GENETIC EVIDENCE
The finding of CDRM in several littermate pairs, combined with the acknowledged high incidence of the disease in the German shepherd breed in general suggested that a genetic factor may well be involved in the aetiology of the disease, as previously suggested (Clemmons, 1989). Due to this unusually high incidence of CDRM in one breed of dog and the discovery of at least two pairs of affected littermates, the investigation of a possible genetic factor was indicated. Following a literature search for diseases in other species with clinical and pathological similarities to CDRM, a working hypothesis was established: CDRM is caused by a CAG trinucleotide repeat expansion in an unknown gene. A number of molecular biological techniques were employed to test this theory, including the Repeat Expansion Detection (RED) technique. This work is still in progress but there is some evidence, still inconclusive, that CDRM may be the result of a trinucleotide repeat expansion. Undoubtedly, CDRM has a complex aetiology which probably involves several different factors but most authors agree there is almost certainly a genetic factor due to the very high incidence of the disease in one breed. [The results from the Glasgow experiments provided some evidence that CDRM is principally genetic, and specifically of an “expansion” as noted, in the CAG nucleotide sequence on a gene that yet has to be found or marked.]
CONCLUSIONS BY JOHNSTON
This project aimed to examine clinically and pathologically a large number of GSDs affected by CDRM. Clinically, we wished to confirm the previously reported clinical signs, and look for any that may not have been reported. We proposed to follow the dogs through the clinical course of the disease, re-examining on a regular basis to establish whether the rate of degeneration was constant or variable. If variable, were there a number of recognisable patterns, which might suggest we were dealing with a syndrome rather than a single disease? In addition, we wished to confirm whether or not GSDs with CDRM had lower serum vitamin E concentrations than other dogs, since this vitamin had been associated with a number of neurodegenerative diseases in other species. The initial aim of the pathology investigation was to carefully examine the spinal cord using immunocytochemistry and electron microscopy, as well as classical techniques, to confirm the pathology previously reported and to look for new clues to the pathogenesis and aetiology using the more modern techniques. The next step was to carefully search through the brain, in particular those structures which, on the basis of the clinical signs, were most likely to be involved in CDRM. This search resulted in the discovery that specific brain nuclei and areas of white matter were altered in dogs with CDRM. These findings suggested marked clinical and pathological similarities between CDRM and a group of late-onset progressive human neurodegenerative conditions which were the result of CAG trinucleotide expansions. This led into an investigation of the hypothesis that “CDRM is the result of a [genetic] CAG trinucleotide repeat expansion”. However, further work would be required to definitively prove whether or not this was the case.
According to an e-mail someone sent me in 2002, “…in an article by W. Marvin Davis (U. of MS School of Pharmacy), he wrote, ‘Promising research on a monoclonal human antibody has shown it to favor re-myelination in laboratory animals after demyelinating disease or spinal cord injury. Such an action could conceivably reverse CNS damage in Multiple Sclerosis’….” Johnson had said, (re “antibody method of searching for the responsible DNA”): “However, there was no clear distinction of western profiles between CDRM cases and control dogs. The technique requires improvement and application to a tighter control population— i.e., aged GSDs with no clinical signs of CDRM.”
DISORDERS WITH SIMILAR SYMPTOMS
Cauda equina syndrome, giant axonal neuropathy, tumors, and other disorders may also mimic or be mistaken for signs of DM. Many cases of spinal and related nerve damage are due to sudden trauma, but some can result from encroachment of bone or tumors into the space occupied by the cord. Since nervous tissue generally does not regenerate, such conditions result in partial or complete paralysis. Symptoms similar to myelopathy may be brought on by a nerve cell degeneration normally associated with age. However, with the latter disorder, the rapidly progressive nature of GSD myelopathy is not seen. Neoplasms also cause the dog to display symptoms similar to those of GSD myelopathy. These tumors on the spinal cord, neuroepitheliomas, have a special predilection for German Shepherd Dogs from six months to maturity at three years of age. There were other progressive neurodegenerative conditions that had been reported in a number of different dog breeds, but these conditions were too dissimilar to DM to warrant discussion in Johnston’s thesis.
CONCLUSION
Much effort has gone into the attempt to find the cause, avoidance, and best treatment for this neurological disease that brings premature death to our beloved canine companions. The best, most scientific and thorough work is that of Dr. Johnston of Glasgow. People often are desperate to try anything, disregarding science and logic, when their faithful pet begins to show signs of this debilitation, resulting in much anxious grasping at shadows. We can’t blame distraught people for going on wild-goose chases, but we can offer them understanding and sympathy as well as the hard facts.
