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HealthCommittee – Page 2 – PBGVCA Health Committee Reference Center

Beagles Are Among Breeds Prone To Steroid-Responsive Meningitis-Arteritis

Beagles Are Among Breeds Prone To Steroid-Responsive Meningitis-Arteritis
Fall 2019
(Used with permission from the Beagle Update, Nestle Purina PetCare.)

Given his handsome looks and outgoing charm, “JR” (GCH Pun Kotzky Jolly Roger Of Sunbriar CD BN RA CA TKI), a 15-inch tricolor male Beagle, easily finished his show championship title. When he was 2 1/2 years old, JR earned an invitation to the Top 20 competition at the 2015 National Beagle Club (NBC) National Specialty.

“JR,” a 15-inch tricolor male Beagle
“JR,” a 15-inch tricolor male Beagle, pictured with owner Susan Sprout, was successfully treated for SRMA.

Months before the National, JR started to limp in his right rear leg and seemed “out of sorts,” recalls owner Brett Sprout of Alliance, Ohio. Soon he recovered and resumed his winning ways only to become suddenly lame again, this time favoring his right front leg.

“The veterinarian thought that JR had an orthopedic problem affecting his legs,” Sprout says. “He took X-rays of JR’s legs and had a specialist examine him. They posted JR’s radiographs on VetRad, a teleradiology internet site for veterinarians, hoping someone would offer clinical suggestions. No one provided feedback.”

Meanwhile, JR’s limping continued to come and go. “One day he would seem all right, and then the lameness would return,” says Sprout.

Sadly, JR missed the 2015 National Specialty because he was too lame to compete and seemed to be in pain. “We were beginning to think JR was on a path leading to a bad end,” Sprout says. “It appeared that he was not enjoying life.”

Sprout and his wife, Susan, attended the National Specialty that year at Purina Farms in Gray Summit, Missouri, without JR. Querying fellow Beagle owners about JR’s mysterious condition, Sprout wasn’t getting anywhere — until he talked to Darlene Stewart, chair of the NBC Health and Genetics Committee. That conversation may have saved JR’s life.

“Darlene homed in on a likely cause of the problem, and the more we talked, it seemed more and more plausible,” Sprout says. “As she described ‘Beagle pain syndrome,’ an inflammatory neurological disorder in dogs now known as steroid-responsive meningitis-arteritis (SRMA), it seemed that this could be the diagnosis. As it turns out, Beagles are among the breeds predisposed to developing this condition.”

When the Sprouts returned home, they shared the information with JR’s veterinarian. After confirming that SRMA was a likely cause of JR’s pain, the veterinarian began treatment with a corticosteroid, prednisone. Within a day, JR was better.

“We were concerned that JR’s pain was becoming unbearable and we might have to euthanize him, but after treatment he became a new dog,” Sprout says.

Stewart (AlaDars) of Theodore, Alabama, was no stranger to SRMA. Nearly two decades earlier, her 14-month-old 15-inch tan-and-white female Beagle, “Sandi” (CH AlaDars Sandwitch), started moving hesitantly as if in pain in her shoulders or neck. The veterinarian began treating her with steroids for a perceived disc disorder. Sandi responded well, so the cycle of treating her with steroids for intermittent pain continued for many years.

At age 8, Sandi suffered a severe bout of pain and was so unresponsive to treatment that euthanasia seemed the only choice. Desperate for answers, Stewart scoured the veterinary literature and found an obscure article describing signs that fit Sandi perfectly. Her veterinarian followed the suggested treatment, and Sandi improved within a day.

“Sandi,” a 15-inch tan-and-white female Beagle
“Sandi,” a 15-inch tan-and-white female Beagle, enlightened owner Darlene Stewart about SRMA when she was diagnosed at age 8 after years of suffering from the neurological condition.

“She never had another severe episode, but at the first sign of her ‘headache look’ I would start her on prednisone for about a week,” Stewart says. “Sandi lived to be 16 and ultimately died of cancer.”

Through the years, Stewart has heard many stories of Beagles experiencing clinical signs and pain similar to Sandi. The typical scenario is a young hound that suddenly develops acute neck pain and lethargy that may progress to whole body pain and often includes lameness and fever. Veterinarians initially presume a dog has suffered an injury or may diagnose disc disease or bacterial infection. Chronic cases may develop other neurological deficits, such as incoordination or weakness of the limbs.

