Jerold S. Bell, DVM, Cummings School of Veterinary Medicine at Tufts University
Jerold S. Bell, DVM, is an adjunct professor of genetics at Cummings School of Veterinary Medicine at Tufts University. He also practices at Freshwater Veterinary Hospital in Enfield, Connecticut. He earned his DVM from Cornell University and was trained in genetics and genetic counseling at Michigan State University and University of Missouri. Dr. Bell serves on the WSAVA hereditary diseases committee, the board of directors for the Orthopedic Foundation for Animals, and the American Kennel Club Canine Health & Welfare advisory panel.
Most feline patients are random-bred domestic cats; random breeding propagates and disperses evolutionarily ancient disease-liability genes, which causes the random development of clinical genetic disease. Pedigreed breeds may have varied incidence of disease, depending on the frequencies of liability genes in their gene pools. Insurance claims and centralized hospital databases monitor the most frequent disease presentations, which helps veterinarians understand the most frequent genetic diseases.1-3 The most frequent conditions are complexly inherited and involve combinations of multiple genes and environmental factors. Genetic diseases should be recognized in practice because they must be treated as chronic illnesses—not episodic diseases.
Sterile FLUTD, including both feline idiopathic cystitis and feline urologic syndrome, is the most frequent feline hereditary predisposition observed in practice, affecting 1% to 2% of domestic cats.4-6 No infectious causes for FLUTD have been identified,7 and it can occur in individual cats in multicat households.8 Persian cats may be at increased risk, and Siamese cats may be at decreased risk for developing FLUTD.8 In an experimental model, when exposed to stressors, only cats predisposed to FLUTD developed clinical signs and showed mRNA responses for biomarkers vs controls.6 Similar gene-expression profiles are found in interstitial cystitis or bladder pain syndrome in humans,9,10 and a hereditary component has been documented.11,12 There is no established mode of inheritance, and no predisposing genes have been identified in cats.
Most practitioners recognize that once diagnosed and controlled, signs associated with FLUTD can recur if owners are not diligent about controlling predisposing factors. Such measures can include minimizing environmental stress, maintaining anti-inflammatory or behavior-modifying drugs that decrease likelihood for bladder inflammation, and maintaining dietary control for cats predisposed to crystalluria.
Diabetes mellitus is a common diagnosis in cats controlled via insulin regulation and diet.13 It is primarily seen in random-bred cats, although an increased incidence is seen in Burmese14 and possibly Siamese, Norwegian forest, Russian blue, and Abyssinian cats.15,16 Obesity is a predisposing factor.17 One study found a mutation in the melanocortin 4 receptor gene to be significantly associated with diabetes in obese domestic shorthair cats.17 This is similar to findings associated with human type 2 diabetes.17
Predisposition toward lymphocytic or plasmacytic inflammation represents a complex immunologic response involving innate, humoral, and cell-mediated immunity. In cats, lymphocytic or plasmacytic inflammatory disease most frequently manifests as gingivostomatitis18 or inflammatory bowel disease (IBD).19 Although the histopathologic descriptions of these 2 entities are similar, they rarely occur in the same patient.
Breed predisposition to IBD has been found in Siamese and other Asian breeds, but causal genetic mutations have not been found.19 Liability genes for IBD have been identified in German shepherd dogs20 and humans.21 Liability genes have been identified for recurrent aphthous stomatitis in humans, the corollary to feline lymphoplasmacytic gingivostomatitis.22
Many possible environmental variables exist, including diet (and possibly dietary reactivity), reactivity to the local microbiome, and behavioral stress.6,19 Affected cats show a lifelong propensity to inflammatory cell infiltration that does not occur in other cats in the same household. Control of both conditions can include dietary changes, anti-inflammatory or immunoregulatory drugs, minimization of environmental stress, and dental extraction in cats with severe gingivostomatitis.
