Is it proof of a hereditary heart disease, or is it just commerce?

Last decade Maine coon cat breeders all over the world faced the serious question regarding the HCM disease. There are a lot of myths, doubts and conflicts in this discussion. Different institutes and organizations were created to study the genetic and hereditary reasons of HCM. Some people maintain their opinion that breeding isn’t possible without the HCM genetic testing and also point with finger to the “unfair” breeders, who don’t make such tests; some are very sceptical towards the animals, whose genetic HCM test showed at least n/HCM; others are using such animals in breeding without any worries and just making standard periodical USG heart testing to be sure that animals are healthy.

With our collected information about the HCM, we don’t try to make some invention, or to be on someone’s side. Simply, we want to find answers to the couple of questions: What is the HCM genetic testing for the Maine coon breed? Is it a proof of the hereditary heart disease? Or it is just well-planned commercial move? Maybe it is just a way to compete for breeders? Or it is a simple misconception of people, who aren’t enough educated in the genetics? Maybe finally representatives of the different international felinological federations will give an official answer to those questions and put a point in these endless doubts? What should the maine coon breeders do with received HCM genetic tests? Should the cats with positive HCM genetic test be dismissed from breeding?

Today the situation looks like this:

Questioning of the cattery owners, who have already neutered and dismissed animals with HCM/HCM from breeding showed, that until today (some animals are more than 8 years old) those animals are ALIVE and have no negative changes in the heart. But still, there were reports about cats, who had a heart disease despite the fact that their HCM genetic testing result was N/N. Today there is no authentic statistics that could approve the connection between the death of an animal and the presence of defective genetics. On the contrary, there is statistics that shows that animals with the result of N/N suffered sudden death from HCM that WAS PROVED BY MEDICAL AUTOPSY.

Genetic tests could be divided to the two main groups: tests for the recognition of mutation for so-called Mendelian diseases and for complex diseases. If there is a mutation in the Mendelian disease, then in most cases it will cause the illness, that's why it is easier to create the genetic tests for such diseases and their accuracy is very high. The situation is more complicated for complex diseases. The risk of getting sick is getting higher if there is a gene mutation, and also if there are some environmental factors. But still, even the presence of both of these factors does not cause the disease every time. HCM, like most of widespread diseases such as breast cancer, hypertension, ischemic heart disease, stroke, osteoporosis, is a complex disease. Yuri Aulchenko, doctor of biological sciences, talks about the lack of base for genetic testing for complex diseases in his article.

We advise to read and investigate the article, where the latest data about genetic testing of cat’s HCM is summarised. We are very thankful to Dr. Gerhard Wess, Priv. Doz., Dr. med. vet., Dr. habil., Dipl ACVIM (Cardiology), Dipl. ECVIM-CA (Cardiology) ,Dipl. ECVIM-CA (Inner Medicine) from Ludwig Maximilian University of Munich; Dr Chris Helps, Senior Research Fellow, Head of Molecular Diagnostic Unit , University of Bristol, Langford Veterinary Services, who introduced the results of researches about cat’s HCM.

The first research of genes responsible for HCM was conducted by Kathryn M. Meurs and Dr. Kittleson, who also postulated autosomal dominant heredity of HCM for maine coons with a 100% penetration in 1999. In 2005, American cardiologists Dr. Meurs and Dr. Kittleson found so-called A31p (Gen 1) MYBPC3 in their Maine Coon population (original article of 2005 is published in Human Molecular Genetics, 2005, Vol. 14, No. 23).

In 2010, a group of scientists lead by Dr. Gerhard Wess from the Ludwig Maximilian University of Munich (Germany) conducted their own research of the Maine Coon population in Germany. The main goal was to determine the clinical connection between both polymorphisms (A31p and A74T) and also to evaluate the authenticity of existing genetic tests. 83 maine coons and 68 cats of different breeds took part in the research. You can also find the information here. Those articles provide the newest information about medical DNA testing of Maine Coons. These articles aren’t written by self-educated veterinarians, all authors are well-known professional doctors and cardiologists.

