Common inherited diseases of cats (Proceedings)

The human genome is composed of about 3 billion base pairs, of which only about 2% forms coding DNA (genes); the rest is non-coding and serves various functions, such as gene regulation. Humans have about 20-25,000 genes, although the function of 50% of them is unknown. A 99% complete map of the human genome was announced in 2003. The cost was approximately $2.7 billion, and the project required a consortium of 20 groups and took 13 years. A light coverage map of the feline genome (2-fold; capturing about 80% of the genome), representing the DNA of an Abyssinian cat named "Cinnamon", was announced by the National Human Genome Research Institute (NHGRI) in 2005. In 2009, NHGRI funded an effort to improve the genome coverage from 2-fold to 10-fold. The feline genome also has about 3 billion base pairs. Improving the detail of the map and filling in gaps will require the collective resources of sequencing facilities, genetic mappers, geneticists, veterinarians, and others over the coming years.

About 250 genetic diseases are known in the cat, many of them having close parallels to human diseases. In fact, the cat serves as animal model for about 200 human diseases. Genetic research focuses not only on inherited diseases, but also on infectious diseases such as feline immunodeficiency virus (FIV; a model for human immunodeficiency virus, HIV). Even genes responsible for coat colors in cats are being identified and may have medical implications. As the feline genome project progresses, more single gene trait diseases will be identified, as well as diseases with a complex genetic component (e.g., feline infectious peritonitis, diabetes, asthma). Currently, more than one dozen genetic tests are available for the cat, including tests for blood type and some coat colors. Veterinarians and veterinary technicians must understand the proper use and interpretation of genetic tests as more become available. Resources for feline genetic diseases include the University of Pennsylvania, Section of Medical Genetics (http://w3.vet.upenn.edu/research/centers/penngen/) and the University of California Veterinary Genetics Lab (www.vgl.ucdavis.edu).

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a primary disease of the left ventricular myocardium characterized by mild to severe concentric hypertrophy. It is the most common cardiac disease of the cat1 and may cause congestive heart failure, sudden death, or arterial thromboembolism in some affected cats. The average age at diagnosis is 5 to 7 years. Diagnosis of HCM requires a combination of tools, such as physical examination, thoracic radiography, and echocardiography.

HCM occurs in 1 in 500 people, and is inherited in at least 60% of cases, usually as an autosomal dominant genetic trait. The mutations causing human HCM are found in several genes, including the β-myosin heavy-chain, α-tropomyosin, cardiac troponin T and I, and myosin-binding protein C (MYBPC). Approximately 35-40% of human mutations are found in the β-myosin heavy-chain gene, with over 50 point mutations identified to date. Some mutations causing HCM produce malignant disease with short survival time; others produce more benign disease with little effect on survival.

Familial HCM was identified in cats 35 years after the first identification of a human family with HCM. To date, two genetic mutations have been identified in cats, one each in the Maine Coon and Ragdoll breeds. Maine Coon cats are the best studied example of feline HCM. The disease is inherited as an autosomal dominant trait in this breed. One causative mutation has been identified in a long-term research colony of Maine Coons. The colony cats were originally obtained from Maine Coon breeders. The mutation is in the myosin-binding protein C3 (MYBPC3) gene changes a conserved amino acid, which alters protein structure and changes the function of the sarcomere, the basic contractile unit in heart muscle. The mutation (referred to as A31P) changes an alanine to a proline in codon 31 of the gene. Cats homozygous for the mutation tend to develop moderate to severe disease, and in one study, most homozygotes died of their disease before 4 years of age. Cats heterozygous for the mutation may live into late middle or old age with moderate disease. The A31P mutation is present in about 34% of all Maine Coon cats worldwide.

Not all Maine Coons with the A31P mutation will be diagnosed with HCM as this is an example of a mutation that has variable expression and age-related penetrance. Genetic heterogeneity – more than one mutation in a gene or mutations in related genes may cause the same disease – also plays a role. At least one other mutation causing HCM is likely present in the breed, but further causative mutations have not yet been definitely identified. Another potential causative mutation, A74T, is not well documented but is offered by some commercial laboratories despite lack of evidence. Other factors that may cause discordance between genetic testing and echocardiographic diagnosis include inaccuracy in methods used to detect the mutation and inaccurate clinical diagnosis.