The disorder originally was known as Beagle pain syndrome because it was first recognized in Beagles exhibiting signs of pain, lameness and fever. An article published in 1989 in Toxicological Pathology on these dogs reported that veterinarians at Cornell University suspected this was an unusual syndrome in Beagles and that cases as far back as 1973 seemed to match Beagle pain syndrome. In the 1990s, several large-scale studies reported on the syndrome occurring in various breeds. Once such study was published in 1994 in the Journal of Small Animal Practice.

The good news is that the pain and other clinical signs of the disease resolve with treatment. Antibiotics and rest are not effective in treating dogs with SRMA. Rather, it is the anti-inflammatory benefits of corticosteroids that help to resolve the clinical signs of SRMA. Not a lot is understood about the cause of SRMA, but it is believed to be an immune-mediated condition.

“Steroid-responsive meningitis-arteritis is a common inflammatory disease of the nervous system of dogs involving the meninges, or membranes that cover the brain and spinal cord, and associated arteries,” says Karen Muñana, DVM, MS, DACVIM (Neurology), professor of neurology at North Carolina State University. “Clinical signs are resolved in most dogs with treatment, but relapses may occur as treatment is tapered or discontinued. Little is known about what triggers SRMA.”

A recently completed study at North Carolina State University evaluated clinical and treatment differences among breeds of dog with acute SRMA and surveyed owners to learn about the quality of life of affected dogs. The research, led by neurology resident Jeanie Lau, BVSc, working with mentor Dr. Muñana, was funded through the AKC (American Kennel Club) Canine Health Foundation Clinician-Scientist Fellowship program.

“The AKC Canine Health Foundation was excited to support this important research, and we are thankful to the breeders who participated in the study,” says Dr. Diane Brown, CEO of the AKC Canine Health Foundation. “We are interested in further supporting investigations into this disorder of young dogs and raising awareness among breeders and the veterinary community.”

“Our retrospective study included 61 dogs,” Dr. Lau says. “We sent an online survey to the owners of 29 dogs identified through an AKC Canine Health Foundation survey and 32 dogs treated at the North Carolina State Veterinary Hospital. Among the questions, we asked owners to rate their dog’s quality of life during treatment, during clinical resolution and since being diagnosed with SRMA.”

The first study of SRMA in dogs in the U.S., the research was published online in the June 7, 2019, issue of the Journal of Veterinary Internal Medicine. The study provided insightful information that included identifying two breeds not previously recognized as being susceptible to SRMA — Golden Retrievers and Wirehaired Pointing Griffons. A review of the medical records of affected dogs looked at their age, breed, sex, neuter status, body weight, length of time between clinical signs and treatment, duration of treatment with corticosteroids, and results of additional diagnostic tests.

All dogs in the study experienced lethargy and neck pain. Many also had decreased appetite and were reluctant to rise or walk and had a stiff gait. Some dogs had a crouched posture or tremors. About three-quarters of the dogs had fever, and 38 percent of dogs had a temperature greater than 104 degrees Fahrenheit.

The study charted four outcomes: 1) clinical resolution, 2) relapse, 3) clinical remission, or 4) death for reasons unrelated to SRMA. A relapse was defined as recurrent clinical signs that resolve completely after treatment with an increased dosage of corticosteroids and the addition of a second immunomodulatory drug or both. Clinical remission was the absence of clinical signs after beginning corticosteroid treatment, and clinical resolution was the absence of clinical signs after completing corticosteroid treatment.


“We asked owners to rate their dogs’ quality of life on a scale of one to 10, with one being poor and 10 being excellent,” Dr. Lau says. “The mean quality of life for dogs during treatment was significantly worse than during clinical resolution and since being diagnosed with SRMA. This was associated with the severity of prednisone’s adverse effects. When we asked owners to assess the severity of their dogs’ neck pain at onset, around 77 percent noted improvement of clinical signs within one to two days of starting prednisone.”

Among the negative effects owners noted about continued use of prednisone were: polydipsia (excessive thirst), polyuria (excessive urination), polyphagia (excessive hunger), panting, weight gain, thinning of hair coat, restlessness, sleeping more than usual, inappropriate urination, “pot belly” appearance, development of non-dermatological infections, diarrhea, dermatitis, and vomiting.