Polycystic kidney disease (PKD) is the most common single-gene feline disorder seen in practice. It is caused by an autosomal dominant gene for which a commercial genetic test exists (UC-Davis VGL). This defective gene is present in 38% of Persian cats (6% of cats worldwide), as well as in high frequencies in Himalayan and other Persian-derived breeds. PKD is also seen in random-bred longhair cats with presumed Persian ancestry. All affected cats are heterozygous for the defective gene, as homozygosity is prenatally lethal.
Most affected cats develop kidney failure at an average age of 7 years (range, 4-10 years).24 Variable expression of this gene can be noted in cats that develop a few cysts but maintain normal renal function. There is no specific treatment aside from support for chronic kidney disease and failure.
Prospective pet owners interested in kittens of susceptible breeds should ask for the PKD DNA test results on both parents and/or the kittens. Breeders who offer a breeding stock that is “PKD clear” on ultrasonography are using an outdated and unreliable diagnostic standard.25 If valid PKD DNA test results are not available from the breeding stock, potential pet owners can collect a cheek swab from kittens for testing.
Hypertrophic cardiomyopathy (HCM) occurs as a breed-related disease in several breeds as well as in random-bred cats.26 A mutation in the myosin-binding protein C gene occurs in 33% of Maine coon cats and causes highly penetrant, autosomal-dominant HCM.26 Affected cats can experience heart failure or sudden death at 6 months to 7 years of age. Cats homozygous for the mutation have a more severe and earlier-age onset than do heterozygotes.26 The disease shows incomplete penetrance, and some heterozygous cats can remain clinically normal.27
Twenty percent of ragdoll cats carry a different mutation in the same gene that causes HCM.28 A genetic test is available for breed-specific mutations in the ragdoll and Maine coon breeds.26 Prospective breeding cats should be tested, or kittens should be tested before placement.
HCM also occurs in individual Maine coon and ragdoll cats not carrying the breed-specific mutations, as well as in random-bred cats and individual cats of other breeds.29 These findings support both within-breed and between-breed genetic heterogeneity for the disease. Clinical treatment for HCM involves controlling heart failure.
Cats of the sphynx breed may develop an earlier-age (average, 2 years) onset HCM.30,31 In Norwegian forest cats, cardiomyopathy with signs of both hypertrophic and restrictive disease has been documented.32 HCM has also been reported in Persian, Chartreux, Bengal, and Birman cats.29 Causative genes have not been identified in these breeds, but pedigree studies suggest dominant inheritance with incomplete penetrance.29
Other common feline diseases with hereditary components include calcium oxalate bladder stones,33 allergic skin disease with or without eosinophilic granuloma complex,34 mammary tumors,35 and lymphoma.36 Hyperthyroidism is frequently seen in practice, but the cause is thought to be related to environmental goitrogens and not heredity.37 There is also no published evidence for heritability of chronic kidney disease seen in older cats.
Many breed-specific genetic diseases are seen at a lower frequency in clinical practice. The WSAVA Canine and Feline Hereditary Disease (DNA) Testing website is an excellent source of information on DNA tests, susceptible breeds, and testing laboratories.38
Cats affected with genetic disorders should not be used for breeding. For complexly inherited genetic disorders, risk for carrying disease-liability genes should be based on knowledge of clinical disease or normalcy in first-degree relatives of prospective breeding cats. Carriers of testable recessive disease-liability genes can be bred with normal-testing mates and replaced for breeding with normal-testing offspring. Cats with testable dominant disease-liability genes should be replaced for breeding with normal-testing relatives.
FLUTD = feline lower urinary tract disease, HCM = hypertrophic cardiomyopathy, IBD = inflammatory bowel disease, PKD = polycystic kidney disease
Egenvall A, Bonnett BN, Häggström J, et al. Morbidity of insured Swedish cats during 1999-2006 by age, breed, sex, and diagnosis. J Feline Med Surg. 2010;12(12):948-959.
Top 10 Reasons Pets Visit Vets. Veterinary Pet Insurance. http://www.petinsurance.com/healthzone/pet-articles/pet-health/Top-10-Rea sons-Pets-Visit-Vets.aspx. Accessed July 1, 2016.
