Jerold S. Bell, DVM
The hallmark of genetic disease is the ability to predict it. This allows us to control the spread of defective genes through informed breeding. It also allows us to intervene in both pet and breeding dogs prior to its onset; enabling us to prevent or lessen its impact. When managing genetic disease, we need to understand the possible variation of affected phenotypes, and how to identify unaffected carriers and sub-clinically affected individuals. The following are the most common genetic disorders:
Canine Genetic Disorders
Cancer: A familial, or breed related incidence of cancer is being investigated in several breeds. These include the common disorders of lymphoma, osteosarcoma, hemangiosarcoma, melanoma, and mast cell cancer. The research is focusing on inherited mutations in tumor suppressor cells (that act to prevent cancer), or oncogenes (that promote cancer). In many cancers, genetic testing of the cells (from biopsy or removal) can allow for a more accurate prognostic indication, as well as determining whether certain drug therapies may be more appropriate than others. Special marker panels for mast cell tumors have now been developed. Genetic markers to differentiate lymphosarcomas that may be more resistant to prolonged remission are also being investigated.
Osteosarcoma is most prevalent in Great Danes, Saint Bernards, Doberman Pinchers, and Labradors. Skin and soft-tissue cancers are most prevalent in Saint Bernards, Bassett Hounds, German Shepherds, Golden Retrievers, English Setters, Great Danes, Pointers, and Flat-Coated Retrievers. Breast tumors are most prevalent in Pointers, Poodles, Pulik, Cocker Spaniels, German Shorthaired Pointers, and Boston Terriers. Melanomas are most prevalent in Scottish Terriers, German Shorthaired Pointers, Cocker Spaniels, Pointers, Weirmeraners, Golden Retrievers, and Boxers. Malignant histiocytosis occurs in Flat Coated Retrievers and Bernese Mountain Dogs. Stomach cancer occurs at a high frequency in the Chow breed. An overall reduced cancer risk is found in Dachshunds and Beagles.
Progressive Retinal Atrophy: There are several inherited PRAs identified in dogs. The most common is an autosomal recessive, late-onset progressive rod cone degeneration. The mutation causing this disease occurred long before the differentiation of many breeds, so it is shared across many breed lines. The genetic testing company Optigen (www.optigen.com) offers a genetic test for this, and other breed specific PRA disorders. The following are test frequencies for prcd-PRA (%affected/%carrier): American Eskimo Dog (13%/57%), Australian Cattle Dog (18%/49%), Chesapeake Bay Retriever (4%/30%), English Cocker Spaniel (11%/45%), Entlebucher Mountain Dog (15%/50%), Labrador Retriever (3%/20%), Nova Scotia Duck Trolling Retriever (6%/46%), Poodle--Miniature (3%/28%), Poodle--Toy (5%/29%), and Portuguese Water Dog (4%/35%). There are also several other autosomal recessive, as well as autosomal dominant, and X-linked PRA disorders identified with genetic tests available in dog breeds.
Hereditary Epilepsy occurs in many breeds, and represents a diverse group of recurring seizure conditions. There are no tests available to diagnose hereditary epilepsy. When diagnosing epilepsy, other non-hereditary seizure disorders must be ruled out.
The onset of hereditary epilepsy can be neonatal, juvenile, or adult, although most dogs have their first seizure sometime after their first birthday. While most hereditary epilepsies cause recurring seizure episodes throughout life, some can cause only one or two seizures, and never occur again. Hereditary epilepsy can be generalized (grand-mal), or localized (petit-mal) causing only staring, "fly-biting", or "tics". Many dogs have only single seizures at a time. Others can cluster seizure, or have status epilepticus.