The form of HCM found in Ragdoll cats seems to cause severe disease, often with an early age of onset. A causative mutation has been identified in the Ragdoll MYBPC3 gene, but it is not the same mutation responsible for HCM in the Maine Coon. The Ragdoll mutation (referred to as R820W) changes an arginine to a tryptophan in codon 820. Other breeds with familial HCM are known (e.g., Persian, British Shorthair, American Shorthair, Sphynx, Norwegian Forest Cat, Bengal, etc.) but further research is required to determine the respective causative mutations. Some cat breeds appear to be at low risk for HCM, such as Siamese and Abyssinians.

Genetic testing for HCM in Maine Coon cats and Ragdoll cats can be performed by some diagnostic laboratories, usually with a simple buccal (cheek) swab. The results are typically reported as "negative", "positive homozygote", or "positive heterozygote." A negative test result means the cat does not have the specific HCM mutation being tested. However, the cat could have another HCM mutation and still develop disease. A positive homozygote has two abnormal copies of the gene and may develop moderate to severe HCM. These cats should be evaluated regularly, including an echocardiogram. A positive heterozygote has one abnormal copy of the gene, and one normal copy. These cats might develop mild to moderate HCM and also should be evaluated regularly. The prevalence of the R820W mutation in the Ragdoll breed is not known.

For more information on testing and research: Veterinary Cardiac Genetics Lab at Washington State University (www.vetmed.wsu.edu/deptsVCGL/).

Polycystic kidney disease

Autosomal dominant polycystic kidney disease (PKD) is the most common genetic disorder of humans, occurring in 1:200 to 1:1000 people. It is the most common cause of end-stage kidney disease and accounts for more than 10% of kidney dialysis patients. At least 5 million people world-wide are affected with PKD. Three known genes are associated with the adult onset form of PKD.

In the 1980s, PKD was identified as an autosomal dominant trait in Persian cats and has become an important medical model for human PKD. All affected cats are heterozygotes as homozygotes are not viable and die in utero. Feline PKD is a slowly progressive, irreversible disease caused by a mutation in the PKD1 gene (a C>A transversion in exon 29). Different mutations in the same gene are responsible for over 85% of PKD in humans. The PKD1 gene produces polycystin-1, a large membrane protein in renal tubular epithelial cells of unknown function. This mutation in the PKD1 gene reduces production of normal polycystin-1 by 33%, leading to the formation of significant lesions. Cysts develop in both kidneys (occasionally in the liver and pancreas) and increase in size over time. The growing cysts compress normal kidney tissue, leading to kidney dysfunction.

The age at onset of kidney insufficiency ranges from 3 to 10 years (average 7 years). The clinical signs of PKD are non-specific, and are those commonly associated with chronic renal disease (lethargy, anorexia, polydipsia, polyuria, vomiting, and weight loss). Diagnosis includes the minimum database for any cat with signs of chronic renal disease (complete blood cell count, serum chemistries, and urinalysis).

Radiography cannot detect the early stages of PKD. With advanced disease, the kidneys will appear bilaterally enlarged and may have dystrophic calcification. Differential diagnoses for cats with renomegaly include lymphoma, feline infectious peritonitis-associated nephritis, and perinephric pseudocysts. Ultrasonography can provide a definitive diagnosis and detect renal cysts as small as 2 mm. Ultrasound is highly reliable for diagnosis after 9 months of age. The cysts appear as smooth, round, anechoic structures. The ultrasonographic diagnosis is based on finding multiple cysts in both kidneys or a few cysts in at least one kidney in cat from a family with known PKD. There is considerable phenotypic variation, with some cats having a few small cysts and other cats having multiple, large cysts. The reasons for this phenotypic variation are not yet understood.

A genetic test is now available for PKD from many diagnostic laboratories. The test is usually performed on buccal swabs and can be performed in very young kittens. The genetic test for PKD is valid in Persians, Exotic Shorthairs, Himalayans and any breed that has Persian cats in its background, such as British Shorthair, Scottish Fold, and Birman. Ultrasound is still useful to assess severity in cats that test positive for PKD. The advent of a genetic test allows breeders to plan matings to avoid producing affected kittens. PKD is a surprisingly prevalent disease in Persians. Various studies have documented prevalence rates from 35-45% in cats tested around the world.