1) Article from Giessen Animal University (06.02.2008)

The new genetic testing that shows presence of two HCM genes was developed in a small veterinary clinic of Ludwig Maximilian University in Munich by testing German Maine Coon cats. The results showed that genetic testing does not guarantee anything at all. The research found that Maine Coons with hypertrophic cardiomyopathy disease had the positive HCM test results just as frequently as cats without the disease. That’s why investments in genetic testing are useless. Further you will find the results of research that were introduced at a specialized veterinary congress: Association of A31P and A74T Polymorphisms in the Myosin Binding Protein C3 Gene and Hypertrophic Cardiomyopathy in Maine Coon and Other Breed Cats by G. Wess, C. Schinner, K. Weber, H. Kuchenhoff, and K. Hartmann.

Introduction: hypertrophic cardiomyopathy (HCM) is an inherited autosomal dominant trait in cats with different penetration. The A31P single nucleotide polymorphism (SNP) in the myosin binding protein C 3 (MYBPC3) gene is thought to be the causative mutation in Maine Coon cats. Additionally, the A74T SNP is offered as a genetic test for HCM. But in practice the USG heart research frequently doesn’t match the genetic testing. Breeders and veterinarians still have no answer what to do with the cats with a healthy cardiovascular system but have positive HCM genetic testing results.
So, the main aim of this paper is to find the clinical connection between both polymorphisms (A31p and A74T) and also to evaluate the authenticity of existing results of HCM genetic tests.

Materials and methods: 83 maine coons and 68 cats of different breeds took part in the research. The females should be older than 36 months and males older than 24 months. They were then further classified into the groups ‘‘healthy’’or ‘‘HCM’’ according to echocardiographic phenotype results. Genotyping was made by gene analysis "Taqman® Genotyping Assays".

Results: 21.13% of animals with healthy hearts had positive genetic testing result of presence of A31p and 32.84% of A74T (SNP). 75% with HCM had the viable allele of A31p gene and 50% of A74T. There was no statistically significant difference observed in allele frequencies between cats with HCM and healthy cats. The research showed that the genetic tests don’t have any prognostic value for the population tested. Evaluation of the potential impact of the amino acid substitutions caused by the A31P and A74T SNPs by PolyPhen did not suggest damaging effects on the protein.

The results of the research are visualized in diagrams below (picture 1 and picture 2))

Picture 1. Phenotypes and genotypes of Maine Coon cats with the A31P mutation. G/C represents heterozygous state and C/C the homozygous state. Age is displayed as mean age of the selected group.

Picture 2. Phenotypes and genotypes of Maine Coon cats with the A74T mutation. G/A represents the heterozygous state and A/A the homozygous state. Age is displayed as mean age of the selected group.

Conclusion: There was no connection found between HCM and researched polymorphisms in the group of animals examined. The golden rule for breeding is the annual ECHO research.

2) The heart of a cat , March, 2010, Dr. Jan-Gerd Kresken, cardiologist. Original Article

Hypertrophic cardiomyopathy (HCM) is the most common cat heart disease. It is an acquired heart disease that is genetically defined. Dr. Jan-Gerd Kresken reported the current situation in HCM diagnostics for cats, and his research of the accuracy of genetic tests for the past 4 years. HCM usually is discovered when a cat is already used in breeding. There are several methods of diagnosing HCM in veterinary cardiology. The classical methods are: auscultation, X-ray, ECHO with its different technical options – 2D high resolution Doppler of the heart muscle, tissue Doppler and stress-analysis. In 2006, these classical methods of HCM diagnostics were used in genetic testing. The first research of the genes responsible for HCM was conducted by Kathryn M. Meurs and Dr. Kittleson, who also postulated autosomal dominant heredity of HCM for Maine coons with a 100% penetration in 1999. In 2005, American cardiologists Dr. Meurs and Dr. Kittleson found the so-called A31p (Gen 1) MYBPC3 in their Maine Coon population. In 2007 Dr. Newberg and colleagues found the point mutation of A74T (Gene II) in codon 74 of heart Gene MYBPC3. Also, in 2007 Dr. Meurs by Ragdoll DNA sequencing discovered the point mutation in codon 820 of heart Gene MYBPC3. The Ragdoll group wasn’t quite big – 21 cat with phenotypically diagnosed HCM.

