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Degenerative Myelopathy

by Sylvia Lueck DVM, 2001

Degenerative Myelopathy (DM) is a poorly understood condition of the spinal cord causing progressive rear quarter weakness, eventually ending in paralysis and death. German Shepherds are noted for this disorder, but unfortunately many Pembroke Welsh Corgis are affected too, and some human disorders act similarly. The breed predilection for the disease raises suspicions of a genetic component, but in fact, DM may be the end result of a variety of causes rather than a specific SINGLE disease or genetic condition.

Age of onset and rate of progression vary from case to case, but it is mainly seen in middle-aged to elderly dogs. Signs begin as a subtle incoordination of the hind limbs. Over the ensuing months, the uncoordination becomes worse and weakness appears. Affected dogs have difficulty rising or jumping, drag their feet when walking, and wobble and weave with the hind limbs. Eventually they lose the ability to control their bowels and bladder and will become completely paralyzed.

Progressive rear end weakness may be a symptom of many other old age disorders such as herniated (slipped) disks, tumors of the spinal cord, or even arthritis. Thus, every Pembroke with a wobbly gait is not by definition a DM victim. Similarly, dogs from families of high incidence of DM that die with no signs of it are not necessarily “clean”. They may have expired from some other problem before their DM became clinically apparent.

There currently is no test available on the live dog to diagnose DM—it is a diagnosis of exclusion, that is, other problems need to be ruled out. This then leaves DM standing alone as the likely cause, but this can only be confirmed at death by examination of the spinal cord by a neuropathologist. Depth of pocketbook is often the limiting factor in accurate documentation/diagnosis. Some cases may be confusing insofar as some dogs

may have numerous problems. The postmortem is really the most important test of all, although MOST vet clinics are NOT set up to properly remove the spinal cord . . . power tools and finesse are required. It is a job for a neurologist or a pathologist.

The bulk of PWCCA funds in the AKC Canine Health Foundation are currently earmarked by a generous donor for DM research (in excess of $21,000). Assorted inquiries through the course of the past year to drum up interest in this issue have been both frustrating and rewarding. Several inquiries to a researcher in Florida who has done a lot of work on the problem in Shepherds were met with no response. Several other inquiries to other sources met also with no, or limited, response.

E-mail with the Genetics Chair for the German Shepherd Dog Club of America revealed that the GSDCA has supported both the Florida researcher and, more recently, Dr. Coates of Texas A and M on DM research. The work by Dr. Coates is still in progress. I think it is safe to say, however, that DM is not likely to be a quickly answered problem with a rapidly available DNA test. It will require time, lots of money, accurate data collection, and archiving of DNA from affected families over a few generations before DM’s cause is determined. Impossible? No. Simple? Again, no.

Contact with Dr. Dennis O’Brien, a neurologist at the Veterinary Teaching Hospital, University of Missouri, has been very useful. He is prompt in his replies, generous with his information, and established contact, on PWCCA’s behalf, with Dr. Joan Coates and Dr Gary Johnson (does DNA archiving). These three researchers, plus six others, have since agreed to be involved in a two-year $44,000 research project to examine DM in the Pembroke Welsh Corgi.

The primary investigator and author of the proposal is Dr. Joan Coates. Her preliminary draft of the project has received approval by the AKC Canine Health Foundation, which I am pleased to report will pay for half of the costs if it gains FULL approval. A final draft will likely have been submitted to the Foundation by the time you are reading this.

Dr. Coates’s hypothesis is that methionine deficiency or a related metabolic imbalance or oxidative stress is associated with development of DM in the Pembroke Welsh Corgi. Her four complimentary and interrelated objectives are to: (1) characterize DM in the Pembroke Welsh Corgi using neurodiagnostic and neuropathologic studies; (2) establish whether evaluation of serum and CSF (cerebrospinal fluid) for methionine and related metabolites are useful antemortem (before death) diagnostic techniques for DM; (3) establish whether evaluation of serum and CSF metabolites related to oxidative stress are useful antemortem diagnostic techniques for DM; and (4) establish an epidemiologic survey of DM within the Pembroke Welsh Corgi breed and bank DNA for future candidate gene studies.

Once exact protocols for sample collection and processing are settled upon, dogs will be accepted for the study. The beauty is that any neurological facility or university will be able to do the workup and submit the samples to “our team” for analysis. This will allow for inclusion of any Pembroke from ANYWHERE, as long as the samples can be shipped

overnight. For dogs that participate in the study and are followed through to post mortem, some amount of monetary compensation will be provided.