“Any breed can develop SRMA, though a predisposition was previously recognized in several breeds,” Dr. Muñana says.

Breeds previously considered predisposed include: Beagle, Bernese Mountain Dog, Border Collie, Boxer, English Springer Spaniel, Jack Russell Terrier, Nova Scotia Duck Tolling Retriever, Weimaraner, and Whippet. The two newly recognized breeds prone to SRMA were highly represented in the study. Golden Retrievers had the highest incidence with 12 dogs affected, and Wirehaired Pointing Griffons had the third-highest incidence with nine dogs affected. Other breeds with a high prevalence were: Bernese Mountain Dogs with 10 dogs affected, Boxers with nine dogs affected, and Beagles with six dogs affected.

“Our findings suggest that Golden Retrievers and Wirehaired Pointing Griffons should be included among breeds recognized to develop SRMA,” says Dr. Muñana. “Golden Retrievers were included in a previous study of SRMA, but Wirehaired Pointing Griffons had not been previously described with SRMA.


“Further, we saw that the Wirehaired Pointing Griffon had a significantly higher number of prednisone-related adverse effects compared to other breeds. This is likely because they were treated with substantially higher prednisone dosages when compared to Beagles, Bernese Mountain Dogs and Golden Retrievers. It also could be due to the difference in their lifestyle as a hunting breed or could reflect an increased genetic susceptibility to corticosteroid-related adverse effects.”

SRMA typically affects dogs from 6 to 18 months of age. The median age at which dogs in the North Carolina State study were diagnosed was 8.5 months, with 95 percent of dogs being under 2 years of age. The study comprised 34 males, 18 intact and 16 neutered, and 27 females, six intact and 21 spayed.

“Diagnosis is based on increased numbers of neutrophils, a type of white blood cell, in the cerebrospinal fluid (CSF) of affected dogs and exclusion of other infectious diseases combined with a positive response to corticosteroids,” Dr. Muñana says. “Some neurologists use magnetic resonance imaging (MRI) to rule out clinically similar conditions, such as intervertebral disc disease, though an MRI is a costly procedure and is not required to diagnose SRMA, particularly in a young dog with signs typical of SRMA.”

A newer noninvasive, more affordable test involves measuring the level of C-reactive protein (CRP), a substance produced by the liver in response to inflammation in the blood serum indicating systemic infection. In affected dogs, the CRP level is elevated parallel to that of neutrophils in CSF.

“CSF analysis is useful for an initial diagnosis followed by CRP analysis to monitor a dog’s response to therapy,” Dr. Muñana says. “Since therapy is associated with side effects, some of which can be quite serious, I do not recommend treatment unless it is supported by a diagnosis.”

The most effective treatment for dogs with SRMA is immunosuppressive dosages of corticosteroids given over several months. “Most dogs improve dramatically within one to three days, then continue on daily high doses of prednisolone or prednisone for four to eight weeks, though some dogs may continue treatment for six months to a year,” says Dr. Muñana. “During this time, dogs should have regular blood work to ensure they are tolerating the steroid therapy and to monitor CRP levels.”

The long-term prognosis for young dogs with acute SRMA is fair to good. Most dogs — at least 80 percent — respond well to the initial course of steroids. About 10 to 15 percent relapse during treatment, and about 20 to 30 percent relapse in the month following discontinuation of treatment. A few dogs will relapse over a year after treatment ends. Some dogs require lifelong therapy.

Whereas acute cases respond well, chronic SRMA is more challenging to treat, says Dr.Muñana. “Chronic SRMA develops in dogs that are not diagnosed and treated in a timely manner or that have recurring relapses. Chronic cases have fewer CSF abnormalities than dogs with acute SRMA, but the abnormalities are consistent with chronic infection. Their treatment is the same — high-dose immunosuppressive corticosteroids, and a second immunosuppressive drug is usually needed.”

“Our research included identifying factors associated with the frequency of relapses and owners’ assessments of the severity of relapses in the 29 dogs that relapsed,” Dr. Lau says. “Among the variables we studied were the age at onset of clinical signs, prednisone dosage and treatment duration, treatment with a second immunomodulatory drug at initial diagnosis, and duration between onset of clinical signs and initiation of treatment.”

Treatment results on prednisone were excellent, with 29 dogs having complete resolution of clinical signs for a median of 37 months. In 25 dogs, remission was achieved, thus they began a tapering schedule to reduce prednisone at follow-up. One dog was euthanized due to developing neurological problems during relapse.

