Genetic Mutation Causes Seizures And An Irregular Heartbeat

The gene that is mutated in many individuals with CPVT carries the information for making a protein known as RyR2, which forms a channel through which Ca2+ passes. The genetic mutations in individuals with CPVT make the RyR2 channel leaky and this is thought to cause the potentially fatal irregular heartbeats. A large proportion of individuals with CPVT also suffer from seizures and these were thought to be caused by changes in the heartbeat.

However, Andrew Marks and colleagues, at Columbia University College of Physicians and Surgeons, New York, have now generated data in mice indicating that the seizures are directly caused by leaky RyR2 channels.

In the study, mice engineered to express the leaky RyR2 channel found in some individuals with CPVT were observed to suffer exercise-induced changes in their heartbeat, sudden death due to such changes, and spontaneous seizures. Importantly, the seizures occurred in the absence of changes in the heartbeat and Ca2+ leak was detected in cells in the brain. Additional evidence that leaky RyR2 channels in the brain and heart cause seizures and irregular heartbeats, respectively, was provided by the demonstration that a molecule that prevents the mutant RyR2 channels from leaking but does not inhibit their normal function reduced the frequency and severity of the seizures as well as eliminated the exercise-induced changes in heartbeat.