Resistance to Phenobarbital in Idiopathic Epilepsy

 

Gene: ABCB1 (MDR1)

Transmission: Autosomal, recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Substitution, ABCB1 gene (MDR1); c.-6-180 T>G

Medical system : Pharmacogenetics

Breeds: Border Collie, Koolie

Age of onset of symptoms: From birth

Epilepsy is a common neurological condition in numerous breeds of dogs.  In the Border Collie breed, a percentage of animals suffering from idiopathic epilepsy are resistant to phenobarbital, a commonly used and generally effective antiepileptic drug.  This resistance is associated with a mutation in the gene encoding a membrane transport protein called P-glycoprotein, which normally is responsible for transporting small molecules (e.g. drugs) out of cells.  When both copies of the gene are mutated it is felt that the transport protein becomes too effective at keeping phenobarbital out of cells, thus blocking the action of this drug.  Phenobarbital resistance complicates the treatment of dogs that suffer from epileptic seizures.

 

References:

OMIA link: [1402-9615]

Beckers E, Casselman I, Soudant E, et al. (2022) The prevalence of the ABCB1-1Δ variant in a clinical veterinary setting: The risk of not genotyping. PLoS One 17:e0273706.  [pubmed/36037240]

Gagliardo T, Gandini G, Gallucci A, Menchetti M, et al. (2019) ABCB1 c.-6-180T>G Polymorphism and Clinical Risk Factors in a Multi-Breed Cohort of Dogs With Refractory Idiopathic Epilepsy. Vet J. 253:105378. [pubmed/31685133]

Mizukami K, Yabuki A, Chang H-S, et al. (2013) High frequency of a single nucleotide substitution (c.-6-180T>G) of the canine MDR1/ABCB1 gene associated with phenobarbital-resistant idiopathic epilepsy in Border Collie dogs.  Disease Markers 35(6):669-672. [pubmed/24302812]

Alves L, Hulsmeyer V, Jaggy A, et al. (2011) Polymorphisms in the ABCB1 gene in phenobarbital responsive and resistant idiopathic epileptic Border Collies.  J Vet Internal Medicine 25(3):484-489. [pubmed/21488961]