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Carolyn Z. Gerganoff – Health and Genetics Chair - GSDCA
Canine degenerative myelopathy (DM) is a naturally occurring progressive adult-onset neurodegenerative disease that is fatal. Performing genome-wide association studies (GWAS) in Pembroke Welsh Corgis (PWC), we identified an association to a SOD1 variant, coding for the E40K amino acid substitution, that occurs in >180 dog breeds. The vast majority of breeds with DM have the same SOD1 mutation. Using PWC with the SOD1 disease allele, we compared early onset cases and elderly healthy dogs that also were homozygous for the DM risk allele. A mutation in SP110 was found to predispose to early onset DM. Given that the frequency of the SOD1 mutation and disease is variable within and across breeds we believe that multiple additional genes may affect at what age the disease starts. Overall, we have collected over 20,000 German shepherd dogs (GSD) dogs and genotyped them for the standard SOD1 mutation. The disease is frequent and the allele frequency in GSD is 35%. In this proposal we will perform health updates for already collected and novel GSDs and look at the age of first appearance distribution. We will then select up to 250 old healthy dogs to compare them to the 250 dogs with the earliest appearance (both categories having two copies of the SOD1 mutation). This should identify novel modifier genes determining if SOD1+ dogs get the disease early or late (or not at all). Finally, we will perform whole-genome sequencing of three GSDs with the disease, but lacking the known SOD1 mutation, to identify additional risk factors.
The DM research sample form is for dogs participating for our now approved DM Research study.
The study is looking for samples for any dog with DM and those that are 7 years and older who are healthy. To submit for the Research, use the "2021 DM Research" form. For a regular submission of a younger unaffected dog, use the plain DM sample form.
2021 DM Research Form (for any dog with DM and those that are 7 years and older who are healthy)
Genetics of fibrotic myopathy in the German Shepherd Dog
September 19th, 2019
Breed(s): German Shepherd Dog and other breeds affected with fibrotic myopathy
Study Type: DNA samples obtained from blood
Study Location: University of Wisconsin-Madison
Fibrotic myopathy is a specific clinical syndrome with a highly characteristic presentation of profound hindlimb lameness and fibrous contracture of thigh musculature (semitendinosus and gracilis). Diagnosis can be confirmed by physical examination. One or both hindlimbs may be affected. Affected hindlimbs have a shortened stride with a rapid elastic internal rotation of the foot, external rotation of the hock (ankle) and internal rotation of the stifle (knee) during the swing phase. This characteristic gait is caused by altered stifle and hock range of motion. Palpation of the medial thigh reveals a firm taut band extending from the midline of the pelvis to the caudomedial aspect of the stifle. The gracilis muscle is usually more severely affected than the semitendinosus. Palpation of the affected muscles is often painful. Prognosis for affected dogs is very poor. There is no curative treatment and dogs experience permanent disability. Surgical cutting of the fibrotic band in the thigh is unsuccessful as the contracture recurs within a few months. Medical therapy is generally unsuccessful, although, anecdotally, stem cell injections may help mobility over time.
The cause of fibrotic myopathy is not known. Most cases are German Shepherd Dogs, particularly males. Fibrotic myopathy is extremely rare in other breeds, but has been diagnosed in 3 Doberman Pinschers, 2 Belgian Shepherds, 1 St. Bernard, and 1 Old English Sheepdog. This marked breed predisposition suggests the disease is genetic. Fibrotic myopathy is likely a simple (Mendelian) genetic disease in which a single mutation causes the condition.
Further investigation of the genetics of fibrotic myopathy is needed. Data from the Comparative Genetics Laboratory at the University of Wisconsin-Madison suggest that fibrotic myopathy in the German Shepherd Dog is very likely a recessive Mendelian genetic disease, meaning that there is a simple mode of inheritance where dogs with two copies of the mutated gene develop the disease and dogs with only one copy of the mutation are carriers of the disease and are healthy clinically. We are studying the German Shepherd Dog for this work because support from the breed organization and strong engagement with this project by the community of German Shepherd Dog owners.
Our work will advance discovery of the causal genetic variant(s) for fibrotic myopathy. This will not only advance genetic testing for the disease and development of new treatments for affected dogs but will also inform understanding of human muscle injury.
Participation Requirements:
Cases must be purebred German Shepherd Dogs with a pedigree affected with fibrotic myopathy. Although very rare, we also wish to study purebred dogs of other breeds with fibrotic myopathy. Unaffected control dogs must be purebred German Shepherd Dogs with a pedigree over the age of 9 years with no history of fibrotic myopathy or other muscle problems.
Owner's Responsibilities (Samples and Information to be collected):
All dogs will be recruited with signed consent from their owners. A copy of the pedigree will be collected from each dog recruited to the study. All dogs will have a blood sample drawn for DNA isolation and genome-wide genotyping or whole genome sequencing. For cases we request photographs of the dog and information from clinical examination. Unaffected controls need to be evaluated at the UW School of Veterinary Medicine to verify physical exam findings confirm absence of fibrotic myopathy. Dog age and sex will also be recorded.
