Genetic epilepsy with febrile seizures plus (GEFS+) is a spectrum of seizure disorders of varying severity. GEFS+ is usually diagnosed in families whose members have a combination of febrile seizures, which are triggered by a high fever, and recurrent seizures (epilepsy) of other types, including seizures that are not related to fevers (afebrile seizures). The additional seizure types usually involve both sides of the brain (generalized seizures); however, seizures that involve only one side of the brain (partial seizures) occur in some affected individuals. The most common types of seizure in people with GEFS+ include myoclonic seizures, which cause involuntary muscle twitches; atonic seizures, which involve sudden episodes of weak muscle tone; and absence seizures, which cause loss of consciousness for short periods that appear as staring spells.

The most common and mildest feature of the GEFS+ spectrum is simple febrile seizures, which begin in infancy and usually stop by age 5. When the febrile seizures continue after age 5 or other types of seizure develop, the condition is called febrile seizures plus (FS+). Seizures in FS+ usually end in early adolescence.

A condition called Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI) is often considered part of the GEFS+ spectrum and is the most severe disorder in this group. Affected infants typically have prolonged seizures lasting several minutes (status epilepticus), which are triggered by fever. Other seizure types, including afebrile seizures, begin in early childhood. These types can include myoclonic or absence seizures. In Dravet syndrome, these seizures are difficult to control with medication, and they can worsen over time. A decline in brain function is also common in Dravet syndrome. Affected individuals usually develop normally in the first year of life, but then development stalls, and some affected children lose already-acquired skills (developmental regression). Many people with Dravet syndrome have difficulty coordinating movements (ataxia) and intellectual disability.

Some people with GEFS+ have seizure disorders of intermediate severity that may not fit into the classical diagnosis of simple febrile seizures, FS+, or Dravet syndrome.

Family members with GEFS+ may have different combinations of febrile seizures and epilepsy. For example, one affected family member may have only febrile seizures, while another also has myoclonic epilepsy. While GEFS+ is usually diagnosed in families, it can occur in individuals with no history of the condition in their family.

Mutations in several genes, including some that have not been identified, can cause GEFS+. The most commonly associated gene is SCN1A. More than 80 percent of Dravet syndrome cases and about 10 percent of other GEFS+ cases are caused by changes in this gene. Mutations in other genes have been found in only a small number of affected individuals or families.

The SCN1A gene and others associated with GEFS+ provide instructions for making pieces (subunits) of channels that transport positively charged sodium atoms (sodium ions) into cells. The transport of these ions helps generate and transmit electrical signals between nerve cells (neurons). Proteins produced from other genes involved in GEFS+ are subunits of another type of ion channel called the GABAA receptor. GABAA receptor channels block (inhibit) signaling between neurons. Still other GEFS+-associated genes are also involved in nerve signaling.

Mutations in the SCN1A gene have a variety of effects on sodium channels. Many mutations that cause Dravet syndrome reduce the number of functional channels in each cell. Mutations that cause the milder GEFS+ disorders likely alter the channel's structure. All of these genetic changes affect the ability of the channels to transport sodium ions into neurons. Some mutations are thought to reduce channel activity while others may increase it. It is unclear, however, how these changes underlie the development of seizures. Some studies show that certain SCN1A gene mutations cause signaling between neurons to be constantly turned on (stimulated). Researchers believe that overstimulation of certain neurons in the brain triggers the abnormal brain activity associated with seizures. It is not known if all SCN1A gene mutations have the same effect.

Changes in GABAA receptor subunit genes impair the channel's function, causing uncontrolled signaling between neurons, which likely leads to seizures.

Researchers do not understand how changes in any one of the genes associated with GEFS+ can lead to a range of seizure disorders. Because the disorders are so varied, even among family members, researchers believe that other genes and environmental factors help determine the severity of the condition.

Normal Function

The SCN1A gene belongs to a family of genes that provide instructions for making sodium channels. These channels, which transport positively charged sodium atoms (sodium ions) into cells, play a key role in a cell's ability to generate and transmit electrical signals.

