Thursday, February 18, 2010

Ragdoll Cardiomyopathy and Little Tular - The Ongoing Story

Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats. In most cats the condition develops spontaneously, for no known reason. In Maine Coons and Ragdolls, however, the disease has an inherited basis, and the genetic mutations responsible have now been identified in both breeds.

The mutation responsible for HCM in Maine Coons has been identified in the gene that codes for a protein called myosin binding protein C (MYBPC3). This protein is necessary for the heart to contract properly. Maine Coons who have this genetic mutation produce an abnormal form of this protein, resulting in dysfunctional contraction of the cardiac muscle.

The Ragdoll cat also has an inherited form of HCM. The genetic mutation also involves the gene that codes for myosin binding protein C (MYBPC3). The mutations in these two breeds did not arise from a common ancestor, because on a molecular level, the mutations are very different and are located in very different regions of the gene for each breed.

The genetics behind HCM in Ragdolls and Maine Coons is complicated. Cats have two copies of every gene – one from each parent. The inherited form of HCM in Maine Coons is an “autosomal dominant” trait. This means that males and females are equally susceptible; every affected cat has at least one affected parent; and the trait is observed in every generation. Maine Coons may carry the mutation on one or both copies of the gene. If they have the mutation on both copies of the gene, they are said to be “homozygous” for the mutation. If bred, they will pass one copy of the mutated gene to all of their offspring. If only one copy of the gene has the mutation, with the other copy being normal, they are said to be “heterozygous” for the mutation. Heterozygous cats, if bred, will produce offspring with a 50% chance of having the gene. Note that this does not mean that 50% of the kittens will carry the gene. Rather, each kitten has a 50% chance of having the mutation. Some litters may end up with 0% having the mutation; others may have 100%. To further complicate matters, the gene is inherited with “incomplete penetrance”. This means that cats who have the mutation will have different degrees of severity of HCM, depending on the “penetrance” of the trait. Some cats with the gene may develop severe cardiac disease, while others may never show any clinical signs of illness. The mode of inheritance has not been completely elucidated in Ragdolls but it is believed to be autosomal dominant as well.
Maine Coons who are homozygous for the gene (two copies of the mutated gene) may develop a more severe form of HCM, often showing signs of the disease before the age of 4. Heterozygous cats (one copy of the mutated gene) develop HCM at a later age and tend to have milder disease.

Ragdolls that are homozygous for the mutation develop a severe form of the disease, often succumbing to heart failure before the age of 2. Heterozygous cats develop a much milder form of the disease.

In early November of 2009, I examined Tular, a 14 month-old Ragdoll belonging to Laura Piskin. Ms. Piskin was concerned because Tular kept getting upper respiratory infections that responded to antibiotics initially, but never seemed to fully resolve.

On physical examination, the cat was 8 ½ lbs. She had mild upper respiratory signs – a few sneezes, but hardly any eye or nasal discharge. No fever. All body systems checked out okay except… she had a heart murmur. We like to grade heart murmurs on their intensity, on a scale from 1 to 6. This was a 2 out of 6. Not very loud, but definitely present. And, the fact that she was a Ragdoll had me concerned. I recommended a cardiac ultrasound, and Ms. Piskin readily agreed.

Two weeks later, the ultrasound was performed. The mitral valve (the valve on the left side of the heart that separates the left atrium from the left ventricle) wasn’t closing perfectly. This was the cause of the murmur, and is a pretty minor problem. Of potentially greater consequence, however, was another finding: the wall of left ventricle was a little bit thicker than normal. Thickening of the ventricle is the cardinal sign of hypertrophic cardiomyopathy (HCM). Also, the papillary muscle (a piece of muscle that branches off the inside wall of the ventricle) was a little thickened as well.

Was this the start of a progressive heart problem? Or was this normal for this particular cat? It’s hard to say, based on just one ultrasound. In order to tell, you have to repeat the ultrasound in a few months and see if there is any progression. The ultrasonographer noted that the heart was functioning perfectly normally, and he recommended no medicine at this time.

I was curious, though. Heterozygous Ragdolls (those with only one copy of the mutated gene) often develop only a mild form of HCM, with one of the features being mild papillary muscle thickening. Homozygous Ragdolls (those with two copies of the mutated gene) usually develop a more severe form of the disease and tend to go into heart failure at a very young age. So how do we know if Tular was heterozygous or homozygous?