Epileptic dogs in a family tend to have similar ages of onset, types of seizures (single or clustering), progression, and response to anticonvulsant medications. These together are considered the phenotype (what you observe) of the epilepsy. It is believed that all dogs in a breed with the same phenotype have epilepsy due to the same genetic cause. In some breeds, affected dogs with different phenotypes may represent two different genetic causes, or the same genetic defect with other unknown (genetic or environmental) modifying factors. Drs. Anita Oberbauer and Thomas Famula at the University of California at Davis have found an epilepsy heritability of 77% in the Belgian Tervuren. Their research suggests that while a simple Mendelian single-gene mode of inheritance is not likely; there appears to be a single major epilepsy susceptibility gene at work in this breed. The high number of cross-bred dogs with epilepsy suggests that dominant or complex modes of inheritance are also possible.
Hip Dysplasia: This disorder of malformation and hip joint laxity occurs across all breeds. Of all dogs with radiographs submitted to the Orthopedic Foundation for Animals (www.offa.org), 14.59% are rated as dysplastic, and this is probably a low estimate due to pre-screening. The breeds with the highest frequency are; Bulldog (73.6%), Pug (61.7%), Otterhound (50.6%), Neopolitan Mastiff (48.5%), and St. Bernard (46.7%). Breeders must use breadth and depth of pedigree normalcy to select against this disorder.
Hypothyroidism: Hypothyroidism is caused by autoimmune thyroiditis; an inherited autoimmune disorder where the thyroid gland is destroyed by autoantibodies. In order to diagnose the disease, you have to identify the autoantibodies. A thyroid profile is a snapshot of a moving picture of the thyroid health of a dog. An affected dog will begin to produce thyroid autoantibodies usually between 1 and 3 years of age. The thyroid hormone levels and consequently the TSH levels will remain in the normal range until the majority of the thyroid gland is destroyed. Once the gland is destroyed and the thyroid levels fall, the antigenic stimulus to produce the autoantibodies is gone, and these levels return to normal. The animal is left with endstage hypothyroidism--low T4, high TSH, and no autoantibodies. Secondary hypothyroidism can be caused by infectious, neoplastic, endocrine, or other disease. Because of the lack of autoantibodies in the end stage, the diagnosis of autoimmune thyroiditis must be made during the immune destruction of the thyroid gland. A thyroid profile including autoantibodies run at 2 and 4 years of age will identify most affected dogs. Of all dogs thyroid tested by the Michigan State University endocrinology laboratory, 9.84% test positive for thyroglobulin autoantibodies. The breeds with the highest percentages are; English Setter (33.5%), Polish Lowland Sheepdog (30.7%), Havanese (25.6%), Old English Sheepdog (22.8%), and Boxer (19.7%). For mixed breed dogs, 11.5% of 49,126 dogs tested positive for thyroid autoantibodies.
Congenital Heart Anomalies: Several breeds of dogs and cats have hereditary congenital heart anomalies. These include patent ductus arteriosus (PDA), aortic stenosis, ventricular septal defect, and ventricular stenosis. Problems with managing these disorders include missed diagnoses on subclinically affected animals, and not utilizing breadth of pedigree in counseling breeders. If a breeder is concerned about carrying genes for the disorder, all related animals should be screened by Doppler echocardiography. This includes both pet and breeding siblings. When managing PDA we have to recognize that expression of this polygenic trait includes a ductus diverticulum. It has been shown that dogs with a ductus diverticulum have as great a chance of producing offspring with PDA than animals affected with PDA.
Subclinically affected individuals can also be identified with aortic stenosis, and other congenital heart disorders. These non-clinically affected individuals can be diagnosed by ultrasound, and should be considered genetically affected. Screening should be performed on all parents, full-sibs, and full-sibs of parents to identify the direction and degree of risk in the pedigree.
Atopic/Allergic Skin Disease: The heritability of atopic disease in Labrador and Golden retrievers is estimated at 47%, which is higher than many polygenically inherited disorders, including hip dysplasia. The breeds with the highest incidence of atopic skin disease are; West Highland White Terrier, Cairn Terrier, English Setter, Irish Setter, and Dalmatian.
