it "?"), so that breeders have unwittingly selected for the A allele along with "?". If so, "?" will be selected against if breeders start selecting against the DM "A" allele unless there are enough animals with a crossover that de-links "A" from "?" -- i.e., chromosomes that have both G and "?".
Meanwhile, as the state of the art evolves, breed AA to GG or AG to GG, and we're not going to get affected dogs, and we'll gain experience about what desirable traits we may be losing in this new selection process.
Excruciating technicality:
The term "affected" means individuals showing symptoms of the disease.
"Homozygous" means having 2 copies of the same allele, i.e., either AA or GG ("homo" meaning "same"). "GG", or "clear, is also "homozygous".
"Heterozygous" mean having different alleles, AG in this case ("hetero" meaning "different").
In this case, homozygous for '"AA" means "at risk", but not "affected" until symptoms show.
So most PW are at-risk (AA) but unaffected. Apparently, no PWC who are not AA are affected with DM.
It is important to remember that this technology/science is in its infancy, also that we all, dogs and humans, have SOMETHING, our warts and imperfections. This knowledge is to be used, but used carefully.
And whenever I think of DM or see a photo of a corgi on wheels, I feel the bond of love between those animlas and their people. -
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They'll find more as they start doing broader genetic testing. I have been involved in human genetic testing, and often one well-funded widespread study can uncover a whole lot of discoveries, which lead to as many questions as answers.
Two thoughts:
1) My guess is that they will uncover other genes which combine to determine expression of symptoms and age of onset in AA dogs. Why, for example, is DM a tragic disease of young-ish dogs in GSD's, and primarily a disease (still tragic) of old age in Corgis? Yes of course there are exceptions, but that is the generality, and there is probably a genetic determinant.
2) Many, perhaps most, researchers of human auto-immune diseases believes there is an environmental component to trigger onset of disease in humans. Genetically engineered mice raised in a germ-free environment never develop symptoms of certain auto-immune diseases. The question is which germs or combination of germs trigger onset, and why? Is it a latent infection that never clears? Is it molecular mimicry? Does the immune pump simply need to be primed by exposure to really any mix of pathogens? No one knows yet. Research in animals lacks some of the ethical concerns of research in humans, so my guess is the animal studies will be pursued vigorously, and in breeders you have a large volume of people willing to hand over samples from their dogs.
I agree that the prevalence indicates there must be some benefit in related genes (and while I had the impression that genetically susceptible dogs were common, I did not really guess that the frequency was as high as it apparently is). An example that comes to mind is that sickle-cell anemia supposedly offers some protection against malaria, hence its prevalence in those whose ancestors are from equatorial regions. With dogs that are so selectively bred from such a small original gene pool, it's possible it's a real advantage (resistance to another disease), a desired breed trait, or pure chance (the original foundation stock just happened to have this genetic variant, and there is no benefit but because the founding stock had it, the majority of descendants carry the gene).
I have a picture of a Corgi-on-wheels hanging at my desk at work. I too am always amazed at the dedication and devotion shown by both sides of the dog/owner relationship for those dogs that are affected by this devastating illness.
As I said, I would sort of suspect breeders to keep the information private to pet owners. Human nature being what it is, people would be clamoring for "clear" or "carrier" dogs, and yet they make up such a small percentage of the population that it is simply not practical to provide them to most people looking for a pet, or even breeding stock. One breeder I saw said she is testing her dogs and currently many of her dogs are AA, as is common with the breed. She did not indicate who was, and who was not, on her site. -
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More research. This was a very small study, but remember the test has been out for only about a year. This study compared 38 Corgis who actually had DM with a 17-Corgi control group that had no symptoms of DM:
" All 38 samples from affected corgis were homozygous for the A allele, whereas the 17-sample asymptomatic control group consisted of 10 A/A homozygotes, 6 A/G heterozygotes and 1 G/G homozygote."
So in symptom-free dogs of a very small sample, we had 59% "affected", 35% carrier, and only 6% clear.
