– DCM in the Great Dane –

July 8, 2002 – This is the third installment in a series about dilated cardiomyopathy (DCM) in the Great Dane. If you have not already done so, please take a look at installment #1 and installment #2 for additional background.

Is dilated cardiomyopathy an inherited disease?

Last week we covered some of the basics about dilated cardiomyopathy (DCM) in general – and how it relates to the Great Dane in particular. Unfortunately Great Danes are the second most common breed of dog to suffer from DCM. We're lucky in one respect, though. Dr. Kathryn M. Meurs, a professor of cardiovascular medicine at Ohio State's College of Veterinary Medicine, has been working in recent years to identify the clinical features of DCM in the Great Dane, to determine whether DCM is inherited in the breed, and if it is inherited, to determine how it is transmitted from parent to offspring. Dr. Meurs is also striving to identify a "marker gene" that can be used to develop a blood test to screen for DCM. Meurs's research has received substantial funding from the AKC's Canine Health Foundation and support from the Great Dane Health Foundation of America (GDHFA) and the Great Dane Club of America (GDCA).

In a recent paper that appeared in the Journal of the American Veterinary Medical Association (JAVMA 2001; 218: 729–732; Meurs, Miller, Wright) Dr. Meurs describes a retrospective study in which pedigrees of Great Danes with confirmed DCM "were assembled and examined for evidence of a specific mode of inheritance." Systematic evaluation of pedigrees from affected Great Danes suggested a strong family tendency. Various modes of inheritance were considered in the context of the pedigrees. An X-linked recessive mode of inheritance was determined to be the most likely. Further work is underway to definitively identify the mode of inheritance.**

What is X-linked recessive?

In humans, the X-linked mode of inheritance is responsible for: - Color Blindness - Hemophilia - Muscular Dystrophy   (Duchenne type)

Dr. Meurs's preliminary data, which strongly suggests DCM in the Great Dane is an inherited X-linked recessive trait, is hard to ignore. But what exactly is an X-linked recessive trait? If you think back to your high school biology class, you'll recall (hopefully) that females have two X chromosomes and males have one X chromosome and one Y chromosome. At the time of conception, the female provides one of her X chromosomes, and the male provides either an X or Y chromosome. If the father gives an X, the offspring will be female. If he gives a Y, the offspring will be male.

The sex chromosomes aren't the only pair of chromosomes that make up a being. Humans have 23 pairs of chromosomes; dogs have 39. Chromosomes carry genes, the principle unit of inheritance for individual traits (for example, blood type). Each gene produces a product that can influence the individual's appearance (for example, eye color) or bodily function (for example, ability to digest food). Genes are described both in terms of being present (carried) in an individual and in terms of having influence (manifesting) in an individual.

Because chromosomes come in pairs, genes for each trait are found in pairs, one coming from the mother and one from the father (genes on sex chromosomes are exceptions, as you will see below). For many traits, there are many possible versions of its gene. Often, one version of a gene will be silent when paired with any other version. A gene version of this type is called a "recessive gene" because it will only influence what the individual is like if it is not paired with a more powerful, or "dominant," version. For non-sex chromosomes, that means the recessive gene must exist on both chromosomes in the pair in order to manifest itself.

In the case of the sex chromosomes, however, the single X-linked (X-chromosome linked) recessive gene will manifest itself in males because it is "unopposed" by anything on the Y chromosome. This means if a male offspring inherits an X-linked recessive gene from his mother he will manifest that gene's influence. A good example of this in humans is hemophilia. It is extremely rare for a woman to have the recessive gene on both of her X chromosomes, but in affected families she may carry the recessive hemophilia gene on one X chromosome. For such a woman with a non-hemophiliac mate, her daughters have a 50% chance of being hemophilia carriers like herself and 50% of her sons will be hemophiliacs.

Here's the bottom line on the behavior of the X-linked recessive gene: The trait will be manifested in any males who inherit the X-recessive gene from their mother. (Their father has nothing to do with it.) The trait will be manifested in females ONLY if they have two copies of the X-recessive gene, one coming from their mother, the other from their father. If females inherit one just copy of the X-recessive gene, they will not develop the trait, but they will be carriers. Bringing this back to DCM, Dr. Meurs's data suggests DCM is a recessive X-linked version of an important gene related to the Great Dane heart. If this is true, that means: If the male carries the DCM (recessive X) gene, he is likely to develop DCM (unless something else kills him first) and he will pass the defective gene onto his female offspring only. If the female carries only one DCM (recessive X) gene, she will not develop the disease, but she will pass the defective gene onto 50% of her offspring. If the female carries two DCM (recessive X) genes, she is likely to develop DCM (unless something else kills her first) and she will pass the defective gene onto all of her offspring.

