As in other breeds, the presumed mode of inheritance for idiopathic epilepsy in the Belgian shepherd dog is polygenic with a recessive gene of major influence. In addition to a genetic component, other factors are believed to contribute to the expression of epilepsy, possibly by lowering the seizure threshold; these factors include stress and sex steroids. In general, seizure activity in the Belgian shepherd dog begins about 4 years of age and treatment varies from none, to anticonvulsive medication (phenobarbital and/or potassium bromide), to euthanasia for intractable cases.
Due to the similarities of seizure activity between humans and dogs, the use of the human International League Against Epilepsy (ILAE) scheme has been proposed for the classification of seizures for dogs to improve consistency in data recording. Using the ILAE system, Berendt completed a comprehensive survey of epilepsy in the Belgian shepherds of Denmark and reported the prevalence of epilepsy at 9.5% (49 out of 516 dogs). Of these 49 epileptic dogs, 71% of the dogs experienced either primary or secondarily generalized seizures.
Identification of a locus linked to the expression of epilepsy would assist in reducing the prevalence of idiopathic epilepsy in the Belgian Tervuren and may also provide clues to mutations contributing to epilepsy in other breeds. Genetic testing currently is used by dog breeders seeking to improve the health of their breeds as evidenced by participation in the Canine Health Information Center while compulsory implementation of existing genetic tests as a condition of registry is being considered in the United Kingdom. Further, the similarities of seizure disorders between humans and dogs suggest that the findings of one species can aid the progress in the other. With that objective, a genome-wide linkage study was undertaken for the Belgian Tervuren.
Dog owners who participated in the study were recruited with cooperation from the American Belgian Tervuren Club, the Belgian Sheepdog Club of America, interested breeders, and individual owners. Research protocols were approved by the Institutional Animal Care and Use Committee of University of California, Davis. The present study included purebred Belgian Tervuren and Belgian Sheepdogs affected with epilepsy, as well as unaffected dogs. Genomic DNA was obtained by owners submitting three buccal swabs from each dog. Along with the DNA sample, owners provided specific seizure information (frequency, onset and duration of seizures), veterinary reports, and a three-generation pedigree. The dogs were designated as phenotypically epileptic based on information provided by the owner and veterinarian. Belgian Tervuren were defined as epileptic if they exhibited repeated "epileptic seizure phenomenology" common to generalized seizures based upon the classification system used for humans and applied in dogs.
The dogs data set consisted of 355 dogs, including 177 dogs for which buccal swab derived DNA was available for analysis and 178 additional dogs included to construct the appropriate pedigrees for analysis. Of the dogs for which DNA was available, 134 were designated as unaffected, 36 designated as having affected epilepsy status, and 7 having indeterminate ("unknown") status. The dogs without DNA submitted and included to complete the pedigrees were largely designated as "unknown" for the status except for deceased dogs known to meet the epileptic designation criteria (five dogs). Dogs classified as epileptic were equally represented by males and females (18 and 18, respectively; p > 0.5). For the dogs classified as epileptic, the average age at first observed seizure was 47.5 months, an age comparable to previously published data. Dogs were designated as "unaffected" if they had no reported seizure activity and were over 6 years of age; six years of age was selected because nearly 90% of BT and BS dogs defined as epileptic were under the age of 6 years at age at first recorded seizure.
The Belgian Shepherd Dog breed, which is highly related to the Belgian Tervuren,was used to independently assess the findings of the Belgian Tervuren association. The BS data set also consisted of 355 dogs, including 189 dogs for which buccal swab derived DNA was available for analysis and 166 additional dogs (again included to construct the appropriate pedigrees for analysis with epilepsy status classified as unknown). Of the dogs for which DNA was available, 147 were designated as unaffected, 38 designated as having affected epilepsy status, and 4 were classified as unknown. Similar to the Belgian Tervuren male and female distribution, epileptic BS dogs were equally distributed between the two sexes (p > 0.5). The average age at seizure onset in the BS dogs was 45.5 months.
Genomic DNA was extracted from the buccal swabs and used in a whole genome-wide linkage study. An initial genome scan of 100 microsatellite markers was run on a modest number of BT and expanded in the present study for a total of 436 microsatellite markers. Markers were selected from various sources, including the 1999 canine genetic linkage map, Minimal Screening Set 2 and the University of California, Davis linkage map. Criteria used in marker selection were to provide 9-Mb coverage of the canine genome and the ability to be amplified by PCR in multiplex reactions. Microsatellite markers were amplified and resolved in multiplexed sets using standard procedures. A high-throughput scanning fluorescence detector system was used to resolve the labeled PCR products (Applied Biosystems, Life Technologies, Carlsbad, CA) and genotypes were captured.
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