by beil79 on 13 February 2020 - 10:02
Is there any database listing German shepherds?
genome of degenerative myelopathy?
by TIG on 14 February 2020 - 21:02
If you search the forums you will come up with a ton of threads discussing DM and the supposed DNA test - which is fraudulent and just a way for U of Missouri and OFA to make money and for breeders to look good while giving false hope to their puppy buyers.
DM until relatively recently was known as the German Shepherd disease since it only showed up in GSDs and known crosses with GSDs. According to Dr. Clemmons' research it had about an 8% penetrance in the breed. It exhibited in two forms - late onset, slow progression: early onset, fast progression often only 6 mo or a year b4 euthansia. As far as I know the research done did not determine whether these are two different etiologies of the same disease or if in fact there are enough difference to label them as two separate but perhaps related disease.
For decades Dr. Clemmons was the only researcher working in this area - it was basically considered an orphan diease. He was successful in developing a high anti oxidant protocol for treating the late onset, slow growth. It did not cure the disease but seemed to put a pause in it or slowed the progression ( I had personal experience with it), Unfortunately based on anecdotal evidence it did nothing for the early onset form. Late in his research and early in the whole dna genome thing, he developed a test for DM called the Jack Flash test (after a dog who died from the disease and who's owner, Marjorie was and is a great supporter of quality research on the disease)
Not long after, some other researcher's decided to get on the band wagon and see if they could develop a profitable dna test. My understanding is that initially there was some question of usurped research - simply don't have enough information on that to comment. However the lead researcher had decided that DM was similiar to/ related to ALS ( Lou Gehrig's disease) in humans. (Note if memory serves me Clemmons had often stated that MS in humans was not a good model for DM but Dm was a good model for MS research. Hope that's right my brain is getting long in the tooth). In part the claim that DM was linked to ALS was based on the researcher's view that ALS was an inherited disease when in fact less than 1/10th of 1% of ALS is deemed to fall into that category. There was some THEORIES that the SOD1 gene was responsible for these cases ( note to this day that theory in either human or dogs has NOT been proved). So the "new" research decided to develop a test that could test for the SOD1 disease. The result is the public test which is now offered and called the DM test when it fact it does not test for DM it only tests for the SOD1 gene and there is scientific proof right out of the researcher's own test animals that DM can be present when the SOD1 gene is not - thus disproving the THEORY that SOD1 was the cause of the inherited neurological disease - at that point they should have gone back to the drawing board as a proper application of the scientific method would dictate. But wait - there was all that money to be made with a dna test. So despite scientific proof that the theory was wrong, the decision was made to go ahead and market the test. This is the test done today and the results can be logged with the OFA and it is an open database.
So why do I say this is an illegitimate test. 1. Initial study group - researcher could not adequately id animals that had the disease ( it is a diagnosis of elimination and can only be proved by a necropsy). A # of study animals on necropsy were shown not to have the disease.2. Intially the results were listed as NN normal NC carrier and AA as affected. You willl note that today AA is listed as At Risk because there was this pesky problem of AA's who did NOT exhibit the disease. The "explanation" for this ( rather than accepting the test was faulty) was the dogs either hadn't lived long enough ( tho some were 13-15 - old for GSDs) or perhaps there was another factor involved tho they have played down this angle. 3. The validity of the test was further compromised by one of the inital test group, a GSD bitch,I think, who was rude enough to be positively identified with DM on necropsy but tested NN - OOPS. Since that time there have been several other GSDs that this was true of ( including one owned by a friend of mine).
So we heve a working theory that the SOD1 is the casue of and/or implicated in causing DM in GSDs. BUT we have necroposied dogs with DM that test NN - this alone disproves the theory under the scientific method but we have further information that dogs testing for 2 copies of the SOD1 gene (AA) often were not affected- again suggesting that the SOD1 gene does NOT play the role hypothosed for it.
Now you will note I have been careful to refer only to GSDs in my comments for two reasons. First that is the breed I know and have been part of for almost 60 years and secondly this whole conversation has been blurred when it comes to other breeds. As noted above historically DM was called the GS disease but sometime in the more recent decades Boxers and Corgies were being diagnosed with a newurological disease that had similarites (as many neurological diseases do) and for some reason the vet community started to call these DM dogs. From descriptions of affected dogs , I have read there are significant differences in the etiologies of diease presented in these breeds from what occurs with classic GSD DM so the very first quesion research should have addressed was were these one diease or two or three or even 4 given the two onset times on GSDs. Then once you KNOW if you are dealing with one or multiple disease a rational approach can be made as to investigating possilbe cause. THIS WAS NOT DONE.