Banfield Pet Hospital State of Pet Health 2016 Report. Banfield Pet Hospital. https://www.banfield.com/Banfield/media/PDF/Downloads/soph/Banfield-State-of-Pet-Health-Report-2016.pdf. Accessed July 1, 2016.
Dorsch R, Remer C, Sauter-Louis C, et al. Feline lower urinary tract disease in a German cat population. A retrospective analysis of demographic data, causes and clinical signs. Tierarztl Prax Ausg K Kleintiere Heimtiere. 2014;42(4):231-239.
Defauw PA, Van de Maele I, Duchateau L, et al. Risk factors and clinical presentation of cats with feline idiopathic cystitis. J Feline Med Surg. 2011;13(12):967-975.
Stella J, Croney C, Buffington T. Effects of stressors on the behavior and physiology of domestic cats. Appl Anim Behav Sci. 2013;143(2-4):157-163.
Lund HS, Rimstad E, Eggertsdóttir AV. Prevalence of viral infections in Norwegian cats with and without feline lower urinary tract disease. J Feline Med Surg. 2012;14(12):895-899.
Buffington CA, Westropp JL, Chew DJ, et al. Risk factors associated with clinical signs of lower urinary tract disease in indoor-housed cats. J Am Vet Med Assoc. 2006;228(5):722-725.
Gheinani AH, Burkhard FC, Monastyrskaya K. Deciphering microRNA code in pain and inflammation: lessons from bladder pain syndrome. Cell Mol Life Sci. 2013;70(20):3773-3789.
Logadottir Y, Delbro D, Fall M, et al. Cytokine expression in patients with bladder pain syndrome/interstitial cystitis ESSIC type 3C. J Urol. 2014;192(5):1564-1568.
Tunitsky E, Barber MD, Jeppson PC, et al. Bladder pain syndrome/interstitial cystitis in twin sisters. J Urol. 2012;187(1):148-152.
Allen-Brady K, Norton PA, Cannon-Albright L. Risk of associated conditions in relatives of subjects with interstitial cystitis. Female Pelvic Med Reconstr Surg. 2015;21(2):93-98.
Nelson RW, Reusch CE. Animal models of disease: classification and etiology of diabetes in dogs and cats. J Endocrinol. 2014;222(3):T1-T9.
O’Leary CA, Duffy DL, Gething MA, et al. Investigation of diabetes mellitus in Burmese cats as an inherited trait: a preliminary study. N Z Vet J. 2013; 61(6):354-358.
Cooper RL, Drobatz KJ, Lennon EM, et al. Retrospective evaluation of risk factors and outcome predictors in cats with diabetic ketoacidosis (1997-2007): 93 cases. J Vet Emerg Crit Care (San Antonio). 2015;25(2):263-272.
Öhlund M, Fall T, Ström Holst B, Hansson-Hamlin H, Bonnett B, Egenvall A. Incidence of diabetes mellitus in insured Swedish cats in relation to age, breed and sex. J Vet Intern Med. 2015;29(5): 1342-1347.
Forcada Y, Holder A, Church DB, et al. A polymorphism in the melanocortin 4 receptor gene (MC4R:c.92C>T) is associated with diabetes mellitus in overweight domestic shorthaired cats. J Vet Intern Med. 2014;28(2):458-464.
Harley R, Gruffydd-Jones TJ, Day MJ. Immunohistochemical characterization of oral mucosal lesions in cats with chronic gingivostomatitis. J Comp Pathol. 2011;144(4):239-250.
Jergens AE. Feline idiopathic inflammatory bowel disease: what we know and what remains to be unraveled. J Feline Med Surg. 2012;14(7): 445-458.
Kathrani A, House A, Catchpole B, et al. Polymorphisms in the TLR4 and TLR5 gene are significantly associated with inflammatory bowel disease in German shepherd dogs. PLoS One. 2010;5(12): e15740.
