Canine Immunogenetics Project: Weimaraner Update

By Judy Colan

Reprinted from the October 1998 issue of the Weimaraner Magazine.

U. C. Davis Update
For over 12 months, the Center for Companion Animal Health (CCAH), the Canine Health Foundation (AKC) and the Weimaraner Club of America have been developing an informative data base to investigate immune system disease in the Weimaraner breed. The aims of the data base at its inception were to identify major diseases within the breed, and to eventually use pedigree and DNA information on the data base to locate genetic markers for use in breed selection programs. In the design of the data base, we elected to use a "closed" format to facilitate identification of disease affected groups. We have now worked with several pure-breed dog clubs, and the "closed" data base has been very useful during the early investigation of a disease, providing anonymity for the breeders submitting information, and thereby reflects more accurately the true status of the problem in the breed.

Current Status of the Weimaraner Data Base
To date, there are over 850 Weimaraners entered into the data base, with several significant disease syndromes already recognized (Table 1).One of the major disease syndromes present in the Weimaraner breed is Hypertrophic Osteodystrophy, which causes pain and lameness associated with swelling of the growth plates in the long bones (e.g. femur, humerus). Other disease syndromes recognized include a post-vaccinal reaction with high fever and variable involvement of other body organs; the "classical" Immunodeficiency syndrome that has been recorded in the veterinary literature, with recurrent infections involving the bowel, skin, and urinary tract; hypothyroidism and mast cell tumors. Other less common diseases are also recorded on the data base, and information on their prevalence is available on request.

Hypertrophic Osteodystrophy (HOD)
HOD is a common disease of rapidly growing, large and giant breed purebred dogs. In a recent study looking at breed predilection for developmental bone diseases, breeds reported at increased risk included the Great Dane (190 x increased risk for HOD compared to mixed-breed dogs), the Boxer (18.4 x), the Irish Setter (14.3 x), and the German Shepherd (9.5 x) [Munjar, 1998]. The Weimaraner breed featured prominently, with a 21 fold greater risk of HOD occurrence compared to mixed breed dogs. An increased risk for HOD in the Weimaraner has been suggested in the veterinary literature, with a litter of four HOD-affected Weimaraner puppies (Grondelen, 1976), and a different litter of four affected puppies (Woodward, 1982) reported.

The CCAH data base currently has 30 Weimaraner puppies diagnosed with HOD. Most of these puppies have presented to veterinarians for acute onset of fever, with swelling present at growth zones of the long bones. Loss of appetite and lameness were present in all these dogs. Males and females were equally affected, and the age of onset of the disease is typically 8-16 weeks of life. We have noted an association with recent vaccination. Of the 30 HOD-affected dogs, 24 received a vaccination within 3-5 days of the onset of the disease. It is important to note, though that there were instances of HOD not associated with vaccination, so that the vaccination may be the trigger for disease expression on the susceptible genetic background.

Diagnosis of HOD relies on the typical history, clinical signs, and the presence of the characteristic radiographic findings showing changes at the growth plate of long bones. The cause of HOD remains unknown, with earlier speculations of vitamin C deficiency (Meier, 1957; Holmes, 1962) or over-nutrition (Riser, 1965) discounted in more recent times (Grondalen, 1976). There is mounting evidence that viral infection may be important in the disease., with Distemper virus detected in the growth plates of dogs with HOD (Mee, 1993). To date, we have not been able to identify a link to the Immunodeficiency disease of the Weimaraner related to low levels of blood antibody IgA or IgM.

Treatment of HOD in other breeds has traditionally relied on rest, non-steroidal anti-inflammatory drugs (such as aspirin), and opiate analgesics (such as butorphanol or fentanyl) as necessary. In most cases, the disease is self-limiting, and most dogs recover in several weeks. The disease in the Weimaraner is different. The Weimaraner breed is prone to a severe form of the disease, with disease progression in many dogs resulting in death without the proper treatment. Our current recommendation is for practitioners to rule out infectious causes for the fever, and in the presence of radiographic changes in growth plates consistent with HOD, to treat these dogs with corticosteroids. Prompt recognition of the disease, and appropriate treatment art the keys to a good outcome in this disease.

Mode of Inheritance of HOD in the Weimaraner
The mode of inheritance of HOD in the dog has not been reported, but there is an obvious breed predisposition suggesting that genetic factors play and important role. A useful index for influence of genetic factors in the disease is the heritability of a condition. Heritability varies from 0.0, in which there is not genetic influence, to 1.0, in which the effect is determined solely by genetics. Diseases with strong management influences (such as exposure to an infectious agent through communal grooming) are expected to have a low heritability, and response to selection against disease will be poor. The more appropriate course would be to identify the common theme, and altar the environment to prevent exposure to the cause of the disease.

A disease with a high heritability suggests that genetic factors are involved, and implies that a selection program against the disease will have and effect on the prevalence of the disease. Calculation of the heritability requires use of pedigrees, with accurate disease status indicated for as many dogs on the pedigree as possible. Preliminary work in our laboratory has found a high heritability for HOD in the Weimaraner of 0.68 (95% confidence interval of 0.65-0.71), suggesting that HOD in the Weimaraner may have a significant genetic component. It is very important to note that this value cannot be extrapolated to other breeds with HOD, as heritablity is only valid in the population from which it is measured. Other breed clubs will need to similarly calculate this value to gauge the likely success of an selection program against HOD.

We suspect that HOD in the Weimaraner is inherited as an autosomal recessive disease, although we still need more HOD-affected dogs to prove this. Some of the characteristics of an autosomal recessive disease that we are seeing in the Weimaraner with HOD include: 1) skipping of generations, and 2) mating of carriers results in the expected proportions of 25% affected, 50% carriers, and 25% unaffected (figure 1). Detection of carriers relies to date on test matings, which is definitely not the desired approach to long term control of the disease. Our data does not support and autosomal dominant mode of inheritance, nor do they support an X-linked (or sex-linked) mode of inheritance .