The opther bone I have to pick with the SOD1 test is that it is marketed to ALL breeds - the overwhelming majority who have never had DM in their genome or even a disease which mimics it. But Lordy lordy look at the money to be made!
by hexe on 15 February 2020 - 06:02
by Hundmutter on 15 February 2020 - 09:02
by Powerflex on 15 February 2020 - 09:02
by Koots on 15 February 2020 - 12:02
I am of the opinion that if commercialized, then the 'research' for testing and diagnosing purposes should be scrutinized. IOW, I am not convinced the commercially-available DM tests are adequate proof. Thanks.
by TIG on 15 February 2020 - 14:02
Thanks guys appreciate the kind words especially in the tinderbox of this subject.
It frustrates me to no end that people will not look at the science which clearly disproves the validity of this "test" but instead choose the easy pass in an attempt to make themselves and their dogs look better. I HATE bad bogus science and people of both stripes that take advantage from it.!
OP I misspoke - OFA is not a true open db. An owner's permission is required b4 negative information is published on it. Thus it being the nature of the beast in the dog world to hide known defects the greatest liklihood is that this db under reports problems. For example take a stud dog with a # of progeny listed with hip & elbow ratings. About 1/3 only show hip results no elbows. We are left with the questions - did their owners not know to also do elbows, perhaps they could not afford both or were the xrays done and a negative result obtained? If you assume the latter do you then assume the dog had elbow dysplasia? Perhaps the dog merely had djd grade 1 another controversial unproven "scientific" designation/theory foisted on the dog world by "scientists" with no practical experience in dog breeding or use and no PROOF the shadows on the xray that they call osteophytes and are measured in milliliters actual cause a disease process they have theorized.
A dog of mine fell into the latter category. Xrays taken , a bit unsure of the quality insulted my beloved vet by asking that they be sent to a radiologist for a reading b4 sending them to OFA. Went to a board certified orthopedic radiologist who in writing stated quality of xrays fine and dog would certify good on hips and clear on elbows. OFA came back w good hips and djd grade 1 in both elbows. Took her to a specialty practice with both board certified radiologists and orthopedic surgeons. They literally filled a CD with xray views, and after much study said that perhaps there was a 1 mm osteophyte on 1 elbow. Did I show the OFA elbow result on their db - hell no. Did I breed her - hell yes she was an outstanding working bitch. NB neither she or her progeny showed any sign of elbow probems or dysfunction.
by TIG on 15 February 2020 - 15:02
Koots, Being a lover and student of our breed and hopefully a steward of it, I do try to be credible.
Re the % of inherited ALS and the progress of SOD1 research on that,m it is available on many public science db including pubmed one of the easier ones for the public to access. Have at it, I do not currently have time to recreate my research path for you . While you r at it look for the quote by Coates where she had claimed to find the cause/cure for ALS - cruelty at the utmost to a population who suffers from a horrendous disease. Let us also ask about her credibility.
When the SOD1 test was initially marketed, the U of M had a statement on their website that acknowledged that one of the original test animals tested NN. I believe it has long since been removed but on one or more of the old computers that litter my house, I had a screen print of that statement.
As I noted, I have personal knowledge and acquaintance with a GSD owned by a friend who was diagnosed WITH DM ,confirmed by necropsy who tested NN. I have heard of several others but did not know them personally. Also, In a discussion with my vet (older, pragmatic both large & small animal vet) who has the same opinion of this test as I do, he shared that he had a client with a boxer who had all the clinical signs of boxer DM but the owner refused to accept the diagnosis because the dog had tested NN on the "dm"(sod1) test and thus would not accept treatment for the dog based on that diagnosis. He felt it was unlikely they would permit necropsy because of the cost and because they were wedded to the test results. I know nothing further of the dog, do not know if the owner was a breeder but suspect that might be the case which would explain the fanaticism of holding on to the test result in the face of overwhelming physical evidence to the contrary.
I think, I am acknowledging uncertainty here, if you search this db you will find folks whose dogs tested NC or carrier which should indicate IF the test was correct that they should NOT SHOW signs of the disease, whose dogs are in fact showing signs of the disease thus throwing more shade on the accuracy & reliability of this test.
Again on credibility should we not look with hard eyes at those marketing this test to breeds that have NEVER been shown to have a dm or related type of disease? ??