As with the success JR and Sandi experienced, treatment results show that dogs with SRMA have an excellent prognosis for remission and a fair to good prognosis for resolution, with remission and resolution rates of 98.4 percent and 54 percent, respectively. “Most dogs experience improvement within 48 hours of beginning treatment,” says Dr. Muñana.

Reflecting, Dr. Lau says, “As a retrospective study, this had several limitations including that the accuracy of the completeness of the data collected was dependent on the information available in the dogs’ medical records. We also were limited in the numbers of particular breed cases, and this restricted the power of the study.”

Many questions remain. “I think the most pressing questions involve determining optimum treatment and the cause of SRMA, including whether there is a genetic basis,” Dr. Muñana says. “Our team feels further investigation is warranted to learn the influence of individual breeds on disease severity and its clinical course and how it impacts a dog’s quality of life.”

Meanwhile, Sprout’s hound JR has rebounded and resumed a busy performance career. At the 2017 NBC National Specialty, JR earned High in Trial in obedience with a score of 194, and he made the final cut for Best of Breed. At the 2018 and 2019 Rally National Championships, JR was the highest-scoring Beagle.

“We recently started JR in agility, and he has already earned two Q’s out of two attempts,” Sprout says proudly. “Plus, he is a bronze Grand Champion. Everything he has achieved has been possible thanks to a conversation with Darlene Stewart at the 2015 National.” 

Purina appreciates the support of the National Beagle Club, particularly Darlene Stewart, chair of the Health and Genetics Committee, for helping us to identify topics for the Beagle Update.


  • Neck pain
  • Lethargy
  • Reluctance to rise or walk
  • Stiff gait
  • Decreased appetite
  • Kyphotic posture
  • Tremors
  • Diarrhea
  • Vomiting
  • Inappropriate urination

*Source: Lau J, Nettifee JA, Early PJ, et al. Clinical Characteristics, Breed Differences, and Quality of Life in North American Dogs with Acute Steroid-Responsive Meningitis-Arteritis. Journal of Veterinary Internal Medicine. 2019;33(4):1719-1727.

Beagle Update articles may be reprinted provided the article is used in its entirety and in a positive manner. To request permission to reprint this article, please contact the editor at: Barbara.Fawver@purina.nestle.com. Reprints should include the following attribution: Used with permission from the Beagle Update, Nestlé Purina PetCare.

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Glaucoma-causing ADAMTS17 Mutations

Glaucoma-causing ADAMTS17 mutations are also reproducibly associated with height in two domestic dog breeds: selection for short stature may have contributed to increased prevalence of glaucoma

BioMed Central Ltd, Canine Genetics & Epidemioloy, May 17, 2019
By Emily C. Jeanes, James A. C. Oliver, Sally L. Ricketts, David J. Gould & Cathryn S. Mellersh

In humans, ADAMTS17 mutations are known to cause Weill-Marchesani-like syndrome, which is characterised by lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Breed-specific homozygous mutations in ADAMTS17 are associated with primary open angle glaucoma (POAG) in several dog breeds, including the Petit Basset Griffon Vendeen (PBGV) and Shar Pei (SP). We hypothesised that these mutations are associated with short stature in these breeds. Learn more

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Cancer Link Resources

Bartonella Bacteria Found in Hemangiosarcoma Tumors from Dogs
Veterinary Medicine News, January 15, 2020 Learn more..

UC Davis Veterinarian Having Success with Innovative Prostate Cancer Treatment
June 16, 2015 Learn more

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Nutrition Link Resources

RVC research finds potential in ground-breaking new dietary treatment for canine epilepsy, Royal Veterinary College University of London, May 14, 2020. Funded by the American Kennel Club Canine Health Foundation. Learn more

Natural Remedies For Dog Ear Infections
dogsnaturallymagazine.com Learn More

Diet-associated dilated cardiomyopathy in dogs: what do we know?
Lisa M. Freeman DVM, PhD;  Joshua A. Stern DVM, PhD;  Ryan Fries DVM;  Darcy B. Adin DVM;  John E. Rush DVM, MS
December 1, 2018 Journal of the American Veterinary Medical Association Learn More