Genetic testing is available to test Maine Coons and Ragdolls for the presence of the mutation. A DNA specimen is required. This is accomplished using blood, or using a cotton swab that has been rubbed on the gums or inside the cheek. The cheek swab is especially useful for testing young kittens from whom it might be difficult to obtain a blood sample. Testing will determine whether the cat is heterozygous, homozygous, or negative for the mutation. If a Maine Coon or Ragdoll tests negative for the mutation, it does not mean that the cat will never develop HCM. Rather, it means that they will not develop the form of HCM that is known to be caused by the specific gene mutation.

Results reported from genetic testing laboratories have revealed that the worldwide prevalence of the gene in Maine Coon cats is 35%, i.e. approximately 1 out of 3 Maine Coons carry the gene. Of the Maine Coons carrying the gene, only 9% are homozygous. The prevalence in Ragdolls is 28%, with only 8% being homozygous.
I asked Ms. Piskin if she wanted me to test her cat. I guess this is where the internal philosophical debate begins. If you have the opportunity to run a test that tells you if your cat is doomed, do you do it? Or would you rather not know? Ms. Piskin was undecided. She said she’d get back to me with her decision.

A few weeks later, she called. “Let’s do it”, she said. “Not knowing is making me crazy.”

I obtained a blood sample from Tular and sent it to Washington State University . Given the statistics – 92% of Ragdolls with the mutation are heterozygous, and only 8% are homozygous – I was feeling optimistic that Tular would be heterozygous and that we would ultrasound the heart every six months and track the progression, prescribing or adjusting medication as necessary. Unfortunately, this was not to be. Tular was homozygous; she had two copies of the mutated gene.

Ms. Piskin was very upset, as you could imagine. She called the breeder. The breeder felt terrible about it. She tried to make amends by offering her another Ragdoll, but this was no consolation, of course. In fact, Ms. Piskin found the offer insulting, as if you can simply replace a cat, months after you’ve lived with it and bonded with it. Given Tular’s results and the poor prognosis that comes with it, we elected to do another ultrasound, three months after the initial one.

The second ultrasound, unfortunately, showed significant progression of the heart disease. The thickness of the ventricle went from 0.84 cm to 1.03 cm. The left atrium increased in size from 1.5 cm to 1.7 cm. The increased size of the atrium is a concern because if the atrium gets too big, blood has a tendency to swirl around in the atrium rather than flow through it, and a blood clot can form. If a blood clot forms and a piece of the clot breaks off and travels down the aorta, it can be disastrous. Unfortunately, Ragdolls who are homozygous for the mutation are prone to these type of events.

The plan: we started Tular on heart medication. One drug we’re giving is enalapril, a drug that will dilate the aorta, encouraging more blood to flow out of the aorta rather than back through the leaky mitral valve. The other two drugs we’re giving are a baby aspirin every three days, and Plavix. The aspirin and Plavix are intended to make the blood less likely to clot.

It would be ideal if all cats carrying the mutation could be removed from breeding programs, however, the high prevalence of the mutation in both Maine Coons and Ragdolls would make this difficult. Bearing in mind that not all cats carrying the mutation (especially heterozygous cats) will develop a clinical form of the disease, a more realistic approach would be to remove homozygous cats from the breeding population, because they have the highest risk of developing HCM and they will pass the mutation to all of their offspring. Heterozygous cats, if bred, should be used only if they have exceptional breed attributes and are free of clinical disease at the time of breeding (suggesting that the cat may have a less penetrant form of the disease).

If they develop clinical HCM later in life, they should be removed from the breeding program. Ideally, they would be bred only to cats that are free of the mutation. Kittens born from the mating of a heterozygous and a negative cat should be genetically tested. If a mutation-negative kitten has the desirable traits of the parents, the kitten should be chosen to replace the mutation-positive parent in the breeding colony. In this fashion, the mutation can be slowly eradicated from the breed without drastically altering the genetic makeup of the breed.

Tular is doing well at the moment. Her next cardiac ultrasound is scheduled to be performed in 3 months. I will keep my readers updated as to Tular’s progress.
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