Re my friend with the NN DM Gsd. I know he notified OFA, I think also U of M, and that he tried to get the OFA to reconsider posting test results since there were legitimate questions about the scientific validity of the test but by this time the income was flowing in and they turned a blind eye to his information! My friend has far more financial resources than I do but who can stand against the combined financial might of a Univ and commercial testing outfits and the OFA who are deriving millions of dollars of profit esp when the one community who should be outraged by this ripoff- dog owners & breeders- stays silent for nefarious reasons of their own. Additionally, shortly after this his family had a personal tragedy which requires all his time & energy.
One last thing. I went to the Missouri site looking for that old admission which unsurprisingly a quick and dirty search did not reveal. What it did turn up was this. https://vhc.missouri.edu/small-animal-hospital/neurology-neurosurgery/current-clinical-trials/ .
Now this is what I find curious. LOOK at who they are soliciting - primarily Boxers and corgis (see my comments above about classic gsd dm and the questions about 1 or many diseases which should have been resolved first).
IN FACT THEY DO NOT EVEN MENTION GSDS the original progenitor of the name Degenerative Mylopathy. Perhaps because it is a different disease or perhaps because this is where the most problematic results come ??? Yes they do mention "other breeds" but limit by age which automatically eliminates from study any GSD with early onset DM. HMMM. Curiouser and curiouser.
Finally a question I hope perhaps you can answer since I've never seen it raised OR answered . Dr. Clemmons research showed about an 8% incidence within the breed. The model proposed by Coates and her research team implicating the SOD1 gene as the primary cause of DM and the test designed would suggest a simple Mendelian inheritance with either a 25% expected incidence if 2 copies of the gene were needed for the disease process or a 75% incidence if only one copy of the gene is needed. Both a far cry from 8% (note here again I am only speaking of GSDS and no other breed). Now there are a number of things that MIGHT explain this including penetrance but it also equally might be explained by the fact that this is simply the wrong tack or that it's a polygenic disease or that there are environmental factors involved. I at least have never seen a discussion OF ANY of these.
It seems that the 8% statistic is just another of those pesky problems from GSDs like the NNs with proven DM and AAs with no disease. The attitude appears to be if we just ignore it people will eventually stop asking and it will fade into the background and we won't have to deal with it.
Seems to be working for them, doesn't it.
by Koots on 15 February 2020 - 16:02
by jillmissal on 15 February 2020 - 17:02
There's a lot of journal lit supporting DM and ALS being essentially the same disorder. ALS is not "a" disease, it refers to a heterogeneous collection of adult onset diseases of progressive neurodegeneration. So I'm not sure why that is controversial or even doubted. Genetics are not as simple as people like to think (partly because reading and understanding them is headache-inducing for non-experts). Anyway I have no problem accepting DM and ALS as one and the same based on the literature. Example (for those who like scientific discussion):
Genome-wide association (GWA) mapping of DM was performed with 38 cases and 17 controls older than 6 years of age (mean age = 9.4 years) from the Pembroke Welsh corgi breed by using the Affymetrix Canine Genome 2.0 Array. The strongest association was detected on CFA31 (praw = 1 × 10−5; pgenome = 0.18), with weaker signals on 4 other chromosomes, suggesting modifiers or population substructure (Fig. 1A). Within the associated CFA31 region, all affected dogs were homozygous for a common haplotype from 28.91 to 29.67 Mb (CanFam2.0), which contains 3 genes: SOD1, TIAM1, and SFRS15. Clinical similarities between DM and ALS made SOD1 a viable candidate gene. Resequencing SOD1 from normal and DM-affected dogs revealed a G to A transition in exon 2 that predicts an E40K missense mutation. The 55 corgi DNA samples were genotyped for the SOD1:c.118G>A polymorphism. 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. To verify our localization of the DM mutation, we fine mapped 90 SNPs across a 1.9-Mb region from 29.04 to 30.97 Mb in 5 breeds, which segregate for DM (Fig. 1B). Affected dogs from all 5 breeds share a 5-SNP haplotype (maximum 195 kb in size), which contains the E40K mutation (Fig. 1C). This haplotype is also present in dogs that do not have the mutation. No other SNP or haplotype in the region is both shared across all breeds and concordant with recessive inheritance. Thus, the significant proportion of A/A mutant homozygotes among the controls and the presence of E40K mutation on an ancestral haplotype still present in the population may explain the relatively weak GWA to this region. Nonetheless, the presented genetic data strongly links the E40K mutation with the disease.
I don't think that researchers just run out to try to make money with every new study and theory; sure some snake oil salesman do but that doesn't discredit the actual scientists nor the studies. Credible testing can produce errors but that doesn't make the testing not credible. (Don't take this as a denial that there are non-credible tests out there because of course there are. But DM can be tested for, absolutely.)