If you have lost a dog to this neurological disorder, I offer my condolences in the form of a poem:
Rondeau on the Death of a Dog
They whimper in their darkness and their pain,
But oh, so softly that one has to strain
To hear. The life that Folly whispered low
Would stay (and how we wished that it were so!)
Ebbs out, although we grasp for it in vain.
Steady the flow, invisible the stain
Their life-blood leaves on those who here remain.
Unwilling to desert us as they go,
They whimper in their darkness.
We pity pets who painfully are slain,
Or even gently enter Death’s domain,
But human-folk will feel Fate’s cruelest blow,
For, long after they lay their friends below,
And sorrow weighs them down like iron chain,
They whimper in their darkness.
Fred Lanting ©, 1980
Here is another sentiment for those of you who are still struggling with the problem:
The Season for Old Friends
In my green youth spring beauties bloomed,
Violets jeweled my life with friendly faces.
Each promised purpled constancy
And each I clasped and cherished.
Years, clustered, ripened in my summer’s sun,
Bade me dream of wine to share.
Friendships warmed in lengthening days
While butterflies, spiraling, ascending, danced.
Now fallen acorns wait for leaf burial;
Now wither white rays and golden heart
Of pearly everlasting, false to its name.
Trees rust in cold, damp nights
To mirror my own autumn oxidation.
The harvest falls to foxes
And purple verities are dun and done with.
Strange, in the grimness of winter’s glare,
Hope ripens orange on persimmon trees
Whose bitter fruit begins to shrink,
To soften, yes, to die.
But mystery unfolds as just before release
It is transformed to total sweetness.
Hold on, my heart, relinquish naught
Which through the seasons love has bought.
Old dogs are dearer than the rest;
Old wine is good, old friends are best.
© 1980, Fred Lanting.
Use poems and articles only with permission
Postscript: ADDITIONAL INFORMATION & UPDATES, 2010
Test for Degenerative Myelopathy gene now available —
Dr. Gary Johnson at the Animal Molecular Genetics Laboratory (www.caninegeneticdiseases.net/), Dr. Joan Coates at the Comparative Neurology Program (www.cvm.missouri.edu/CNP/) of the University of Missouri, Drs. Claire Wade and Kerstin Lindblad-Toh at the Broad Institute of MIT/Harvard and their colleagues have identified a DNA mutation that is a major risk factor for development of degenerative myelopathy in dogs. See the early-2009 article in the Proceedings of the National Academy of Sciences for details.
A DNA test is now available for use by veterinarians, breeders and pet owners. This test is available through the OFA (Orthopedic Foundation for Animals). The test clearly identifies dogs that are clear (have 2 normal copies of the gene), those who are carriers (have one normal copy of the gene and one mutated copy of the gene), and those who are at much higher risk for developing DM (have 2 mutated copies of the gene).
However, having two mutated copies of the gene does not necessarily result in disease.
Dogs that have clinical signs and a confirmed diagnosis of DM have tested as genetically affected. A relatively high percentage of dogs in several breeds (including Boxers, Pembroke Welsh Corgis, Chesapeake Bay Retrievers and Rhodesian Ridgebacks) have the predisposing mutation. It is important to note that there are a large number of dogs that have tested as genetically affected, but are reported as clinically normal by their owners. It may be that many of these dogs will develop clinical signs as they get older or it is possible that symptoms will never manifest in these dogs. Research is still needed to determine the frequency of the mutation in other breeds known to have DM (German Shepherd Dogs, Rhodesian Ridgebacks, Pembroke and Cardigan Welsh Corgis, Boxers, Chesapeake Bay Retrievers, Standard Poodles). In the future, we may identify other risk factors in those dogs that have tested as genetically affected. Wise use of this test can reduce the incidence of dogs at risk for DM in the long-term, particularly if other low frequency risk factors are identified that can more easily be reduced. It is likely to take many generations to reduce the frequency of this disease in breeds with higher frequency of the mutation.
As part of an ongoing collaborative effort by research scientists at the University of Missouri and the Broad Institute, a free DNA test is offered for dogs that have been diagnosed with DM, and for older dogs in selected breeds. Details are outlined in the research section of the websites listed in the following paragraphs.
