Management of Hereditary Disorders and Genetic Counseling by Clinicians and Working with Breeders
World Small Animal Veterinary Association World Congress Proceedings, 2009
Urs Giger, Prof. Dr. med. vet., MS, FVH, DACVIM, DECVIM (Internal Medicine), ECVCP (Clinical Pathology)
School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

Although therapeutic interventions for affected animals are limited, there are novel therapies being investigated in small animals. Advising breeders regarding the control of hereditary diseases has become an important task. Some guidelines and examples are being discussed.

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 breeding. In a few cases a deficient protein, cofactor, substrate, or metabolite can be supplemented to correct the defect. For instance, vitamin B12 deficiency in cachectic and lethargic giant schnauzers, Australian Shepherds and Border collies 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. An example of dietary management of copper hepatopathy is reported below by Markwell et al. 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 coagulopathies and von Willebrand disease.

Although kidney transplants have been established in clinical practice for chronic renal failure in dogs and cats, they have not been applied in animals with hereditary (juvenile) renal disorders. Several hereditary disorders of hematopoietic cells have been experimentally corrected by bone marrow transplantation, e.g., pyruvate kinase and phosphofructokinase deficiency, cyclic hematopoiesis, 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., for lysosomal storage diseases. 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 hemophilia and severe x-linked combined immunodeficiency. Such treatments are being developed for humans, and once the technique is established, it may with ease also be applied in companion animals in the near future. Much more important than the treatment of hereditary disorders is the control of these traits in breeding programs. Considering an autosomal-recessive trait--the most common form of inheritance--breeding of two (asymptomatic) carriers results on average in 25% affecteds (homozygous for 2 mutant alleles), 50% carriers (heterozygote), and 25% normals (clear; 2 normal/wild-type alleles) or in other words 75% show no clinical signs. However, as some diseases are mild or may not become clinical until a few years of life, unfortunately, affecteds have also been used for breeding. Our responsibility as veterinarians is to offer advice to breeders and prospective buyers who should become informed consumers.

Dominant traits are relative easy to control in a population as one of the parents would show clinical signs. However, some dominant traits are associated with incomplete penetrance and thus their signs may be mild and missed. For autosomal recessive traits parents and offspring of affecteds are obligate carriers (they could even be affected, if it is a late onset [e.g., MPSIIIB in Schipperkes] or an intermittent disease or predisposition such as bleeding tendency). For x-chromosomal recessive traits the mother is typically the carrier passing the mutant or normal allele to the affected or healthy male offspring (hemizygote), respectively, while the female offspring are either again carriers or clear; indeed affected females are only very rarely produced when affected males are bred to carriers, e.g., for hemophilia A in German Shepherds).

In order to reduce the frequency or eliminate altogether a recessive 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 the most desirable traits and potentially all breeders in an entire kennel or cattery, and may severely reduce the genetic diversity of a breed. This may further 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 offspring of affecteds) and X-chromosomal recessive (mother of affected) disorders based upon the production of affected animals. As mentioned in a previous presentation, 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 by a DNA test.

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. 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.

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. These DNA tests are also extremely valuable to detect carriers and thus select breeding animals that will not cause disease or further spread the disease-causing allele. If an animal with all the desirable qualities is found to be a carrier, it could be safely bred to a clear animal (homozygous normal), as this would not result in any affected offspring. However, all offspring should be tested and only clear animals should be used in the next generation.

These advancements have far-reaching benefits for promoting canine and feline health permitting the elimination of deleterious gene defects, while preserving desirable traits in a breed. Several genetic disease registries have been established. While breeders and veterinarians are encouraged to participate in them, these registries are often biased just like frequency reports from testing laboratories. Often only clear animals are registered and more animals related to known affecteds and carriers are tested than in the random population. Thus the true frequency of deleterious trait is likely overestimated by a screening laboratory and under-reported in a registry. Canine Health Information Center or CHIC ( is a database which includes test results obtained from DNA testing but also OFA hip dysplasia and elbow scores, degree of patella luxation, and serum thyroid hormone values. Breed clubs are determining the tests included in CHIC and as more tests are included there will be fewer unaffected animals. 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 control. In addition to the clinician's responsibility to suspect a genetic disease and to appropriately diagnose it with modern specific techniques, clinicians must become involved in the control of these disorders with breeders. Clinicians can thereby make an important contribution toward controlling the further spread of mutant genes and reducing future suffering of animals.

Dietary Management of Hepatic Copper Accumulation in Labrador Retrievers

P.J. Markwell1, P.G. Jones1, J. Rothuizen2, G. Hoffmann2
1WALTHAM, a Division of Mars Incorporated, Melton Mowbray, Leicestershire, UK; 2Department of Clinical Sciences of Companion Animals, Utrecht University, NL

Hepatic copper storage and associated hepatitis has been described in a number of dog breeds, including the Bedlington, West Highland White and Skye Terriers, Doberman Pinscher and Dalmatian. Investigations suggested there is a hereditary form of hepatitis in Labrador retrievers caused by a defect in hepatic copper metabolism. D-penicillamine has been shown to be effective in reducing hepatic copper concentrations in affected Labradors, but until recently dietary intervention had not been studied. The effect of a commercial diet (Royal Canin Veterinary Diet LS14, Royal Canin, Aimargues, F) with a low copper concentration and high zinc: copper ratio, together with zinc supplementation, was investigated in 24 affected client owned Labrador retrievers. All dogs were fed the commercial diet with either zinc gluconate (7.5mg/kg PO BID) or a placebo. Hepatic copper concentrations decreased significantly in both groups after 8 months; no differences were observed between the zinc gluconate and placebo treated groups. This study showed that dietary management could decrease hepatic copper concentrations in Labrador Retrievers affected by a hereditary form of hepatitis associated with abnormal copper metabolism. Adjunctive treatment with zinc did not amplify the de-coppering effect.

Speaker Information
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Urs Giger, Prof. Dr. med. vet., MS FVH, DACVIM & DECVIM (Internal Medicine), ECVCP (Clinical Pathology)
School of Veterinary Medicine
University of Pennsylvania
Philadelphia, PA, USA

Peter Markwell, BSc, BvetMed, MRCVS

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