Genetic Counseling Interactions with Breeders and Control of Hereditary Diseases
World Small Animal Veterinary Association World Congress Proceedings, 2008
School of Veterinary Medicine, University of Pennsylvania
Philadelphia, PA, USA

Therapeutic Options

At present, the therapeutic options in the treatment of hereditary diseases are limited and ethical principles need to be carefully considered. Many hereditary diseases are progressive with currently only palliative therapy available, and thus lead to the early demise of a diseased animal or euthanasia. Surgical interventions may correct some malformations including some orthopedic and eye problems as well as hepatic shunts, but such animals should be altered to prevent them from being used for future breeding. In a few cases a deficient protein, cofactor, substrate, or metabolite can be supplemented to correct the defect. For instance, cobalamin deficiency in cachectic, neurologic, cytopenic and/or lethargic border collies and several other breeds with an ileal receptor defect can be helped by monthly cobalamin injections. Pancreatic enzyme supplementation and daily insulin injections are used to manage animals with exocrine or endocrine pancreatic insufficiency, respectively. Fresh frozen plasma is administered in the treatment of hereditary coagulopathies and von Willebrand disease whenever animals excessively bleed. Other enzyme and protein replacements are also experimentally attempted. For instance, recombinant coagulation factors such as human recombinant factor VIIa has been successfully used for factor VII deficiency in beagles and has also been tried as a bypassing agent in other hereditary coagulopathies and von Willebrand disease.

Although kidney transplants have been established in clinical practice for chronic renal failure in cats (including amyloidosis), they have not been applied in animals with hereditary (juvenile) renal disorders. Several hereditary disorders of hematopoetic cells have been experimentally corrected by bone marrow transplantation, e.g., erythrocytic pyruvate and phosphofructokinase deficiency, cyclic hematopoesis, and interleukin-2 (IL-2) receptor defects. Furthermore, bone marrow transplantation is being attempted to deliver functional cells or active proteins to other tissues including liver, bone, and brain, e.g., in lysosomal storage disease. Finally, gene therapy, the integration of a functional gene into the patient's own defective cells, will likely be clinically feasible in the twenty-first century. Experiments in rodent models have provided encouraging results. However, effective gene therapy has proven more difficult in larger mammals, and the technology needs to be further improved to achieve persistent and regulated gene expression in larger mammals including humans, dogs and cats. One of the first and most promising canine gene therapy experiments has been the correction of mucopolysaccharidosis type VII in neonatal puppies with a retroviral vector carrying the beta-glucuronidase gene; these treated animals remain ambulatory, whereas affected become tetraparetic by a few months. Other examples include feline mannosidosis, canine hemophilia and severe x-linked combined immunodeficiency. Such treatments are being developed for humans and once the technique is established, it may also be applied in companion animals in the near future.

Genetic Screening

Nevertheless, of much greater importance is the screening of animals prior to breeding to assure that they are free of known hereditary diseases. Through various genetic screening programs, genetic counseling by veterinarians and with responsible breeders many hereditary disorders can be prevented from future generations. This should not be done without careful consideration of the severity of the disease, the treatment options and efficacy, prevalence of the mutant allele in the breed, and the overall gene pool in the breed.

In order to reduce the frequency or eliminate altogether a genetic defect, the further spread of the mutant gene has to be prevented in a family and eventually the entire breed. It is obvious that affected animals of any genetic disease should not be used for breeding. This approach is simple and effectively eliminates disorders with a dominant trait. For recessively inherited disorders, however, the elimination of affected animals is not sufficient and does not markedly reduce the prevalence of a defect within a breed or kennel/cattery. Although it may be safest not to breed any relatives of affected animals, as requested by some kennel clubs, this practice may, because of inbreeding and narrow gene pools in some breeds, eliminate all breeders in an entire kennel or cattery, and may severely reduce the genetic diversity of a breed. This may result in the propagation of other defects in a breed. Thus, it will be pivotal to detect carriers (heterozygotes) and truly 'clear' animals (homozygous normal) for simple recessively inherited disorders. Obligate carriers can be readily identified for autosomal (both parents of affected) and X-chromosomal recessive (mother of affected) disorders based upon the production of affected animals. As mentioned above, for some diseases, reliable carrier detection tests are available and many breeders know about them and inform the veterinarian. For instance, carriers have approximately half-normal (~50%) enzyme activity by functional assays, or have a normal and mutant DNA sequence for the diseased gene on a DNA test.

Genetic screening tests permit the identification of animals at risk for many of the single-gene hereditary diseases prior to the development of clinical signs, mitigating the suffering of dogs and cats carrying 2 mutant alleles for autosomal recessive traits. This advancement has far-reaching benefits for promoting canine and feline health permitting the elimination of deleterious gene defects, while preserving desirable traits in a breed. Identification of complex trait markers, such as those responsible for temperament and trainability, will likely prove extremely valuable to guide- and service-dog organizations, but also the common pet dog and cats. For the first time, the investigation and identification of polygenic diseases is a realistic proposition. Lastly, collaborative comparative veterinary-human studies will serve to accelerate the rate of discovery and the extent to which both human and veterinary medicine accrues benefits from gene-based research.

Breeders should, therefore, be encouraged to screen their animals for known genetic diseases before breeding whenever carrier tests are available. The availability of genetic tests can be found on several web sites including the WSAVA web site and Unfortunately, many breeders mistrust these newer tests; either they were disappointed by the inaccuracy of early tests, such as the radiographic examination for hip dysplasia, or they fear that the results may become publicly known which could hurt their business. If a carrier is used because of a narrow gene pool and many other desirable traits, it should only be bred with a homozygously normal (clear) animal; all its offspring need to be tested, and only clear animals should be used in future breedings. If carriers are used they need to be bred to clear and again any offspring intended for breeding should be screened. If no carrier tests are available, a test mating between the dog in question and a known carrier or affected could be performed, and no affected and at least 5 and 11 healthy puppies/kittens, respectively, need to be born to 'clear' an animal of a carrier state. For many breeders and veterinarians, this approach is ethically unacceptable because it may produce affecteds. Thus, breeders need to be educated by well-informed veterinarians; clinical genetic counseling is labor intense and not necessarily lucrative, but has the potential to affect the health of numerous animals far beyond the kennel or cattery involved and thereby also improve the future health of the breed.


In conclusion, it is most exciting to learn about many recent advances for many hereditary disorders and genetic predispositions in small animal practice, be it for the diagnostic approach to a hereditary disease, the understanding of its pathophysiology, or its genetic control. In addition to the clinician's responsibility to suspect a genetic disease and to appropriately diagnose it with modern specific techniques, clinicians should become involved in the control of these disorders in the breeders' kennels or catteries. Clinicians thus can make an important contribution toward controlling the further spread of mutant genes and reducing future suffering of animals.

Speaker Information
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School of Veterinary Medicine
University of Pennsylvania
Philadelphia, Pennsylvania, USA

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