Mette Berendt, DVM, PhD; Christina Gulloev, DVM; Merete Fredholm, DVM, PhD, Dr. Med. Vet. Sci
Genetic factors are increasingly being identified as the underlying mechanisms of specific types of epilepsy in both humans and canines.1-3 In dogs, certain breeds express an accumulation of epileptic individuals in the population. Among others, the Belgian shepherd, Beagle, Keeshond, Labrador retriever, Bernese Mountain dog, Shetland sheep dog, Irish wolfhound, English Springer spaniel and Lagotto Romagnolo, are believed to have an increased risk of epilepsy with a suspected genetic influence.1-17
An epileptic seizure occurs due to a number of intricately linked mechanisms at the neuronal network, cellular, and molecular levels. Genes and their mutations can influence these processes at various levels, producing a particular seizure phenotype.1
Although much is still obscure regarding the genes underlying epileptic seizures, some gene defects in human epileptic syndromes have been revealed including e.g., channelopathies (potassium, natrium, calcium), receptor anomalies, abnormal neurotransmitter metabolism, which ultimately predispose to neuronal hyperexcitability.
Allelic variation at the same locus can produce different phenotypes, while mutations at different loci can produce a similar phenotype, and vice versa1. Furthermore, genetic and environmental factors can interact, such that a gene lowers the seizure threshold, whereas an environmental factor can trigger the seizure expression, e.g., stress.1,18 However, since the dog populations are much more homogeneous compared to the human population, these populations constitute a unique resource for understanding the genetic basis of phenotypic variation.19
The Belgian Groenendael and Tervueren are known to have a high incidence of seizures, and several papers have been published supporting that hereditary epilepsy exist in this breed.4-8 In 2000, Famula & Oberbauer suggested that a single gene with a large impact on seizures is segregating in the Belgian Tervueren.7 The genetics of epilepsy in this breed is suspected to be of a polygenic inheritance with a single gene of large effect, inherited as an autosomal recessive locus.8
In Denmark, breeders of the Belgian Groenendael and Tervueren have noticed an increase in individuals with epilepsy over the last ten years. It was therefore decided to perform a population study investigating prevalence, distribution, hereditary aspects and characteristics of epilepsy in the Belgian Groenendael and Tervueren population born in Denmark in the time period 1991-2004. During this investigation an extended family of dogs with an accumulation of individuals with epileptic seizures was identified and studied. The family study and status of epilepsy in this particular family is presented here.
Study Population and Study Design
The study population consisted of members of a specific Danish Belgian shepherd family of Groenendael and Tervueren with an unusual accumulation of individuals suffering from epileptic seizures. Dogs were born between 1991 and 2005. The study was designed as a longitudinal study investigating epilepsy status in both living and deceased individuals.
The identity of the dogs and their owners were retrieved from the central register of the Danish Kennel Club. In this register, all purebred Groenendael and Tervueren are recorded chronologically by date of registration and litter number. Individuals suffering from seizures were identified by contacting all owners of living and deceased dogs belonging to the family. Owners were interviewed by the investigators using a standardized questionnaire containing questions regarding age at first seizure, seizure frequency, seizure duration, as well as a detailed description of seizure phenomenology, post-ictal signs, if the dog had been diagnosed with epilepsy by a veterinarian and possible anticonvulsive treatment. Finally, the owners were asked if the dog was known to suffer from diseases other than epilepsy and if the dog appeared normal interictally. If the clinical signs described could be mistaken for a possible differential diagnosis to epilepsy, clarifying questions were asked. All living dogs were asked to participate in clinical and laboratory investigations at the Department of Small Animal Clinical Sciences, Faculty of Life Sciences, The University of Copenhagen, Denmark.
The reference population (the dog family) consisted of 203 dogs in November 2007. Fifty-two dogs were identified as epilepsy positive. A majority of dogs experienced focal seizures with or without secondary generalization. The most commonly reported focal seizure phenomenology included ataxia, crawling, swaying, fearful behavior, salivation, excessive attention seeking and disorientation. In cases with secondary generalization focal seizure phenomenology was followed by tonic-clonic convulsions. The average duration of a seizure was between 30 seconds and 2.5 minutes. Age of onset was between 3-5 years. All dogs were normal interictally.
The segregation of the disease was studied in the extended pedigree comprising 27 litters and a total of 203 dogs. Based on the questionnaire investigation and the clinical investigations, it was possible to obtain detailed information on all offspring and parents in 19 of the litters in the extended pedigree. However, since the dogs belonging to nine of these litters were younger than 3 years of age, these litters were excluded from the segregation analysis (as they might not yet have expressed the disease). In nine of the remaining 10 litters, one of the parents was affected while both of the parents were affected in the last litter. The segregation of epilepsy in all 10 litters (i.e., 1:1 and 3:1 respectively) was strongly suggestive of autosomal dominant inheritance of epilepsy in the family.
Together the clinical and genetic characterization of epilepsy in Belgian shepherds provides the starting point for molecular genetic studies of the disease. We have established a prospective study following the Danish population of Belgian shepherds and a DNA bank comprising DNA from the dogs included in the present study. Thus, based on the tools that have been established for mapping of genes behind phenotypic traits in the dog genome we will continue to work on identifying the gene and the mutation responsible for epilepsy in Belgian shepherds.19
1. Prasad AN, et al. Epilepsia 1999;40:1329-1352.
2. Berkovic SF, et al. Epilepsia 2001;42 Suppl 5:16-23.
3. Chandler K. Vet J2006;172,207-217.
4. Van der Velden M J. Small Anim Pract 1968;9:63-70.
5. Famula TR, et al. J Small Anim Pract 1997;38:349-352.
6. Famula TR, et al. Prevent Vet Med 1998;33:251-259.
7. Famula TR, et al. Vet Rec 2000;147:218-221.
8. Oberbauer AM, et al. J Hered 2003;94:57-63.
9. Bielfelt SW, et al. Am J Vet Res 1971;32:2039-2048.
10. Hall SJ, et al. Vet Rec 1996;138:358-360.
11. Berendt M, et al. J Vet Int Med 2002;16:262-268.
12. Jaggy A, et al. J Small Anim Pract 1998;39;275-280.
13. Kathmann I, et al. J Small Anim Pract 1999;40:319-325.
14. Morita T, et al. Can J Vet Res 2002;66:35-41.
15. Casal ML, et al. J Vet Int Med 2006;20:131-135.
16. Patterson EE, et al. J Am Vet Med Assoc 2005;226:54-58.
17. Jokinen TS, et al. J Vet Int Med 2007;21;464-471.
18. Callenbach PM, et al. Epilepsia 2003;44:1298-1305.
19. Karlsson EK, et al. Nature Gen 2007, 11: 1321-1328.