Patella Luxation: This disorder is much more common in the small stature breeds. However, as many of these small dogs do not develop significant arthritis and discomfort from the condition, many breeders do not track the disorder or forward the results of patella evaluations to the OFA. The OFA patella database reports an average of 5.55% of submitted dogs with patella luxation. The breeds with the highest incidence are Pomeranian (47.9%), Chow Chow (29.5%), and Cocker Spaniel (27.2%).
Elbow Dysplasia: This disorder is classically defined as one of three disorders; ununited anconeal process, fractured coronoid process, or osteochondritis dessicans of the elbow joint. More recent research indicates that elbow dysplasia may actually be a disorder of uncoordinated growth of the radius and ulna. When the radius grows longer than the ulna allows, it causes elbow joint incongruity. The radius pushes the humeral condyles into the anconeal process, preventing its normal ossification onto the ulna. Of all dogs with radiographs submitted to the Orthopedic Foundation for Animals, 15.42% are rated with elbow dysplasia. Over 70% of these dogs have Grade I elbow dysplasia, which is a radiographic diagnosis that will never cause clinical disease. However, whenever a dog with Grade II or Grade III elbow dysplasia is identified, we find usually find several close relatives with Grade I elbow dysplasia.
Gastric Dilatation/Volvulus (Bloat): Bloat occurs primarily in the large and giant breeds. Dr. Larry Glickman at Purdue University conducted an epidemiological survey, and found that the Great Dane has the highest average lifetime risk of a bloat episode of 42.4%. Other breeds at higher-than average risk include the Bloodhound, Irish Wolfhound, Irish Setter, Akita, standard Poodle, German Shepherd Dog, and Boxer.
The dogs with the greatest risk of developing bloat have one or more of the following: An increased measurable chest depth to width ratio, are lean versus overweight, eat quickly, have a nervous or aggressive personality, or eat a single large meal per day of dry dog food.
Dogs do not inherit bloat; they inherit a predisposition for the condition. Perhaps the best selective tool against bloat is the chest-depth to chest-width ratio. Dogs that have lower ratios and whose littermates have not bloated are the best breeding candidates. If prospective breeding dogs are compared, and breeders select against those with high ratios, the prevalence of bloat should diminish. Breeders should use selection for polygenically controlled disorders.
von Willebrand's disease (vWD): Autosomal recessive vWD is the most common canine hereditary bleeding disorder, and has been reported in over 50 different breeds of dogs. Blood assays for vWD factor shows that the disorder is most prevalent in the Corgi, Doberman Pinscher, German Shepherd Dog, German Shorthaired Pointer, Golden Retriever, Shetland Sheepdog, and Standard Poodle. The genetic testing company VetGen (www.vetgen.com) has developed a genetic test for several breeds, that allows the diagnosis of affected, carrier, and normal dogs. VetGen lists the following frequencies of affected and carrier dogs from tested breeds (%affected/%carrier): Bernese Mountain Dog (1%/16%), Doberman (26%/49%), Manchester Terrier (4%/37%), Pembroke Welsh Corgi (6%/37%), Poodle-all varieties (1%/9%), Scottish Terrier (1%/12%), and Shetland Sheep Dog (1%/7%). VetGen also offers genetic tests for vWD in the German Pinscher, Kerry Blue Terrier, and Papillon. For breeds that do not have a genetic test, the phenotypic blood test for vWD factor should be run to identify affected dogs.
Drug Sensitivity/Ivermectin Sensitivity: The defect causing ivermectin sensitivity in Collies and other breeds has been identified as a mutation in the MDR1 or multi-drug resistance gene. This defective gene can also cause neurotoxicity from loperamide, vincristine, and other drugs, through alterations in the blood brain barrier. Homozygous recessive dogs can develop neurological signs, through alterations in the blood brain barrier. Heterozygous carriers are only sensitive at high dosages. A genetic test is available, and the following are results of testing in several breeds (%homozygous/%heterozygous): Collie (32%/46%), Australian Shepherd (2%/30%), Old English Sheepdog (1%/9%), Shetland Sheepdog (2%/17%), Longhaired Whippet (16%/52%), English Shepherd (<1%/14%).