Blood type

Blood type is determined by antigenic, species-specific markers on the surface of red blood cells. In cats, blood type is characterized by an AB system. Blood type A is caused by the dominant allele and is found in 95-98% of non-pedigreed cats. Blood type A cats have low titers of naturally occurring anti-B antibodies. Blood type B is recessive and prevalence varies with geographic location and breed. The lowest prevalence is in the northeast, and the north central/Rocky Mountain regions. The highest prevalence is on the west coast and in the northwest. Certain cat breeds have a very high prevalence of blood type B, such as the British Shorthair, Cornish and Devon Rex, and Birman. Blood type B cats have high, naturally occurring titers of anti-A antibodies. Blood type AB is rare, occurring in less than 1% of cats, although it may be more common in certain pedigreed breeds, such as the Ragdoll. The heritability of type AB is not well understood.

Ragdoll cats appear to be unique with regard to blood types. Approximately 3.2% of Ragdoll cats are discordant for blood group when genotyping is compared to serology, necessitating further investigation in this breed.

Unlike other mammals, cats produce naturally occurring alloantibodies against red blood cell antigens not present on their own cells. No previous pregnancy or transfusion is necessary to induce antibody formation. If type A blood is transfused to a blood type B cat, an acute, severe, and potentially fatal reaction may occur, even with only 1 or 2 ml of blood. The hemolytic reaction is characterized by apnea, hypotension, arrhythmia, collapse, and even death. However, if type B blood is transfused to a blood type A cat, transfusion reactions are rare since type A cats have very low levels of anti-B antibodies. The transfused red cells may have a shorter life span. Cats with blood type AB are best transfused with type AB or type A blood.

It is therefore very important to blood type cats before a transfusion. Blood typing can be done by traditional methods at many referral laboratories. Recently, the mutation causing blood type B has been identified. This has allowed the development of a genetic test for blood type in cats using a buccal swab. The test identifies a cat as having one B allele (type A or AB cat), or two B alleles (type B), or no B alleles (type A or AB). For certain breeds of cats, or cats living in geographic locations where blood type B is more common, an individual's blood type should be determined at the earliest convenience and incorporated into the medical record.

References

Rodriguez D, Harpster N. Feline hypertrophic cardiomyopathy: etiology, pathophysiology, and clinical features. Comp Contin Edu Pract Vet 2002;24:364.

Meurs K, Sanchez X, David R, et al. A cardiac myosin binding protein C mutation in the Maine Coon cat with familial hypertrophic cardiomyopathy. Hum Mol Genet 2005;14:3587-3593.

Fries R, Heaney AM, Meurs KM. Prevalence of the myosin-binding protein C mutation in Maine Coon cats. J Vet Intern Med 2008;22:893-896.

Lefbom B, Rosenthal S, Tyrrell Jr. W, et al. Severe hypertrophic cardiomyopathy in 10 young Ragdoll cats (abstract). J Vet Intern Med 2001;15:308.

Meurs KM, Norgard MM, Ederer MM, et al. A substitution mutation in the myosin binding protein C gene in ragdoll hypertrophic cardiomyopathy. Genomics 2007;90:261-264.

Biller D, DiBartola S, Eaton K, et al. Inheritance of polycystic kidney disease in Persian cats. J Hered 1996;87:1-5.

Lyons LA, Biller DS, Erdman CA, et al. Feline polycystic kidney disease mutation identified in PKD1. J Am Soc Nephrol 2004;15:2548-2555.

Eaton K, Biller D, DiBartola S, et al. Autosomal dominant polycystic kidney disease in Persian and Persian-cross cats. Vet Pathol 1997;34:117-126.

Cooper B, Piveral P. Autosomal dominant polycystic kidney disease in Persian cats. Feline Pract 2000;28:20-21.

Auer L, Bell K. The AB blood group system of cats. Anim Blood Grps Biochem Genet 1981;12:287-297.

Giger U, Griot-Wenk M, Bucheler J, et al. Geographical variation of the feline blood type frequencies in the United States. Feline Pract 1991;19:21-27.

Giger U, Bucheler J, Patterson DF. Frequency and inheritance of A and B blood types in feline breeds of the United States. J Hered 1991;82:15-20.

Bighignoli B, Owens SD, Froenicke L, et al. Blood types of the domestic cat In: August J, ed. Consultations in feline internal medicine. 6 ed. St. Louis: Saunders Elsevier, 2010;628-638.

Giger U, Bucheler J. Transfusion of type-A and type-B blood to cats. J Am Vet Med Assoc 1991;198:411-418.

Griot-Wenk ME, Callan MB, Casal ML, et al. Blood type AB in the feline AB blood group system. Am J Vet Res1996;57:1438-1442.

Bighignoli B, Niini T, Grahn RA, et al. Cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH) mutations associated with the domestic cat AB blood group. BMC genetics 2007;8:27.