Understanding epilepsy in a canine model Open Access

Genetic epilepsies generally present in children aged 2–10 years, during the developmental phase when the neural network undergoes ‘pruning’, and often spontaneously remit. Idiopathic epilepsies are common in dogs and in some breeds are ten times more common than in humans. It was previously reported that the Lagotto romagnolo breed exhibits an epileptic disorder with onset at ∼7 weeks (equivalent to age 2 years in humans) and remit at ∼4 months (age 8 years in humans). Seppälä et al. now report the genetic defect and affected neurological pathways underlying this phenotype. Mapping studies showed that the genetic defect results in truncation of the secreted neuronal protein LGI2, preventing its secretion and interaction with three ADAM-family neuronal membrane receptors. LGI2 mutations have not been associated with human epilepsy, but autosomal dominant lateral temporal lobe epilepsy (ADLTE) is associated with mutations in LGI1, which interacts with the same ADAM-family receptors. These interactions are thought to stabilize synapses, and LGI1 seems to protect the brain against seizures during and/or after the pruning phase. By contrast, the authors propose, based on LGI gene expression data, that LGI2 might be important for preventing seizures early during development of the neural network, before pruning. These results suggest that LGI2 should be considered as a candidate gene in childhood epilepsies.