Importance of Carriers in Autosomal Recessive Disease
The success of any selection program in autosomal recessive diseases relies on accurate detection of animals carrying susceptibility genes (figure 2). In the best case scenario, the mating of an unsuspected carrier animal to an unaffected animal will still result in the production of 50% carriers in the progeny. This in effect maintains the susceptibility gene for the disease at high levels in the population, even if the disease is seen only sporadically when chance matings of two carriers occurs. We believe this is one of the difficulties in the control of HOD in the Weimaraner.

Weimaraners with HOD-susceptibility genes do not have any known phenotypic markers that permit identification, and to date the only way to detect these carriers has been by test matings. Detection of these carriers has also been hampered by use of modified vaccination protocols that are designed to prevent expression of HOD during the susceptible growth period. While it is important to look after the health of our puppies, this factor must be borne in mind when a selection program against HOD is to be implemented in the absence of a sensitive genetic marker. One of the aims of our group has been to locate a genetic marker for susceptibility to HOD, allowing for sensitive detection of these carriers, and thereby, design a suitable breeding program.

Immunodeficiency in the Weimaraner breed is well known, although the cause is poorly understood (Couto, 1989; Hansen, 1995; Day, 1997), Low immunoglobulin levels are the consistent feature in all of these reports, and low IgA, IgG, or IgM have been associated with the chronic, recurrent disease involving a variety of tissues including the bowel, skin, and the central nervous system. This disease syndrome is present in the Weimaraner breed in the U.S.A., and we suspect many of the chronic diarrhea and inflammatory bowel disease animals may have low immunoglobulin levels (Table 1), but have not had these specifically measured to confirm the diagnosis.

Another disease syndrome that has not been reported previously in the Weimaraner is a breed-specific meningitis. We raised the possibility of this disease at the 1998 Weimaraner Nationals, and have now documented eight Weimaraners with the disease. All of these dogs are included within the “ vaccine-reaction” group (T-1), and were presented to veterinarians for fever and neck/back pain. All eight have been male, but we are aware of two similar cases that have involved female dogs. The age of onset is typically between 16-30 weeks of life. The diagnosis confirmed by cerebral fluid (CSF) analysis, and requires anesthesia for sample collection. Many of these dogs have required long term treatment with corticosteroids to control the disease with recurrence seen at lower doses.

How Can You Help?

It is very important samples for both healthy and disease affected Weimaraners continue to be submitted. While 850 Weimaraners sounds like a large number, many more animals will be required for the type of statistical testing necessary for genetic marker analysis. In particular, we are interested in talking to anyone who has information on Weimaraners with any of the diseases we have discussed above, and who are not part of the Weimaraner data base at present. Any information provided is strictly confidential. For DNA swab kits and further information, please contact Dr. John via email at john.angles@ucd.ie
Dr. John M. Angles
BVSC, MV Studies, Diplomat ACVIM
University College, DublinDonations Appreciated

Great strides have been made but there is still a great deal of work to do to complete this project. Again, I am asking for your financial support. Please send donations to me payable WCA Health Fund. All donations are tax deductible.
Judy Colan
22A Paris Olney
Hopkins Road
Foster, RI., 02825

Acknowledgments:
This work has been supported in part by the Center for Companion Animal Health, University of California (Davis), and by the Canine Health Foundation (American Kennel Club). We thank all of those who have submitted samples, and have worked so hard to make this project a success.

References:
Couto, CG, Krakowka, S, Johnson, G, Ciekot, P, Hill, R, Lafrado, L and Kociba, G (1989). In vitro immunologic features of Weimaraner dogs with neutrophil abnormalities and recurrent infections. Veterinary Immunology and Immunopathology, 23: 103-112.
Day, MJ, Power, C, Oleshenko, J and Rose, M (1997) Low serum immunoglobulin concentrations in related Weimaraner dogs. Journal Small Animal Practice, 38: 311-315.
Grondalen, J (1976) Metaphyseal osteopathy (hypertrophic osteodystrophy) in growing dogs. A clinical study. J Small Animal Practice, 17: 721-735.
Hansen, P, Clerex, Henroteaux, M, Ritten, VPMG and Bernadina, WE (1995) Neutrophil phagocyte dysfunction in a Weimaraner with recurrent infections. Journal Small Animal Practice, 36: 128-131.
Holmes, JR (1962) Suspected skeletal scurvy in the dog. Veterinary Record, 74:801-813.
Mee, AP, Gordon, MT, May, C, Benett, D, Anderson, DC and Sharpe, PT (1993) Canine distemper virus transcripts detected in the bone cells of dogs with metaphysical osteopathy. Bone, 14:59-67.
Meier, H, Clark, ST, Schnelle, GB, Will, DH, (1957) Hypertrophic osteodystrophy associated with disturbance of vitamin C synthesis in dogs. Journal American Veterinary Medical Association. 130: 483-494.
Munjar, TA, Austin, CC and Breur, GJ (1998) Comparison risk factors for Hypertrophic Osteodystrophy, Craniomandibular Osteopathy and Canine Distemper Virus infection, Veterinary Comparitive Orthopedic Traumatology, 11:37-43.
Riser, WH, Shirer, JF, (1965) Normal and abnormal growth of the distal foreleg in large and giant dogs. Journal American Radiological Society, 6: 50-64.
Woodard, JC (1982) Canine Hypertrophic Osteodystrophy, a study of the spontaneous disease in litermates. Veterinary Pathology, 19: 337-354.