The PWCCA Genetics Committee is pleased that Dr. O’Brien has accepted an invitation to speak to us at the 2001 National. He will discuss Degenerative Myelopathy and the development of DNA tests in general.


from the berner-l

Univ. of Missouri

DM statistics for the BMD

For those who did not read my prior email, the ALS-like pathology described in Coates et al's PNAS publication is not required for establishing the diagnosis of spinal cord DM in canines. The previously described pathology of upper motor neuron lesions is all that is required to diagnose DM in the Univ. of Missouri lab and it can be assumed that all dogs with a DM pathologic diagnosis mentioned here had that pathology. Whether the ALS pathology is present in any of these dogs is not known.

To date, spinal cords from 5 BMD with clinical DM have been submitted to the Univ. of Missouri. One of the five does not have complete results and the diagnosis is not known. Of the remaining 4 dogs all for were homozygous for the DM mutation and listed as "affected". Three of the 4 dogs had spinal cord pathology of DM and the other dog did not. Dr. Johnson does not know what diagnosis the fourth dog has but states it did not have DM.

When questioned about the 25% false positive rate of the DM DNA test he commented that it is very difficult to get a completely accurate DNA test in a disease that occurs late in life and that it is likely that had this dog lived long enough that it would have developed DM.

Dr. Johnson also reported that 83 BMD have had their DNA tested for the mutation. 24 were homozygous normal, 37 were carriers and 22 were homozygous affected with the DM mutation. That means the mutated gene was present in 70% of the BMD's tested. Dr. Johnson feels this number is likely to be high since the pool of samples came from primarily dogs thought to clinically have DM.

By way of reference, their lab has tested DNA on 9931 dogs covering 179 breeds. The SOD1 (super oxide dismutase 1 gene) mutation, described in the PNAS article, has been found in 80 different breeds (45%). Of the 9931 dogs, 5545 (56%) were homozygous normal, 2350 (24%) were carriers or heterozygous and 2036 (21%) were homozygous affected. The mutated SOD1 gene was present in 45% of the dogs tested from a pool of less selected dogs.

Dr. Johnson also stated that several of the dogs thought to have clinical DM actually had radiographic evidence of spinal cord compression and not DM. Unfortunately I did not get the DNA status of all of these dogs.

Based on the number of "affected" dogs in our breed and other breeds, based on DNA and the relatively uncommon occurrence of this disease clinically, as well as the presence of the "affected" genotype in dogs lacking the pathology, we may not have a complete picture. When asked about these discrepancies, Dr. Johnson responded that the dogs had simply not lived long enough but had died of other illnesses. He feels that all dogs that are homozygous for the mutation will develop DM if they live 15-25 years.

Where do we go from here? Clearly we need more spinal cords to correlate the pathology with the DNA. In my mind this needs to include unrelated dogs to make sure it is not related to certain lines. Dr. Johnson did not know if the 5 current samples came from related dogs but he also did not feel that it was an important question.

There are a number of questions left in my mind. 1) What does being heterozygous mean beyond carrier status i.e. is there a risk for disease development? I think the answer to that question from Univ. of Missouri is there is no risk but I am not sure that is the correct answer. 2) What do we do with a high false positive rate (25%)? Not all dogs with clinical DM and affected DNA status have pathology consistent with DM. 3) What do we do with this test in our breed with regards to breeding decisions? 4) Is canine DM really a variant of ALS? We don't know what percentage of spinal cords really contain the ALS-like lesion described in the Univ. of Missouri's PNAS article but according to Dr. Johnson it is not the majority. Will all dogs with homozygous for the SOD1 mutation really go on to develop the ALS-like pathology? 5) Is a fairly uncommon disease that occurs fairly late in life really important in our breed given all the other diseases that keep most of our dogs from reaching 8-9 years of age? I realize that the dogs and their families that experience this disease are devastated. But, do we eliminate every homozygous affected dog from the gene pool because if they live to 15+ years of age every one will develop DM, as hypothesized by Dr. Johnson?

To be honest, I don't have the answers to these questions and I'm not sure anyone does. We have a lot of work ahead of us with this disease as well as many others that afflict our breed.


Canine Health Foundation

Degenerative Myelopathy DVD Available

The AKC Canine Health Foundation (CHF), in cooperation with Scout's House in Menlo Park, California, is pleased to announce the release of an instructional video outlining how dog owners can correctly care for their pets diagnosed with degenerative myelopathy (DM).

DM is a degenerative spinal cord disease affecting primarily, but not exclusively, German Shepherd Dogs. Affected dogs show progressive rear limb weakness and ataxia and eventually paralysis. DM is a "diagnosis of exclusion" meaning that since there is no genetic test available at the present time, other diagnoses must be ruled out before clinicians settle on DM. — so, the process of diagnosing DM can become time consuming and costly for the owner.

http://www.akcchf.org/

Video links can be found on our website: http://www.akcchf.org/video/