Chen GB, Lee SH, Brion MJ, et al. Estimation and partitioning of (co)heritability of inflammatory bowel disease from GWAS and immunochip data. Hum Mol Genet. 2014;23(17):4710-4720.
Najafi S, Yousefi H, Mohammadzadeh M, et al. Association study of interleukin-1 family and interleukin-6 gene single nucleotide polymorphisms in recurrent aphthous stomatitis. Int J Immunogenet. 2015.
Lyons LA, Biller DS, Erdman CA, et al. Feline polycystic kidney disease mutation identified in PKD1. J Am Soc Nephrol. 2004;15(10):2548-2555.
Eaton KA, Biller DS, Dibartola SP, et al. Autosomal dominant polycystic kidney disease in Persian and Persian-cross cats. Vet Pathol. 1997; 34:117-126.
Biller DS, DiBartola SP, Eaton KA, Pflueger S, Wellman ML, Radin MJ. Inheritance of polycystic kidney disease in Persian cats. J Hered. 1996;87(1):1-5.
Longeri M, Ferrari P, Knafelz P, et al. Myosin- binding protein C DNA variants in domestic cats (A31P, A74T, R820W) and their association with hypertrophic cardiomyopathy. J Vet Intern Med. 2013;27(2):275-285.
Sampedrano C, Chetboul V, Mary J, et al. Prospective echocardiographic and tissue Doppler imaging screening of a population of Maine Coon cats tested for the A31P mutation in the myosin-binding protein C gene: a specific analysis of the heterozygous status. J Vet Intern Med. 2009;23(1):91-99.
Borgeat K, Casamian-Sorrosal D, Helps C, et al. Association of the myosin binding protein C3 mutation (MYBPC3 R820W) with cardiac death in a survey of 236 ragdoll cats. J Vet Cardiol. 2014;16(2): 73-80.
Trehiou-Sechi E, Tissier R, Gouni V, et. al. Comparative echocardiographic and clinical features of hypertrophic cardiomyopathy in 5 breeds of cats: a retrospective analysis of 344 cases (2001-2011). J Vet Intern Med. 2012;26(3): 532-541.
Chetboul V, Petit A, Gouni V, et al. Prospective echocardio-graphic and tissue Doppler screening of a large Sphynx cat population: reference ranges, heart disease prevalence and genetic aspects. J Vet Cardiol. 2012;14(4):497-509.
Silverman SJ, Stern JA, Meurs KM. Hypertrophic cardiomyopathy in the Sphynx cat: a retrospective evaluation of clinical presentation and heritable etiology. J Feline Med Surg. 2012;14(4): 246-249.
März I, Wilkie LJ, Harrington N, et al. Familial cardiomyopathy in Norwegian forest cats. J Feline Med Surg. 2014 Oct 30. pii: 1098612X14553686. [Epub ahead of print]
Houston DM, Vanstone NP, Moore AE, Weese HE, Weese JS. Evaluation of 21 426 feline bladder urolith submissions to the Canadian Veterinary Urolith Centre (1998-2014). Can Vet J. 2016;57(2): 196-201.
Ravens PA, Xu BJ, Vogelnest LJ. Feline atopic dermatitis: a retrospective study of 45 cases (2001-2012). Vet Dermatol. 2014;25(2):95-102, e27-e28.
Graf R, Grüntzig K, Boo G, et al. Swiss Feline Cancer Registry 1965-2008: the influence of sex, breed and age on tumour types and tumour locations. J Comp Pathol. 2016;154(2-3):195-210.
Louwerens M, London CA, Pedersen NC, Lyons LA. Feline lymphoma in the post-feline leukemia virus era. J Vet Intern Med. 2005;19(3):329-335.
Carney HC, Ward CR, Bailey SJ, et al. 2016 AAFP guidelines for the management of feline hyperthyroidism. J Feline Med Surg. 2016;18(5):400-416.
Slutsky J, Raj K, Yuhnke S, et al. A web resource on DNA tests for canine and feline hereditary diseases. Vet J. 2013;197(2):182-187.
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