These mutations result in almost any imaginable mutation type in the gene, short of duplications. The results of these mutations are highly variable, some producing functional channels while others result in non-functional channels. Some functional channels result in membrane hyperexcitability while others result in hypoexcitability. Most of the functional mutant channels result in hyperexcitability due to decreased frequency dependent rundown. An example of this is the D188V mutation. A 10 Hz stimulation of wild-type channels causes current to decrease to approximately 70% of maximum whereas the same stimulation of mutant channels results in rundown to 90% of maximum. This is caused by an expedited recovery from inactivation for mutant channels versus wild-type. The D188V mutant, for example, recovers to 90% maximal current in 200ms while wild-type channels are unable to recover to this degree in >1000ms. Some other functional mutations that lead to hyperexcitability do so by other means, such as decreasing the rate of entrance into the slow inactivated state.Some of the other functional mutations are believed to result in hypoexcitability. The R859C mutation, for example, has a more depolarized voltage dependence of activation, meaning that the membrane must be more depolarized for the channel to open. This mutant also recovers more slowly from inactivation. The nonfunctional channels are believed to produce similar changes in cell excitability. Likewise, many of the nonsense mutations likely result in nonfunctional channels and hypoexcitability, though this has yet to be tested. It is also unclear how this membrane hypoexcitability leads to the GEFS+ phenotype.
This is due in part to the effect of inhibitory neurons, electrical changes within the excitatory neuron, and the negative effects of adenosine.Focal seizures begin in one area of the brain while generalized seizures begin in both hemispheres. Some types of seizures may change brain structure, while others appear to have little effect. Gliosis, neuronal loss, and atrophy of specific areas of the brain are linked to epilepsy but it is unclear if epilepsy causes these changes or if these changes result in epilepsy.The seizures can be described on different scales, from the cellular level to the whole brain. These are several concomitant factor, which on different scale can "drive" the brain to pathological states and trigger a seizure. Diagnosis
The diagnosis of epilepsy is typically made based on observation of the seizure onset and the underlying cause. An electroencephalogram (EEG) to look for abnormal patterns of brain waves and neuroimaging (CT scan or MRI) to look at the structure of the brain are also usually part of the initial investigations. While figuring out a specific epileptic syndrome is often attempted, it is not always possible. Video and EEG monitoring may be useful in difficult cases.