Familial focal epilepsy with variable foci (FFEVF) is an uncommon form of recurrent seizures (epilepsy) that runs in families. Seizures associated with FFEVF can begin at any time from infancy to adulthood. The seizures are described as focal or partial, which means they begin in one region of the brain and do not cause a loss of consciousness. In more than 70 percent of affected individuals, these seizures begin in one of two areas of the brain, either the temporal lobe or the frontal lobe. The region of the brain where the seizures start tends to stay the same over time. In rare instances, seizure activity that starts in one area spreads to affect the entire brain and causes a loss of consciousness, muscle stiffening, and rhythmic jerking. Episodes that begin as partial seizures and spread throughout the brain are known as secondarily generalized seizures.

Among family members with FFEVF, individuals may not have the same brain region affected (variable foci), meaning that one person's seizures may not begin in the same part of the brain as their affected relative.

Some individuals with FFEVF also have a brain malformation called focal cortical dysplasia. Seizures in these individuals are typically not well-controlled with medication.

Most people with FFEVF are intellectually normal, and there are no problems with their brain function between seizures. However, some people with FFEVF have developed psychiatric disorders (such as schizophrenia), behavioral problems, or intellectual disability. It is unclear whether these additional features are directly related to epilepsy in these individuals.

Most cases of FFEVF are caused by mutations in the DEPDC5 gene with fewer cases caused by mutations in the NPRL2 or NPRL3 gene. These three genes provide instructions for making proteins that attach (bind) to each other to form a protein complex called GATOR1. This complex is found in cells throughout the body, where it regulates a signaling pathway involved in cell growth and division (proliferation), the survival of cells, and the creation (synthesis) of new proteins. The role of the GATOR1 complex is to block (inhibit) this pathway when it is not needed.

A mutation in any one of the three genes associated with FFEVF reduces GATOR1 complex formation, leading to an abnormally active signaling pathway. It is unclear how overactivity in this pathway leads to the focal seizures of FFEVF. Research suggests that increased signaling in the brain leads to changes in the development of the junctions between nerve cells (synapses) and increased activation (excitation) of nerve cells, which can cause seizures. Increased excitation of nerve cells can also cause enlargement of these cells, which is characteristic of focal cortical dysplasia.

It is unknown why some individuals with the same mutation have seizures that start in different regions of the brain. Researchers believe that other, unknown genes may influence the features of FFEVF.

Some individuals with FFEVF do not have an identified mutation in any of these three genes. The cause of the condition in these individuals is unknown.

Normal Function

The DEPDC5 gene provides instructions for making a protein that is one piece of a group of proteins (complex) called GATOR1. This complex is found in cells throughout the body, where it regulates a signaling pathway called the mTOR pathway. The mTOR pathway is involved in cell growth and division (proliferation), the survival of cells, and the creation (synthesis) of new proteins. The role of the GATOR1 complex is to block this pathway by inhibiting (stopping) the activity of a complex called mTOR complex 1 (mTORC1) that is integral to the mTOR pathway.

In the brain, the mTOR pathway regulates many processes, including the growth and development of nerve cells and their ability to change and adapt over time (plasticity).

Health Conditions Related to Genetic Changes

Familial focal epilepsy with variable foci

More than 80 mutations in the DEPDC5 gene have been found to cause familial focal epilepsy with variable foci (FFEVF), which is an uncommon form of recurrent seizures (epilepsy) that runs in families. Affected individuals experience focal seizures, which are seizures that do not cause a loss of consciousness. Most of the DEPDC5 gene mutations lead to the production of an abnormally short protein that is quickly broken down. As a result, formation of normal GATOR1 complex is reduced, leading to overactivity of mTORC1 and excessive signaling of the mTOR pathway. It is not clear how an abnormally active mTOR pathway leads to the focal seizures of FFEVF. Research suggests that increased mTOR pathway signaling in the brain leads to changes in the connections between nerve cells (synapses) and increased activation (excitation) of nerve cells, which can cause seizures.

For unknown reasons, some people with FFEVF caused by a DEPDC5 gene mutation never develop the condition, a situation known as reduced penetrance. It is estimated that 60 percent of individuals with DEPDC5 gene mutations go on to develop FFEVF.

Other disorders

Mutations in the DEPDC5 gene can cause other seizure disorders, known as familial mesial temporal lobe epilepsy and infantile spasms. Similar to individuals with FFEVF (described above), people with familial mesial temporal lobe epilepsy have focal seizures. They may also have feelings of déjà vu, fear, or nausea during the seizure. Infantile spasms are seizures that usually appear before the age of 1 and involve recurrent muscle contractions.

As in FFEVF, most of the DEPDC5 gene mutations that cause familial mesial temporal lobe epilepsy or infantile spasms lead to reduced GATOR1 complex formation and an abnormally active mTOR pathway. It is unclear why individuals with mutations in the same gene develop different seizure disorders.

Other Names for This Gene

• DEP.5
• FFEVF
• FFEVF1
• KIAA0645

Genomic Location

FFEVF is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the mutation from one parent.

For unknown reasons, some people with FFEVF caused by a DEPDC5 gene mutation never develop the condition, a situation known as reduced penetrance. Approximately 60 percent of individuals with DEPDC5 gene mutations go on to develop FFEVF.

The prevalence of FFEVF is unknown.