Echocardiographic phenotype of canine dilated cardiomyopathy differs based on diet type
By Darcy Adin DVM, Teresa C. DeFrancesco DVM, Bruce Keene DVM, Sandra Tou DVM, Kathryn Meurs DVM, PhD, Clarke Atkins DVM, Brent Aona DVM, Kari Kurtz DVM, Lara Barron DVM, Korinn Saker DVM, PhD
December 2018 Journal of Veterinary Cardiology  Learn more

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Cardiovascular Link Resources

Diet-associated dilated cardiomyopathy in dogs: what do we know?
By Lisa M. Freeman DVM, PhD;  Joshua A. Stern DVM, PhD;  Ryan Fries DVM;  Darcy B. Adin DVM;  John E. Rush DVM, MS
December 1, 2018, Journal of the American Veterinary Medical Association

(Dilated cardiomyopathy (DCM) is a disease of the heart muscle that is characterized by an enlarged heart that does not function properly.)
Learn more

Echocardiographic phenotype of canine dilated cardiomyopathy differs based on diet type
By Darcy Adin DVM, Teresa C. DeFrancesco DVM, Bruce Keene DVM, Sandra Tou DVM, Kathryn Meurs DVM, PhD, Clarke Atkins DVM, Brent Aona DVM, Kari Kurtz DVM, Lara Barron DVM, Korinn Saker DVM, PhD
December 2018 Journal of Veterinary Cardiology Learn more


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Should We Breed With Carriers?

By Cathryn Mellersh, Animal Health Trust, November 2011

carrier‘ is the term given to an individual (of any species) that carries a single copy of a recessive mutation that is associated with a specific inherited condition, usually an inherited disorder. An individual will only suffer from a recessive disorder if in inherits two copies of the causal mutation, one from each parent. If it inherits a single copy of the mutation it will remain healthy but will pass the mutation on to about half of its offspring.

Breeding with Carriers
Once a specific disease mutation has been identified a DNA test can be developed that enables the identification of non-symptomatic carriers. Knowing which dogs carry the mutation and which don’t (the so-called ‘clear’ dogs) enables breeders to make sensible choices about the dogs they mate together. All dogs can be safely bred with provided at least one of the mating pair is clear of the mutation (see Table below). Breeding dogs that will never develop the condition should obviously be the priority for all conscientious breeders and the desire to eliminate a disease-associated mutation from a breed should therefore be the long-term goal. But the instinct to choose only clear dogs to breed from, as soon as a DNA test becomes available, may not always be a sensible choice and the rest of this document discusses why.

If carriers are prevented from breeding the opportunity to pass the rest of their genetic material to the next generation is also lost and the genetic diversity of the remaining population is thus reduced. It is worth remembering that there is a clear and well-established link between the genetic diversity of a population and its overall health, and that breeding closely related individuals tends to lead to the accumulation of deleterious recessive mutations in the population. This is due to the fact that an individual is more likely to inherit two identical copies of a mutation if its parents share common ancestors than if they are unrelated, and the more com man ancestors the parents share the greater that chance is.

It is also worth remembering that the disease mutation for which there is a DNA test is not the only mutation a carrier has. Every human, on average, carries about 50 recessive mutations and there is no reason to believe the average dog won’t carry a similar number. So the only real difference between a clear and a carrier is the single mutation that can be tested for. Both dogs will both carry around 49 other mutations that the breeder doesn’t know about and can’t test for. If carriers are not bred from and clear dogs are used extensively then there is a real risk that other mutations will increase in frequency in the breed and new inherited disease(s) could emerge.

There is no reason why the eventual elimination of a disease mutation from a breed shouldn’t be the goal, once a DNA test for that mutation becomes available. But, providing all breeding dogs are tested for the mutation prior to mating, the breeders can take their time and ensure that desirable traits are not eliminated along with the disease mutation and that the genetic diversity of the breed is not reduced.

Mutation Frequency
The speed with which the mutation can be eliminated depends on several factors, including the frequency of the mutation, the population structure and the rate of inbreeding for that breed. The more frequent the mutation is the more slowly it should be eliminated. Calculating the true frequency of a mutation is not trivial, and requires a random subset of a breed be screened. Dogs that are tested once a commercial DNA test becomes available are not always representative of the breed as a whole, and similar1y cohorts of dogs that have been sampled by a research institute during development of the DNA test are also rarely characteristic of the breed.