This research was funded by the AKC Canine Health Foundation, American Boxer Charitable Foundation, Pembroke Welsh Corgi Club of America, Rhodesian Ridgeback Club of the United States, French Bulldog Club of America, and French Bulldog Rescue League. To them and the many breeders, pet owners, and veterinarians who assisted, thank you!
The following paragraphs from OFA are not covered by my copyright:
Degenerative Myelopathy Research — Ongoing and Additional
As explained in the DM test announcement and the “Using the DNA test” sections of this website: , we have recently discovered a mutation that can greatly increase a dog’s risk of developing degenerative myelopathy. We have found that dogs with 2 copies of the mutation (testing “affected”) are at risk for developing DM although many dogs that test “affected” remain free from symptoms. On the other hand, dogs that test “carrier” (one mutant copy and one normal copy) or “clear” (two normal copies) are highly unlikely to develop DM. (See also www.caninegeneticdiseases.net/DM/ancmntDM.htm )
We are trying to determine if there are genetic or environmental factors that explain why some dogs that test “affected” develop symptoms, while others are spared. If genetic or environmental modifiers do exist, we want to identify them. We are also trying to develop therapies that will slow or halt the progression of symptoms once they start. We expect this ongoing research will yield benefits not only for dogs at risk of developing DM and their owners, but also for people at risk of developing the human equivalent of DM. The entire research team would like to thank all who have participated in the research so far, and encourage participation from owners and breeders and their veterinarians to assist the ongoing research.
One target of ongoing research is determining why some at risk dogs develop symptoms and others do not. Researchers at the Broad Institute are searching for possible modifier genes that may influence onset of symptoms. For this work, we need information and samples from additional dogs. We are offering a free DNA test for dogs that fit our research criteria.
DOGS ELIGIBLE FOR A FREE DNA TEST:
Dogs must meet one of the following criteria to be eligible for a free DNA test:
- Any dog (any breed) with a presumptive diagnosis of DM made by your veterinarian or a veterinary neurologist. To locate a neurologist use the “Find a Specialist” link on the ACVIM website: www.ACVIM.org
- Any dog, healthy or not, 10 years of age or older from the breeds listed below only:
- Boxer
- Chesapeake Bay Retriever
- French Bulldog
- Pembroke Welsh Corgi
- Rhodesian Ridgeback
Samples for free testing must be sent as blood samples to provide the quality and quantity of DNA needed for the additional research. Please go to the website to download the instructions and the form for sending these samples or for a link to the online store at OFA where you can order the test. Dogs that do not qualify for the free test still may be tested using the screening test offered by OFA.
TISSUE SAMPLES ALSO NEEDED
We also are continuing to study the pathology of this disease. To do this, we are examining tissues from the nervous system of dogs with DM symptoms, as well as older dogs that do not show any symptoms of DM. When it comes time to have your dog humanely euthanized we would be very grateful for your assistance in obtaining an autopsy. We have a protocol that will assist with collection of tissues from specific areas of the nervous system – see the website for this protocol.
BREEDS AT RISK for Degenerative Myelopathy
As part of this research, we have been surveying many breeds for the presence of the newly discovered mutation. As of May 19, 2009 we have found the mutation present in over 75 breeds as well as mixed breed dogs. Some of these breeds have been previously reported with individuals diagnosed with DM and others have not. We are very interested in blood samples and spinal cord samples from presumptively diagnosed dogs of any breed, so that we can confirm the presence of the disease using all useful diagnostic methods.
Although any dog can be tested for DM, it is possible that the genetic background that predominates in some breeds prevents the development of symptoms even in dogs testing as affected. We are reluctant to recommend testing for members of breeds where we have not yet proven susceptibility to DM through microscopic examination of spinal cords from deceased dogs that exhibited symptoms of the disease. At this time we have the required evidence that there is an association between DM symptoms and the mutation in the following breeds;
- Bernese Mountain Dog
- Boxer
- Cardigan Welsh Corgi
- Chesapeake Bay Retriever
- German Shepherd Dog
- Kerry Blue Terrier
- Pembroke Welsh Corgi
- Rhodesian Ridgeback
- Standard Poodle
We do want additional samples from these breeds for ongoing research, as stated above.
Many other breeds have been reported with DM symptoms. We will add breeds to the above list of confirmed breeds as we are able to confirm susceptibility by DNA testing and microscopic examination of spinal cords. OFA