Facts about genetic HCM tests for cats:

Heredity

Autosomal-dominant heredity is proven or supposed:

• Maine Coons
• American Shorthair
• British Shorthair

Breeds, that have predisposition:

• Maine Coon
• American and British Shorthair
• Norwegian and Siberian Forest Cat
• Persian
• Ragdoll
• Blue Van
• Scottish Fold
• Sphynx

There are only 3 discovered Gene mutations at the moment:

• A31p
• A74T
• R820W

The frequency of the Gene mutation in different countries

The research of Dr. Meurs (Washington State University) shows that 33.6% of the USA Maine Coon population are carriers of the A31p Gene mutation. Dr. Jan-Gerd Kreksen research in 2007 shows that 30% of 119 Maine coons with healthy cardiovascular system have a positive Gen test of A31p (SNP). In recently published article from Bristol University it was reported that 30% of tested cats have genetic mutation – 193 Maine Coons had A31p, and 898 Ragdolls had R820W mutation, which means that every third cat has a genetic mutation.

Note: the existence of gene mutation for cat DOESN’T mean that the cat will automatically become sick with the HCM disease!

So, after a couple of months of the first genetic tests, when the beginning euphoria went away, the doubts about the accuracy of the prediction of genetic testing started to show up. What is wrong in the connection of HCM phenotype and genotype? Are cats with genetic testing result HCM/HCM healthy? Dr. Kittleson described the autosomal-dominant heredity with 100% penetration. The proof was 33% of stillborn kittens, which he took as homozygote. In total, the 45% of this population was diagnosed as sick with HCM, so he supposed that they were genetically heterozygotes. The results of testing this population of cats wasn’t quite convincing. After testing the homozygote, cats with HCM were alive and healthy! This simple fact shows that the HCM Gene doesn’t have a 100% penetration. And still, there were cats with negative genetic test results (N/N) which were diagnosed with HCM by USG! So we are back to the article of Giessen Animal University (06.02.2008)

A31p (Gen I)

83 Maine coons from South Germany were tested for A31p mutation. 21.7% of them were genetically positive and 78.3% negative. BUT 83.3% of cats, whose genetic test was positive, had negative result of phenotype testing by ultrasound. Only for 16.7% of genetically HCM positive cats, the USG showed HCM positive results. 13.9% of Maine Coons with genetically HCM negative results were diagnosed with HCM by ultrasound testing. The average age of tested animals was about 5 years, so these results are quite significant.

Note: Only one of five cats with genetically positive HCM had the heart disease.

A74T (Gen II)

The mutation A74T was found in 35.4% out of 79 Maine coons. 78.06% of those cats had NO HCM discovered by ECHO. From the other side, 76.05% of cats suffering HCM, had normal alleles G/G, which means, that there are other reasons and factors that cause the sickness.

Note: ¾ of cats really suffering HCM genetically weren’t significant!

Polymorphism A74T (Gen II) of MYBPC3 is discovered as frequent for Maine Coons as for other breeds, so it can’t be a disease, that occurs in Maine Coons only. Also, there is no connection found if the disease is more severe, if there are both polymorphisms A31p (Gen I) and A74T (Gen II) at the same time. Therefore it is suggested, that HCM is a genetically complex disease.

Heart research by ultrasound. (Echocardiography)

Echocardiography and its variations as Doppler, Tissue Doppler, stress and stress/speed test are the best methods to diagnose the hypertrophy of heart muscle by phenotype. Of course, there are other methods for diagnostics, such as EKG and X-ray but they are less effective in recognizing HCM at an early stage. Ultrasound investigation is a very reliable method of hypertrophy recognition, but it doesn’t exclude the presence of disease for cats that are genetically negative and further appearance of the disease.