More information regarding the Comparative Orthopaedic & Genetics Laboratory
For the opportunity to make a financial gift to this project!
Contact Information:
Names: Dr. Emily Binversie, Dr. Peter Muir
Email: genetics@vetmed.wisc.edu
Phone: 608-265-5828
Facebook: Comparative Genetics Laboratory at UW School of Veterinary Medicine
Is Canine Epilepsy Associated with Gut Dysbiosis?
Participate from home!
The Companion Animal Epilepsy Research program at NC State University College of Veterinary Medicine is recruiting for a new clinical trial to determine whether dogs with idiopathic epilepsy have alterations in their gut microbial population. Our study team is looking for households with an epileptic dog and an unaffected dog to compare the bacterial populations within their gastrointestinal tract. Feces will be collected from both dogs to compare their gut microbiome.
PARTICIPATION-
STUDY BENEFITS (FREE OF CHARGE TO PARTICIPANTS)
INCLUSION CRITERIA -
For more information or to enroll your dogs, contact Julie Nettifee, RVT, BS, VTS (Neurology): janettif@ncsu.edu
go.ncsu.edu/epilepsyresearch
Principal Investigator Cheryl London, DVM, PhD at Tufts University School of Medicine recently sent her Final Report on her grant "Identification of Novel Synthetic Lethal Partners to Optimize P13K Targeted Therapies in Canine Hemangiosarcoma".
The American German Shepherd Dog Charitable Foundation helped fund this American Kennel Club Canine Health Foundation study.
Carolyn Z. Gerganoff – Health and Genetics Chair - GSDCA
A conversation with Dr. Robert A. Grahn, Ph.D, UC Davis about the status and predictability of current Degenerative Myelopathy (DM) testing.
I had the requirements for the GSDCA Health Award of Merit recently sent to the membership via Constant Contact. I received numerous emails about why Degenerative Myelopathy (DM) testing had to be submitted on a nominee, however the results were not disqualifying. Those who had lost dogs to DM were understandably upset by this. When I went to the University of Missouri website, the DM information was dated 2009. I reached out to University of Missouri to see if they had any updated information. To date, I have not heard back.
I saw that UC Davis also provided DM testing so I reached out to them to see if they could provide me with any updated information. Dr. Robert A. Grahn, Ph.D, Associate Director of Service and Test Development, Forensic Analyst/Technical Reviewer, Veterinary Genetics Laboratory, University of California at Davis, was kind enough to respond to me and provided me with considerable information and explanations for the current status of DM testing for German Shepherds. Below is a summary of our conversation.
The genetic DM test that UC Davis does is the same test as the University of Missouri.
First, we should clarify some terminology. The types of test results vary depending on the test being done, such as tests for Hip Dysplasia will range from Excellent, Good, and Fair as passing, to Borderline, Mild, Moderate and Severe as not passing. DNA based genetic testing looks at the two genes or alleles associated with a specific disease or condition. An individual gets half of their genes from the dam and half of their genes from the sire. When we submit our dogs for DNA based genetic testing, we expect to get one of three results, “Clear” / “Normal” (N/N), “Carrier” (A/N) or “Affected” (A/A) or At Risk, depending on the disease being tested. For DM, the more appropriate term is “At Risk.”
Dr. Toedebusche advised Dr. Grahn that some older dogs with one copy of the gene can develop the disease. If that is the case, “Carrier” is not appropriate. As devil’s advocate, the research community is operating under the hypothesis that there is something else, then maybe one copy is not relevant, and these DM carriers have two copies of something else below.
I have included a simple which demonstrates the statistics of getting an Affected or Carrier based on the genetic test results for each parent.
The primary purpose of doing genetic testing on our dogs is to facilitate our improving the health of our breed, while at the same time breeding to the standard. The original thought with testing was that if a dog came back as “Affected,” then that individual dog would be removed from the breeding pool. But the Geneticist soon realized we were going to narrow our gene pool so severely as to destroy the breed. So, the thought now is to do the testing and use the results as tools to breed intelligently. If you have an outstanding individual who tests as “Affected” or “At Risk” on a specific DNA test, you do not have to necessarily exclude that individual from your breeding program. You just need to insure that “Affected” / “At Risk” individuals are only bred to “Clear” and then your litter will be “Carriers.” Then the next generation, again breed to “Clears” and that generation will be a combination of “Clear” and “Carriers.”
A diagnosis of DM is one of exclusion and only confirmed upon necropsy.