As I said, much more research is needed.
http://www.pnas.org/content/106/8/2794.full -
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Permalink Reply by Ann B., Scout and Summer on
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Beth,
The breeder of our corgi, Scout, is one who is trying to breed the DM gene out of her bloodline (she is Kathleen Mallery of Parma, ID, Castell Corgis). We are currently waiting for a new pup from her, and she has been trying to get a litter from a "DM clear" dog. She recently forwarded a very interesting podcast to us, and I will give out the link because some corgi folks may be very interested. It is a 30 minute interview with Dr. Joan Coates of Univ. of Missouri, who is doing DM research:
scoutshouse.sprnetwork.com/2009/08/04/episode-4/ -
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Just listened. Very interesting, as there really is still so little info but we seem to be on the verge of finding out so much more.
I was surprised that they think it is NOT an auto-immune disease; I had mistakenly thought it was.
However, they are as I suspected looking for modifying genes, because the rate of expression seems relatively low and they don't know why double-positive dogs don't always develop symptoms.
Moreover, while to date all confirmed DM dogs are double-positive, right now they are closely watching a "carrier" dog who might be showing some symptoms of DM.
Moreover, there are other degenerative neurological diseases that can seem similar at early onset to DM as well. It seems that only autopsy is 100% certain for diagnosis.
I applaud your breeder for trying to have negative pups, HOWEVER if the gene pull of negatives is really as low as it seems, it would be dangerous for all breeders to follow suit. Even the researchers urge caution about the possibility of "bottlenecking" the gene pool when so little is yet known.
Thanks so much for the link; I found it fascinating. -
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Bobbi, I appreciate your informed response, and you are obviously close to the situation.
Your post is enlightening and also troubling. If indeed "at risk" dogs end up making up something like 50% of the population, it is probably not scientifically sound to expect breeders to breed them ONLY to clear dogs, if clear makes up only 7-10% of the population. Simply too rapid a reduction in the gene pool.
Moreover, if breeders do start trying to minimize DM in their gene pools, that means that in the short term at least there will be a spike in "at risk" puppies placed in pet homes, as they choose "carriers" or "clears" for their breeding programs.
But how will pet-puppy buyers react to that? Will they put their own dog's short-term health at risk for the long-term good of the breed? I am, sadly, a bit skeptical that it will work that way.
Again, I don't think we have enough info to demand anything of breeders yet, on a test that is only about a year old.
http://www.offa.org/dnateststats.html
According to this, only about 600 dogs have been tested so far. I understand your feeling that mostly breeders are testing if they have DM in their lines, but I am inclined to think the opposite might also be true: breeders with no DM are hoping they have clear dogs which they can use as a selling point.
I will try to talk to a breeder I know and see what's going on, but she may be hesitant to discuss it. -
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And I did say in one of my early posts that I think as many people as practical should test for the sake of moving forward the science.
But again, I'm not willing to write off as "irresponsible" any breeder who is not testing just one year after the test is released. OFA so far has data on 600 dogs, unless the database I linked to is woefully behind. By your standard, most breeders then are irresponsible.
Also, what you are suggesting is going far beyond what the scientists doing the study are suggesting, and also is doing exactly what the scientists caution could do major harm to the breed.
Pembrokes are listed on most multi-dog breed info sources as being relatively clear of many of the health problems that nag other purebred dogs. Let's not, in our rush to clear out this one problem, create a host more.
You are emotionally close to the situation because of the work that you do, and I appreciate it. However it is also trying to watch a young dog die of cancer, a dog die of kidney disease, a young dog succumb to heart problems, and endless other things that are rampant in some breeds but relatively less common in Corgis.
I think we have to agree to disagree here. When I got my dog just two years ago, DM testing did NOT exist. Having not talked to many breeders about health clearances since then, I am not willing to condemn the lot of them based on what little info we have on who is testing, and what they are doing with the results.
If indeed about half the dogs are at risk and another 25% or so are carriers, it will take many generations to make a major impact and still keep the viability of the gene pool.
I checked the page in Finland for my dog's sire, who has a list of health and behavior clearances as long as your arm and no mention at all of DM. I think we have a long way to go. I respect your feelings on the matter, but I am not willing to form a solid opinion until we start seeing more numbers come in.