Note: EKG and X-ray aren’t good methods of HCM recognition at early state:

The main requirement in addition for expert experience is the high resolution converter (7.5-10 MHz) and high frequency of frames. Hypertrophy could be found as symmetric and asymmetric thickenings of heart wall and papillary muscles. The left ventricle is almost always harmed. The testing is conducted by measuring the thicknesses of the wall in diastole in phase of relaxing the heart muscle. At first, the heart muscle is evaluated in a 2D image at several angles. After that, diastole thickness of the wall is measured in M-regime to determine the standard level. The thickening of the wall could be measured and classified for symmetric hypertrophy. The norm wall thickness is 5.5 mm. The value between 5.5 and 6.0 mm provides ambiguous results. That is because there are different values of normal wall thickness for cats in different literature.

Note: It is harder to measure asymmetric or papillary hypertrophy of muscle wall. The presence of an experienced cardiologist is needed.

So, if we observe significant thickening of the wall in ultrasound, then hypertrophy is present. Hypertrophy could be the result of a primary genetic defect (HCM) or a secondary reaction to increased blood pressure and (or) changes in hormones. Secondary hypertrophy almost always is shown as concentric symmetric thickening of all clusters.

Recommendations:

Unfortunately, there is no genetic testing offered that could be useful for breeding. Currently offered Genetic tests can only recognize A31p (Gen I) mutation and only for Maine Coons of Dr. Kittleson population. The genetic tests that diagnose HCM for other breeds are useless. It is recommended to make regular ultrasound tests of heart of animals that are used in breeding. The tests should be repeated in 1-2 years – the frequency depending on the result.

HCM treatment:

There is no preparation that could slow down the tendency of hypertrophy. Blocks, hyper coagulation and thrombus formation in blood are seen only using ultrasound and such testing should be conducted together with therapy.

Conclusion:

Taking into account all that was mentioned, all the original information and the different opinions of different people world-wide, there could be only one possible conclusion: Cat HCM is a complex disease, which could be caused by many factors. Genetic mutation, that is discovered in 3 of 200 genes COULD NOT be a reliable indication of obligatory development of HCM disease. There is NO authentic statistics about the connection between mutations and an animal’s death. Any conclusion could be made in 10 years, when enough correct statistical data with diagnoses and causes of death is gathered. As for today, we think, that the most appropriate way for responsible breeders is not to pay attention on genetic tests, because it is just self-delusion, but to pay serious attention on everything that is going on in their catteries. This is mostly true for breeders, who have a lot of stillborn kittens, repeated miscarriages, birth of ugly or underdeveloped kittens, early death after seven days and until three months. Each breeder should try to trace the destiny of every offspring.It is very important to explain to the new owner how they should treat the cat, what is the appropriate medical treatment, how they should feed the cat. Unfortunately, we know about situations, where the new owner is feeding the cat with porridges, vegetables, soups and other products that are toxic to cats. Breeders try to explain, that a cat’s pancreas is working completely different than a human’s. People don’t want to understand that cats don’t naturally hunt cows, go fishing, steal carrots from a yard and so on.

We offer a scheme of causal-investigatory connection of HCM development:

Stress – reduction of immunity – bacteriological infection of cells affected by viruses – secondary complications – development of pathologies – early sudden death. Incorrect treatment, feeding could cause stress to a cat. Humans have immunity to a lot of diseases and reasons that cause those diseases. Cats could be infected and die because of a simple scratch, change of the living space, parting from beloved owner and other factors, that are not fatal to humans.

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Authors: Genadijus Movinas (Maine Coon Cattery Lordcoon Lithuania*LT), Angela Fomicheva (Latvia)

2013 07 16

Bibliogaphy:

1. Болезни сердечно-сосудистой системы у кошек
2. «В России пациент рискует по назначению врача купить «уринотерапию». Доктор биологических наук Юрий Аульченко о генетических тестах: каким из них можно верить, а какие являются откровенной коммерцией.
3. Cat heart, March/2010 by Dr. Jan-Gerd Kresken, Cardiologist
4. Association of A31P and A74T Polymorphisms in the Myosin Binding Protein C3 Gene and Hypertrophic Cardiomyopathy in Maine Coon and Other Breed Cats - G. Wess, C. Schinner, K. Weber, H. Ku¨ chenhoff, and K. Hartmann (J Vet Intern Med 2010;24:527–532)
5. A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy - Kathryn M. Meurs (Human Molecular Genetics, 2005, Vol. 14, No. 23)