The frequency of a mutation is typically expressed as the fraction of chromosomes in a population that carry the mutation. For example, if the frequency of a mutation is described as 0.1, this means that 10% of the chromosomes in that breed carry the mutation and the remaining 90% carry the normal copy of DNA. If 10% of the chromosomes carry the mutation then just under 20% of dogs are expected to be carriers and about 1 % of dogs will be affected.

Breeding Advice
Carriers should always be included in the first one to two generations that follow the launch of a DNA test for a recessive mutation, regardless of the frequency of the mutation, to give breeders the opportunity to capture desirable traits, such as breed type and temperament, before they start to select for dogs that are clear of the mutation. Specific breeding policy for future generations should be breed-dependent and ideally formulated after consideration of factors such as the population structure and rate of inbreeding. But in general terms, carriers should only be removed from the breeding population if the frequency of the mutation is below 0.01 (1 %), as this will mean only around 2% of dogs will be prevented from breeding. Avoiding carriers of a mutation that is more frequent will result in a greater number of dogs being prevented from breeding and could lead to a detrimental loss of diversity for the breed.

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Genetic Testing and Genetic Counseling in Pet and Breeding Animals

by Jerold S. Bell, DVM, Tufts University School of Veterinary Medicine  Jerold.Bell@tufts.edu

Genetic testing and genetic counseling are not just for breeding animals. They include; testing for the bleeding disorder von Willebrand’s disease before performing surgery on susceptible breeds, altering diets for pets that are prone to developing bladder stones or crystals, and switching from rapid growth puppy food to lower calorie foods in young, large breed dogs, so that joint tissues can develop at a more uniform rate.

The hallmark of genetic disease is the ability to predict disease before its onset. This allows the possibility of medical or surgical intervention in order to prevent later suffering. Knowledge of breed-related genetic disease and the tests that are available permit early diagnosis and treatment.

Breeders and veterinarians have been utilizing genetic tests since the beginning of domestic animal breeding. Most genetic tests measure the phenotype of an animal, or what you can see. These include radiographs, blood values, eye examinations, skin biopsies, urinalysis for crystals or metabolites, observations on structure or behavior, and ausculting for heart murmurs. Most tests of the phenotype only identify affected individuals, and not carriers. These may, or may not directly relate to the genotype, or the genes regulating the defect.

A test of the genotype is one that assesses the DNA of the animal. These tests can be run at any age, regardless of the age of onset of the disorder. Utilizing polymerase chain reaction (PCR) technology, affected, carrier, and normal individuals can be identified. As the majority of genetic disorders are recessive or have a major recessive component, the identification of carriers is important for effective management.

As additional DNA tests are developed for disorders, the role of genetic counseling becomes more important. Without these tests, the number of individuals that can be identified as carriers is low, even though many may be suspect due to having affected relatives. Breeds have closed gene pools; in other words, the diversity of genes in a given breed is fixed. The number of individuals removed from consideration for breeding based on concerns regarding a specific genetic disease is usually low. While this has slowed the management of genetic disease, it has also prevented genetic drift and diversity problems for pure breeds.

History has shown that breeders can be successful in reducing breed-wide genetic disease through testing and making informed breeding choices. However, there are also examples of breeds that have actually experienced more problems as a result of unwarranted culling and restriction of their gene pools. These problems include: reducing the incidence of one disease and increasing the incidence of another by repeated use of males known to be clear of the gene that causes the first condition, creating bottlenecks and  diminishing  diversity by eliminating all carriers of a gene from the

breeding pool, instead of breeding and replacing them, and concentrating on the presence or absence of a single gene and not the quality of the whole animal.

DNA tests have to be developed specifically for each breed (or group of related breeds that share an ancestral mutation). There are two different types of tests of the genotype; direct gene tests and linkage-based tests. Direct gene tests check for a specific mutation in a defective gene.  The animal either carries the defective gene, or does not.

Linkage-based DNA tests can be developed even if the defective gene causing a disorder has not been identified. Genome research has identified thousands of genetic markers, or “marker-DNA” that are spread across the chromosomes of the species. A linked-marker is a piece of DNA that lies close to the defective gene on a chromosome.

Breeders can use linkage-based genetic tests the same way direct genetic tests are used. The only difference is that you are not directly testing for the defective gene, only an associated marker; so false-positive and false-negative test results can occur.