Unfortunately, the test for DM is not a definitive test at this time for German Shepherds, but it is the best available to us. The University of Missouri identified the SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis (ALS/Lou Gehrig’s Disease). It is believed that the SOD1 mutation in conjunction with something else causes DM. Some breeds have already identified that “something else”, such as Bernese Mountain Dogs have identified a second mutation/gene, that when paired with the SOD1 mutation, is a 95% predictor of DM.
The reason the SOD1 test results are not a failing consideration in the GSDCA HAM, is that some dogs who test “Clear” for the current DM test later develop DM. Just as some dogs who test “At Risk” never develop DM. Most dogs that have the SOD1 mutation will develop DM, and some dogs that do not have the SOD1 mutation will develop DM. Additional research has been conducted by specific breeds. Attached is a link to research conducted on Pembroke Welsh Corgis. In this study, it revealed an additional mutation within the SP110 was present in 40% of Affected dogs versus 4% of dogs not affected. The research suggests that this variation in the SP110 in addition to the SOD1 may help identify the true risk an individual has at developing DM.
The Health and Genetics Chair/GSDCA is looking at what would be involved in funding similar research in German Shepherds. As UC davis neurologist Dr. Toedebusch (DVM, PhD, DACVIM (Neurology)) notes, “It bugs me that only a few breeds get dominant disease, so there must be a modifier(s). We just need to find them.”
A diagnosis of DM is often one of exclusion and only confirmed upon necropsy. At necropsy, the caudal thoracic spinal cord needs to be evaluated by a pathologist. There are a few ways to do this: 1) the dogs could be euthanized and tissue harvested by the referring veterinarian, but taking the spinal cord out of a German Shepherd dog is a lot of work and most general practitioners do not have access to appropriate equipment. 2) The whole dog could be submitted by the primary veterinarian for necropsy at any diagnostic lab. 3) The dog could come in through UCD for euthanasia and free necropsy, but the appointment would be probably cost $300-400. If it is necessary to obtain several dozen dogs, it might be best to run a clinical trial of sorts, where the dogs are clinically evaluated and then euthanized.
Dr. Christine advised they were not sure what the cost per sample would be if UC Davis submitted the cords themselves. In this scenario, Dr. Grahn would have to take out the spinal cords, or we could train a resident (I like this idea ☺). It’s a bit of work to get the cords out of a big dog. I do not miss it from grad school…..I can find out.
I asked Dr. Grahn what the cost per dog would be and how big of a sample size would they need. Dr. Grahn advised UC Davis can operate under $400/dog for clinical work-up and necropsy. He stated ‘I think for whole genome sequencing I would want 10 dogs with DM. These would need to be DM SOD1 clear (N/N) so I would want to test them first and getting enough could be a task. To be safe it would also be best to have 10 clear DM dogs (so really old dogs with no DM) that are also confirmed by necropsy. These are the ones I would whole genome sequence- which costs about $16,000. (we could do this with 5 and 5 and if we get the answer no more would be necessary). The histopathology will cost more- Dr. Christine indicated she would look into that. Dr. Grahn advised “I could probably do the genome wide association study with buccal samples but blood would be better. The 10-20 above could be used but it I would need at least 20 samples from DM positive, SOD1 negative dogs and 40 DM negative and SOD1 negative dogs (these would need to be old dogs). 60 dogs at $110 = $6600.
I would need to genotype all dogs and this could become a large number given what we are looking for- or people will come forward with exact dogs we need.
Other considerations (maybe for a later study)
The other thing is Dr. Toedebusche is also interested in DM carriers who get disease. These could be part of the "something else" or something completely unrelated.
An additional thing- do dogs with two copies of SOD1 but do not develop disease have something protective? If would great to whole genome sequence 10 very old SOD1/SOD1 positive dogs who are DM- along with including a GWAS group of these (an additional 10).”
Additionally, there are other diseases that mimic DM and can lead to a misdiagnosis, such as Type II intervertebral disc protrusion, neoplasia or other primary axonal diseases. Type II disc disease is the most common offender, particularly in an older German Shepherd dogs.
We got a German Shepherd donated today with DM symptoms. They will post him, Dr. Christine will check the cord and I will run the sample for SOD1.
We will keep you informed as we move forward in trying to further identify what dogs are at risk, so that hopefully, we can breed this dreaded disease out of our breed.
Dr. Kerstin Linblad-Toh, Scientific Director, Vertebrate Genomics, Broad Institute of MIT and Harvard, was one of the researchers on the Corgi study. I have previously worked with her on various DNA collections I have done. I reached out to Dr. Linblad-Toh about doing similar research for German Shepherds. She has previously conducted DM research jointly with University of Missouri. She advised me they had submitted a grant proposal to NIH for funding, however, it appears that the only studies receiving NIH funding are those involving cancer. Dr. Linblad-Toh submitted a research proposal for DM in German Shepherds.
I will do my best to keep everyone informed on the direction and status of any research. My goal is to provide updates on the GSDCA Health and Genetics’ website.
Sample Submission Information and PDF Form
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