2.1. SCN8A-related epilepsy with encephalopathy

More than 100 mutations in the SCN8A gene have been found to cause SCN8A-related epilepsy with encephalopathy. This condition is characterized by recurrent seizures (epilepsy), abnormal brain function (encephalopathy), and intellectual disability. The signs and symptoms of this condition typically begin in infancy.

Most of these SCN8A gene mutations change a single protein building block (amino acid) in the Na_v1.6 channel. The mutations that cause SCN8A-related epilepsy with encephalopathy result in altered channels that stay open longer than usual, which increases the flow of sodium ions into neurons. The persistently open channels abnormally increase electrical signals, which can lead to excess activation (excitation) of neurons in the brain. This increased neuronal activity leads to seizures in people with SCN8A-related epilepsy with encephalopathy.

It is unknown how SCN8A gene mutations lead to intellectual disability, movement problems, and the other features of SCN8A-related epilepsy with encephalopathy. Because some affected children experience the loss of previously acquired skills (developmental regression) after the onset of seizures, it has been suggested that the seizures may impair brain function, but it is unclear if that is the case.

2.2. Other disorders

Mutations in the SCN8A gene have been found to cause intellectual disability and movement problems in some individuals. Unlike the mutations that cause SCN8A-related epilepsy with encephalopathy (described above), the SCN8A gene mutations that cause this condition result in the production of a Na_v1.6 sodium channel that is less active than normal, resulting in a decrease in the flow of sodium into neurons. This change does not increase neuronal signaling, so individuals with these mutations do not develop seizures. Researchers suspect that decreased neuronal signaling in the part of the brain that coordinates movement is the likely cause of the movement problems.

Other SCN8A gene mutations can cause movement problems and seizures called benign infantile seizures, which usually develop in the first year of life and stop by age 3. Unlike most other individuals with SCN8A gene mutations, these individuals have normal intellectual function. It is unknown why some SCN8A gene mutations cause these milder signs and symptoms while other mutations cause the more severe features of SCN8A-related epilepsy with encephalopathy.