A genetic crossover between paired chromosomes mixes the genes that an individual receives from its sire and dam. This occurs on a regular basis during the formation of eggs and sperm. As a defective gene and the linked marker are different areas of DNA that lie close together on a chromosome, it is possible that a genetic crossover can occur between them. This would separate the marker from the defective gene and create false positive (testing for the marker without the defective gene), or false negative (testing as normal, but having the defective gene) results. Depending on the relative distance between the marker and the defective gene on the chromosome, researchers can predict the frequency of false results for a linkage-based test; for example: 1 in 100.

If an individual’s linkage-based test for the defective gene is producing false-positive or false-negative results, all of its descendants that inherit this portion of the chromosome will also have false test results. This has been documented with families of Bedlington Terriers tested for the autosomal recessive copper toxicosis gene.

It is obvious that direct gene tests are better than linkage-based tests. However, a test with 90% or 95% confidence is better than no test at all. As genomic research progresses, researchers can identify the defective genes responsible for disorders, and can develop direct gene tests to replace linkage-based tests. The defective gene for copper toxicosis in the Bedlington Terrier has now been identified, and a direct gene test is now possible.

Based on the mode of inheritance of a disorder, and the availability of genotypic or phenotypic genetic tests, breeding management recommendations can be used to prevent or reduce the frequency of carrier or affected offspring. See the article “Breeding Strategies for the Management of Genetic Disorders” in the proceedings for specific recommendations.
Once a genetic test is developed, it allows breeders to positively determine if an individual is a carrier of a defective gene. The typical response of a breeder on finding that their animal is a carrier is to remove it from a breeding program. If a majority of breeders do this, it puts the breed’s gene pool through a genetic bottleneck that can significantly limit the diversity of the breed. The goal of genetic testing is to allow the superior genes of a breeding individual to be propagated, even if the animal is a carrier. One defective gene that can be identified through a genetic test, out of tens of thousands of genes is not a reason to stop breeding. If an owner would breed an individual if it tested normal for a genetic disease, then a carrier result should not change that decision.

Owners of carrier animals who are of breeding quality in other health, temperament, performance and conformation aspects should be bred to normal testing mates. This prevents the production of affected offspring. The breeder should be counseled to test the offspring prior to placement; to determine whether a pet or breeding home is appropriate. The goal is to replace the carrier parent with a quality, normal testing offspring that carries on the lineage of the breeding program.

If the only quality offspring is also a carrier, then breeders can use that offspring to replace the original carrier. The breeder has improved the quality of the breeding stock, even though the defective gene remains in the next generation. The health of the breed does depend on diminishing the carrier frequency and not increasing it. Breeders should therefore limit the number of carrier-testing offspring placed in breeding homes. It is important to carry on lines. A test that should be used to help maintain breed diversity should not result in limiting it.

By breeding and not selecting against carriers, breeders are selecting for a carrier frequency of fifty-percent; higher than most breed averages. Each breeder must assess the frequency of the defective gene in their own breeding stock and determine their own rate of progress. As each breeder reduces the number of carrier breeding stock, the frequency of the defective gene for the breed will decrease.

We know that most individuals carry some unfavorable recessive genes. The more genetic tests that are developed, the greater chance there is of identifying an undesirable gene. Remember, however, that an animal is not a single gene, an eye, a hip, or a heart. Each individual carries tens of thousands of genes, and each is a part of the breed’s gene pool. When considering a mating, breeders must consider all aspects – such as health issues, conformation, temperament and performance – and weigh the pros and cons.

Without tests, the management of genetic disease involves breeding higher-risk animals to lower-risk animals. Occasionally, a breeding male is determined to not carry a defective gene for which there is no carrier test. The tendency is for everyone to breed to this male, as a guarantee against the disorder.  Any major shift in the breeding choices to a limited number of males will restrict genetic diversity, and increase the possibility of propagating additional undetected defective recessive genes in a breeding population. Such genes have become widespread even in populous breeds due to prolific breeding of popular sires.

Breeders are the custodians of their breed’s past and future. “Above all, do no harm” is a primary oath of all medical professionals. Genetic tests are powerful tools, and their use can cause significant positive or negative changes. Breeders should be counseled on how to utilize test results for the best interests of the breed.

This article can be reproduced with the permission of the author. Jerold.Bell@tufts.edu

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