How Do Potassium Channel Mutations Cause Epilepsy?

In the March 18th issue of the journal Annals of Neurology, Dr. Orhan and investigators representing a large consortium of neurology and epilepsy departments throughout the world present an important analysis as to how potassium channel mutations result in certain epilepsies. The point of this particular analysis was to determine the mechanism of seven KCNQ2 mutations in causing epilepsy.

• Using animal models, the investigators found a clear loss of function for all mutations.

• Five of seven mutations exhibited a drastic, dominant, negative effect on wild type Kv 7.2 or Kv 7.3 subunits by either globally reducing current amplitudes (three mutations) or by a depolarizing shift of the activation curve (two voltage sensor mutations).

• Decreasing potassium currents at the sub-threshold level is known to critically influence neuronal firing. One mutation significantly reduced surface expression. The investigators went on to utilize ezogabine or retigabine,a Kv 7 channel opener, partially reversing these effects for the majority of analyzed mutations.

• The investigators concluded that the development of severe epilepsy and cognitive decline in children carrying five of the seven studied KC and Q2 mutations can be related to a dominant negative reduction of the resulting potassium current at subthreshold membrane potentials. Other factors, such as genetic modifiers, are postulated for the remaining two mutations.

• Moreover, retigabine, ezogabine or similar potassium-modifying drugs might be useful as a personalized therapy for this severe disease.