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Identification of a Novel Idiopathic Epilepsy Locus in Belgian Shepherd Dogs

 

Eija H. Seppälä1,2,3, Lotta L. E. Koskinen1,2,3, Christina H. Gulløv4, Päivi Jokinen1,2,3, Peter Karlskov-Mortensen5, Luciana Bergamasco6, Izabella Baranowska Körberg7, Sigitas Cizinauskas8, Anita M. Oberbauer9, Mette Berendt4, Merete Fredholm5, Hannes Lohi1,2,3*

 

 

1 Research Programs Unit, Molecular Medicine, University of Helsinki, Helsinki, Finland, 2 Department of Veterinary Biosciences and Department of Medical Genetics, University of Helsinki, Helsinki, Finland, 3 Folkhälsan Institute of Genetics, Helsinki, Finland, 4 Department of Small Animal Clinical Sciences, University of Copenhagen, Copenhagen, Denmark, 5 Department of Basic Animal and Veterinary Sciences, University of Copenhagen, Copenhagen, Denmark, 6 College of Veterinary Medicine, Kansas State University, Manhattan, Kansas, United States of America, 7 Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden, 8 Referral Animal Neurology Hospital Aisti, Vantaa, Finland, 9 Department of Animal Science, University of California Davis, Davis, California, United States of America

 

Abstract

 

Epilepsy is the most common neurological disorder in dogs, with an incidence ranging from 0.5% to up to 20% in particular breeds. Canine epilepsy can be etiologically defined as idiopathic or symptomatic. Epileptic seizures may be classified as focal with or without secondary generalization, or as primary generalized. Nine genes have been identified for symptomatic (storage diseases) and one for idiopathic epilepsy in different breeds. However, the genetic background of common canine epilepsies remains unknown. We have studied the clinical and genetic background of epilepsy in Belgian Shepherds. We collected 159 cases and 148 controls and confirmed the presence of epilepsy through epilepsy questionnaires and clinical examinations. The MRI was normal while interictal EEG revealed abnormalities and variable foci in the clinically examined affected dogs. A genome-wide association study using Affymetrix 50K SNP arrays in 40 cases and 44 controls mapped the epilepsy locus on CFA37, which was replicated in an independent cohort (81 cases and 88 controls; combined p = 9.70×10−10, OR = 3.3). Fine mapping study defined a ~1 Mb region including 12 genes of which none are known epilepsy genes or encode ion channels. Exonic sequencing was performed for two candidate genes, KLF7 and ADAM23. No variation was found in KLF7 but a highly-associated non-synonymous variant, G1203A (R387H) was present in the ADAM23 gene (p = 3.7×10−8, OR = 3.9 for homozygosity). Homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for epilepsy (p = 6.28×10−11, OR = 7.4). ADAM23 interacts with known epilepsy proteins LGI1 and LGI2. However, our data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted re-sequencing study across the locus to identify the causative mutation. It would establish the affected breed as a novel therapeutic model, help to develop a DNA test for breeding purposes and introduce a novel candidate gene for human idiopathic epilepsies.

 

 

 

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Candidate gene sequencing

The associated 1 Mb region at CFA37 contains 12 genes of which two, ADAM23 and KLF7, have functions in neuronal systems (Fig. 2C). Mutations in ADAM23 have not been found in epileptic patients, but it interacts with LGI1, a gene associated with familial temporal lobe epilepsy-1 (ETL1) in human [44] and with LGI2, which is the causative gene for benign focal epilepsy in dogs [33]. KLF7 is a neuronal transcription factor, which is required for neuronal morphogenesis and axon guidance in selected regions of the brain [45]. Sequence analysis of KLF7 did not reveal any coding variants. Screening of the ADAM23 exons revealed a non-synonymous variant in exon 12 (G1203A according to predicted mRNA XM_844759) at 18,113,688 bp causing an amino acid change (R387H according to XP_849852.1) in four affected dogs. To further investigate the frequency of the variant, we genotyped a total of 159 cases and 148 controls. The risk allele A frequency was 72% in the cases compared to 49% in the controls (p = 3.1×10−9, OR = 2.7, 95% CI: 1.9–3.8). Homozygosity for the A allele increased the risk (p = 3.7×10−8, OR = 3.9, 95% CI: 2.4–6.4). However, 22% of controls were also homozygous. Comparison of frequency of the R387H variant in different epilepsy types did not show enrichment to specific seizures (data not shown). This variation was also screened in three epileptic dogs from 38 other breeds (altogether 114 epileptic dogs), and we found that the homozygous AA genotype was present in some of the three affected dogs in altogether 12 breeds (19% of tested dogs) (Barbet, Beagle, Border Collie, Dachshund, Dalmatian, Golden Retriever, Irish Water Spaniel, Miniature Pinscher, Petit Basset Griffon Vendeen, Miniature Poodle, Rottweiler and Whippet).

 

 

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  • 8 years later...
  • 1 month later...

Am posting to inquire about seizure related disorders, if there be such a thing?

We lost one of our two 4YO BC's during the night. He had been observed in his lifetime as having only 2 separate incidences of seizure activity, about 3 months apart. Taken off of Simparica after the first episode. No anti-seizure meds.

Yesterday, he was unable to defecate despite multiple attempts, showed what seemed to be all the symptoms of constipation/ possible blockage. Taken to our vet- she could feel what seemed to be hard stool but too high to finger retrieve/ 2 enemas unproductive. Kept overnight, IV fluids/ cathed/ stool softeners.

This morning they found him deceased. Necropsy reveals dead bowel, from ileum onward - dx sepsis secondary to that. Perhaps mesenteric infarct. No intussusception, torsion, or perforation, no peritonitis. 

Have any connections been observed between seizures in dogs that are perhaps related to clotting disorders, affecting other body structures?
Thank you for your time and response.

I'm sorry, I forgot how to "tag" a member in a post - @Mark Billadeau

Maybe I'm looking down the wrong rabbit trail - I'm sorry.

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  • 2 weeks later...

Thank you, @Mark Billadeau.

Thank you, @Journey. It's been devastating, to say the least. I fault myself to some extent, as- when the vet made her initial assessment of stool obstruction, she also said "I haven't pulled any labs..."  I should've said, yes, let's look at labs, a white count would be good :(..."

I should've, I SHOULD HAVE- but I didn't. Maybe he could've shown an elevation, and if an ex-lap had been done, maybe, just maybe, just a small segment of bowel might only have been affected at that moment, and been resected. The only issue seemed to be "the elephant in the room".
So many what-if's. It's been just over a week, and feels like only yesterday that we lost him.

Thank you.

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