The SCN1A gene provides instructions for making one part (the alpha subunit) of a sodium channel called NaV1.1. These channels are primarily found in the brain, where they control the flow of sodium ions into cells. NaV1.1 channels are involved in transmitting signals from one nerve cell (neuron) to another. Communication between neurons depends on chemicals called neurotransmitters, which are released from one neuron and taken up by neighboring neurons. The flow of sodium ions through NaV1.1 channels helps determine when neurotransmitters will be released.

Health Conditions Related to Genetic Changes

Familial hemiplegic migraine

At least seven mutations in the SCN1A gene have been identified in people with familial hemiplegic migraine type 3 (FHM3), a form of migraine headache that runs in families. Each of these mutations changes a single protein building block (amino acid) in the NaV1.1 channel, which alters the channel's structure. The abnormal channels stay open longer than usual, which increases the flow of sodium ions into neurons. This increase triggers the cell to release more neurotransmitters. The resulting changes in signaling between neurons make people with FHM3 more susceptible to developing these severe headaches.

Genetic epilepsy with febrile seizures plus

Hundreds of mutations in the SCN1A gene have been found to cause genetic epilepsy with febrile seizures plus (GEFS+), which is a spectrum of seizure disorders of varying severity. These conditions include simple febrile (fever-associated) seizures, which start in infancy and usually stop by age 5, and febrile seizures plus (FS+). FS+ involves febrile and other types of seizures, including those not related to fevers (afebrile seizures), that continue beyond childhood. The GEFS+ spectrum also includes other conditions, such as Dravet syndrome (also known as severe myoclonic epilepsy of infancy or SMEI), that cause more serious seizures that last longer and may be difficult to control. These recurrent seizures (epilepsy) can worsen over time and are often accompanied by a decline in brain function.

The SCN1A gene mutations that underlie GEFS+ have a variety of effects on the function of the NaV1.1 channel. Some mutations change single amino acids in the channel, which alter the channel's structure. Others lead to the production of a nonfunctional version of the NaV1.1 channel or reduce the number of these channels produced in each cell. Still other mutations change single amino acids in critical regions of the channel. All of these genetic changes affect the ability of NaV1.1 channels to transport sodium ions into neurons. Some mutations are thought to reduce channel activity while others may increase it. It is unclear, however, how these genetic changes underlie the development of seizures or why they lead to a range of seizure disorders with varying severity.

Lennox-Gastaut syndrome

MedlinePlus Genetics provides information about Lennox-Gastaut syndrome

Malignant migrating partial seizures of infancy

MedlinePlus Genetics provides information about Malignant migrating partial seizures of infancy

Other disorders

A common change (polymorphism) in the SCN1A gene has been associated with the effectiveness of certain anti-seizure medications. This polymorphism, which is written as ICS5N+5G>A, alters a single DNA building block (nucleotide) in the SCN1A gene. Studies suggest that this polymorphism is associated with the maximum safe amount (dose) of the anti-seizure drugs phenytoin and carbamazepine. These drugs treat epilepsy by blocking sodium channels (such as NaV1.1) in neurons. A dose that is too small may not control seizures effectively, while a dose that is too large may cause unwanted side effects. Researchers are hopeful that doctors will be able to test for the ICS5N+5G>A polymorphism to help determine the safest and most effective dose of anti-seizure medications for each individual.

Other Names for This Gene

• GEFSP2
• HBSCI
• NAC1
• Nav1.1
• SCN1
• SCN1A_HUMAN
• sodium channel protein, brain I alpha subunit
• sodium channel, voltage gated, type I alpha subunit
• sodium channel, voltage-gated, type I, alpha
• sodium channel, voltage-gated, type I, alpha polypeptide
• sodium channel, voltage-gated, type I, alpha subunit

Genomic Location

GEFS+ is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new (de novo) mutations in the gene and occur in people with no history of the disorder in their family.

Dravet syndrome is almost always caused by de novo mutations, although it can be inherited from a parent who has a milder form of GEFS+. Other forms of GEFS+ are usually inherited from an affected parent. Rarely, Dravet syndrome or other forms of GEFS+ are inherited from a parent with somatic mosaicism. Somatic mosaicism means that some of the body's cells have the gene mutation, and others do not. A parent with mosaicism may be less severely affected or not show any signs or symptoms of GEFS+.

GEFS+ is a rare condition. Its prevalence is unknown.