Your feeling that more dogs are getting it now may be true. It may also be that more dogs are living into old age due to improved care, and therefore living long enough to develop symptoms. Or it may be that with the rise of the internet, people have more access to info and are sort of coming out of the woodwork instead of dealing on their own. We just don't know. -
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Permalink Reply by shelby geisler on
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I am a corgi girl through and through. I got my first corgi in 1960 when very few people knew what they were. He sold me on the breed. In 1979 I finally found my second corgi, he was then 2 years old. a rehome. In 1990 I got Casey. This boy was with me 24/7 and we always had to be within sight of one another. He was the perfect boy in every way including stature. When I'd walk in to events with him I heard the crowd "look at that sable, look at that sable". He was my buddy, companion, friend. I never went anywhere without him. He went with me to the bank, to job sites wherein he watched the truck or helped run wires. We install automatic alarm systems.
We'd stop at fast food 2 for 1 beef, he got the meat I ate the roll. He never weighed more than 23lbs, was not a chow hound. I do not remember ever having to correct him, he was perfect.
In the summer of 2003 he lost 2 pounds and I started noticing him sometimes muster to traverse two steps. By September we were out back just off the porch and he went to take a step and it was like a disconnect. His left rear leg didn't follow him. He looked at me and back at his foot as if to say, hey what's wrong here.
Off to the vets or should I say vets. One day at dog school the instructor said your dog has DM. Back to the vet. I didn't know what DM was, never heard of it. Apparently the vet didn't know either as she grabbed him up, took him to Xray and insisted he had arthritis. Put us on shots, then meds for the rest of his life. After 3 more vets determined this was not arthritis by now Casey was seal walking. I never had a handicapped dog before and all anyone told me was "make him comfortable" Fine but how, we were on our own.
I had one time seen a dog on a cart at an event so I began my search. The cart shipped in in April. What a deal I had with carts but that's another long story. I did attempt to research DM, had 3 computers literally blow up meanwhile my boy was getting worse. Talk about stress level.
After inquiring multiple times about swimming him, I finally found a place 60 miles away, scheduled an appt only to have them call back asking if I read the University of ____ web site. I got the distinct impression they didn't want to help my boy.
I then found a stable who allowed dogs to swim in their pool. We went up there only to find we were alone in the facility. I bought a livestock galvanized tub and started swimming him here at home. Now I didn't know how long to swim him nor what temp the water was to be.
Casey was never incontinent but certainly we had accidents. I stayed with him and took him out around the clock every 3 hours carrying him up a flight of stairs, out through 2 doors and then yet another 2. The butt lifts didn't fit. We did a lot of wheelbarrow. I was his back legs. Fortunately I'm 5' tall and he could take me across the yard at light speed until my back went out so he soon learned the command Whoa.
I found by sitting him on all 4's blocked with pillows was better than laying him on his side. I bought a battery operated motion detector to alert me when he wanted to move. At least now I could go to the kitchen to prepare a meal. He continued to have the desire to travel with me on errands and jobs. I can not tell you how many times I had to quick look for a pull off as he was uncomfortable.
Our best times together was when I'd sit on the floor hip to hip with him twice a day and finger feed him. Boy did he love cooked carrots. Now I'm getting tears in the eyes. The looks he gave me are/were priceless. Would I do it again for him. You betcha. Do I want to go there again NO!
For those of you who hae never gone down this path, I sincerely hope you never do. This is such a wonderful breed, please breeders do test your dogs. -
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I am sorry to hear your sad story. To be fair, he was 13 and most of the dogs I have owned did not make it to that age. We had one who lived to be 16, but the last several years of her life she had dementia. She recognized no one, she could not see, she could not hold weight, and she was often incontinent.
When the time finally came, she had kidney failure. She was acting ill. I took her outside to go to the bathroom, put her on the ground, and she staggered a few times and fell. It was very sad.
However, if you feel I don't appreciate that it's a serious disease, you are mistaken. Tell me, though, what would you advise breeders to do if fully half or more of all their stock is homozygous positive, and another quarter are carriers?
I still have not really heard that answer from those who say any responsible breeder should test. And then do what with the results?
You vividly describe a sad and painful disease, that hit a thirteen year old dog. For many of the larger breeds, the average lifespan is only 10 years. So if we vigorously breed out DM, and inadvertently end up with a sickly breed that has an average lifespan of 8-10 years, would that be worth it?
We're not talking about a perfect world here. We are talking about tough tradeoffs that breeders will need to make, and right now they have limited information to go on. -
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