How might we predict DCM in our Great Danes?
Can you be certain that a given percentage of all pups from a carrier female will inherit her DCM gene? No, and here is why. Inheritance is like flipping a coin. If you only flip the coin once, then heads or tails will occur 100% of the time. If you flip the coin twice, you could easily get heads twice or tails twice, even though they each have a 50% chance of turning up each time. It is only by flipping the coin many times that you start to see the 50:50 odds (Try the coin flip, if you can't picture this). This illustrates why in some pedigrees DCM may appear more – or less – than predicted, because Danes generally do not have large numbers of pups. Only by studying many generations of related Danes can the pattern be detected.

In addition, there are bound to be other influences on the DCM gene besides its dominant counterparts, influences that can soften the symptoms or make them worse. That is why all Danes with the symptoms of DCM are not equally sick and do not die at the same age. These influences could be completely separate genes, elements in the dog's environment, and/or other factors. We are only beginning to understand what causes DCM in Great Danes and much additional research will have to be done to fill in the picture.

That said, you may use the charts below as a general guide to what might be expected to occur in a breeding. Keep in mind that in any single litter, it's unlikely the numbers would exactly match these percentages. In a large sampling involving multiple litters, however, the numbers would be much closer.

DCM male, clean female: In a breeding, if the sire is positive for DCM and the dam is totally clean (not a carrier), statistically here's what should happen: 1) 100% of the female puppies would be silent carriers of DCM, but none would be affected. 2) None of the male puppies would inherit the DCM gene.

DCM male, carrier female: In a breeding, if the sire is positive for DCM and the dam is a carrier, statistically here's what should happen: 1) 50% of the female puppies would be silent carriers of DCM. 2) 50% of the female puppies would be affected and at high risk for developing DCM. 3) 50% of the male puppies would be "clean." 4) 50% of the male puppies would be affected and at high risk for developing DCM.

DCM male, DCM female: In a breeding, if the sire is positive for DCM and the dam is positive for DCM, statistically here's what should happen: 100% of the puppies would be affected and at high risk for developing DCM.

Clean male, DCM female: In a breeding, if the sire is negative for DCM and the dam is positive, statistically here's what should happen: 1) 100% of the female puppies would be silent carriers of DCM. 2) 100% of the male puppies would be affected and at high risk for developing DCM.

Clean male, carrier female: In a breeding, if the sire is negative for DCM and the dam is a carrier, statistically here's what should happen: 1) 50% of the female puppies would be "clean." 2) 50% of the female puppies would be silent carriers of DCM. 3) 50% of the male puppies would be "clean." 4) 50% of the male puppies would be affected and at high risk for developing DCM.

Some additional information and comments:

• Remember that X-linked recessive traits are overwhelmingly manifested in the male population (meaning many more males are affected), yet it is the female chromosome which provides the inherited defective gene.
  
• According to Dr. Meurs, DCM in the Great Dane can develop from age 1 to age 10 (or older). For breeding stock, or dogs at risk, she recommends screening with echocardiography (ultrasound) every year. Early detection and drug treatment may slow the progression of the disease.
  
• When/if abnormalities are observed on an echocardiogram, Dr. Meurs recommends those dogs with suspect findings be held out from a breeding program for 6 months to a year. They should then be retested. If still abnormal, you may want to avoid using them for breeding.
  
• Dr. Meurs emphasizes that the perfect screening test does not exist. She would like to develop a noninvasive diagnostic test to identify DCM at an early stage before a dog is used for breeding. Her ultimate goal is to develop a genetic test for DCM. She can't do this alone. She needs the support of the Dane community.
  
• A brief Cardiomyopathy Questionnaire by Dr. Meurs is available through the Great Dane Health Foundation's website. You are invited to contribute to the ongoing DCM study by filling out the survey and mailing it directly to Dr. Meurs. Information gathered from the questionnaire will be kept strictly confidential.
  
  If you'd like to get more involved, Dr. Meurs is interested in recruiting Great Danes from families with a history of DCM. She states, "We particularly need to evaluate affected dogs as well as their family members. Additionally, we are in great need of healthy Great Danes that are at least 7 years of age who could come to Ohio State for an echocardiogram and who would be willing to donate a small blood sample. These animals will serve as 'healthy controls' and their DNA will be compared to the DNA from the affected animals."
  
  Dr. Meurs can be reached at meurs.1@osu.edu if you would like to inquire about participating. (I believe all work-ups performed on Danes for this study are free of charge.)
  
• JP Yousha, chair of the Great Dane Club of America's Health and Welfare Committee, has written an informative article on the subject of heart disease in the Great Dane. She provides information about various congenital heart defects, discusses DCM, and elaborates on Dr. Meurs' research. The article can be found on JP's website.
  
• Dr. Meurs will be speaking at the Great Dane Club of America's 2002 National Specialty in Kentucky this October. She will discuss DCM in the Great Dane, and provide us with an update on her current work. Everyone is invited to attend.

What's ahead...
Next week we'll hear from one breeder who has come forward to talk candidly about her personal experiences with DCM. If you would like to share your own comments, stories and/or insights, please drop me a line.

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— ©2002 by Ginnie Saunders