SCN8A-related epilepsy with encephalopathy is a condition characterized by recurrent seizures (epilepsy), abnormal brain function (encephalopathy), and intellectual disability. The signs and symptoms of this condition typically begin in infancy.

The seizures in SCN8A-related epilepsy with encephalopathy include involuntary muscle contractions that occur before age 1 (infantile spasms), partial or complete loss of consciousness (absence seizures), involuntary muscle twitches (myoclonic seizures), or loss of consciousness with muscle rigidity and convulsions (tonic-clonic seizures). Most people with SCN8A-related epilepsy with encephalopathy have more than one type of seizure. The frequency of seizures in different individuals with this condition ranges from hundreds per day to fewer than one per month. In many individuals, the seizures are described as refractory because they do not respond to therapy with anti-epileptic medications.

Other signs and symptoms of SCN8A-related epilepsy with encephalopathy include intellectual disability that may be mild to severe. Some affected infants have normal early development but begin to lose previously acquired skills (developmental regression) and have a gradual loss in thinking ability (cognitive decline) when epilepsy develops. Problems with movement are common, and about half of affected infants cannot perform intentional movements. Behavior disorders may also occur.

In rare cases, individuals with this condition die unexpectedly for no known reason (sudden unexpected death in epilepsy or SUDEP).

As its name suggests, SCN8A-related epilepsy with encephalopathy is caused by mutations in the SCN8A gene. This gene provides instructions for making one part (the alpha subunit) of a sodium channel called Nav1.6. This channel allows positively charged sodium (Na) atoms (sodium ions) to pass into nerve cells (neurons) and plays a key role in the ability of neurons to communicate by generating and transmitting electrical signals.

SCN8A gene mutations result in altered Nav1.6 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. The 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 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.

Normal Function

The SCN8A gene belongs to a family of genes that provide instructions for making sodium channels. These channels allow positively charged sodium (Na) atoms (sodium ions) to pass into cells; they play a key role in a cell's ability to generate and transmit electrical signals.

The SCN8A gene provides instructions for making one part (the alpha subunit) of a sodium channel called Nav1.6. The alpha subunit forms the hole (pore) in the cell membrane through which sodium ions flow. Nav1.6 channels are primarily found in the nerve cells (neurons) of the brain and spinal cord (central nervous system) and neurons that connect the central nervous system to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound (the peripheral nervous system). Nav1.6 channels control the flow of sodium ions into cells, which makes it possible for neurons to communicate by generating and transmitting electrical signals.

Health Conditions Related to Genetic Changes

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 Nav1.6 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.

Lennox-Gastaut syndrome

MedlinePlus Genetics provides information about Lennox-Gastaut syndrome

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 Nav1.6 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.

Other Names for This Gene

• BFIS5
• CERIII
• CIAT
• hNa6/Scn8a voltage-gated sodium channel
• NaCh6
• Nav1.6
• sodium channel, voltage gated, type VIII, alpha subunit
• voltage-gated sodium channel subunit alpha Nav1.6
• voltage-gated sodium channel type VIII alpha protein

Genomic Location

This condition follows an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Most cases of this condition result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.

There are at least 140 individuals with SCN8A-related epilepsy with encephalopathy. This condition is estimated to account for 1 percent of all cases of epilepsy with encephalopathy.