Feline Genetic Disorders
Polycystic Kidney Disease (PKD) is an autosomal dominant disorder in Persian and Himalayan cats. Many of these cats develop kidney failure, while some only develop isolated cysts that do not impair normal kidney function. There is now a direct cheek swab genetic test available to identify kittens and cats with this defective gene (www.vgl.ucdavis.edu). Purchasers of Persian and Himalayan cats should see test results from UC-Davis, or should ask to do cheek swabs themselves on prospective kittens prior to purchase. Diagnostic testing in DNA positive cats includes kidney function testing and abdominal ultrasound. 38% of all Persian cats carry the defective gene for PKD. Even in a breed as populous and diverse as the Persian, removal of over a third of the breed in a short period of time will put a significant negative pressure on the gene pool. Hopefully the breeders will not resort to widespread euthanasia of kittens as the breed moves away from this disorder. PKD positive kittens should be sold or placed with full disclosure about the disorder. PKD has also been diagnosed in other long-haired breeds that trace back to Persian and Himalayan ancestry.
Hypertrophic Cardiomyopathy is a dominantly inherited disorder progressing to heart failure in the Maine Coon and Ragdoll breeds. Different mutations in the same causative gene for cardiomyopathy have been identified in both breeds, and genetic tests are available from Washington State Univ. (http://www.vetmed.wsu.edu/deptsVCGL/). In the Maine Coon, the gene frequency is estimated to be over 30%, with both homozygous and heterozygous affected cats. The Maine Coon breed also has a high incidence of hip dysplasia. A rarely reported abnormality in the breed is an autosomal recessive Spinal Muscle Atrophy. Affected cats show a progressive weakness, ataxia, and muscular atrophy.
Lethal Craniofacial Defect is a fatal autosomal recessive disorder in the Bernese breed. Research at the University of California Davis suggests that the defective gene will be linked to the wide "contemporary" facial structure that has been selected for in the breed.
Renal Amyloidosis occurs as a hereditary disorder in the Abyssinian breed. Affected cats show variable severity of proteinuria and progressive kidney failure. The mode of inheritance has not been determined. An autosomal recessive Pyruvate Kinase Deficiency has been identified in this breed, as well as in the Somali.
Neuromuscular Spasticity occurs in the Devon Rex. The mode of inheritance has not been worked out.
Glycogenolysis is an autosomal recessive disorder in the Norwegian Forest Cat.A genetic test is available from PennGen (www.vet.upenn.edu/penngen).
Polydactyly: Multiple toes is a common autosomal dominant trait with high penetrance and variable expression (numbers of toes). All cats with polydactyly usually have a similarly affected parent.
Deafness with blue eyes: The autosomal dominant white (W) gene can cause deafness in cats. Not all white, blue eyed cats are due to the W gene, and therefore can have normal hearing. There is also a possibly of incomplete penetrance of deafness with the W gene. Other blue eyed cats (Siamese and Burmese, etc.) have blue eyes due to the C gene, and have normal hearing. There are also other sensioneural deafness syndromes identified in cats.
Black skin spots on orange cats, especially around the mucous membranes of the mouth, nose, and eyelids are due to somatic back mutations of the orange to the black gene during cell regeneration. These occur and increase in frequency with age, but are a normal occurrence and require no treatment.
Calico and Tortoiseshell cats are all expected to be females, as the black and orange genes are alleles on the X-chromosome. To have both colors on the same cat, you would need two X-chromosomes to carry the two different alleles. Occasionally male calico or tortoiseshell cats are seen. These are most often males with Klinefelter's syndrome (XXY), or individuals with various forms of chimeric genotypes from the fusion of two fertilized eggs in utero. Fertile male calico or tortoiseshell cats with normal XY sex chromosomes are usually due to a back mutation of the color allele from orange to black in a subpopulation of their cells during fetal development.