Familial focal epilepsy with variable foci

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

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.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

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.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

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.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

The prevalence of FFEVF is unknown.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

EEG with focal epileptiform discharges · Very frequent (99-80%)

EEG discharges recorded in particular areas of a localized (focal) abnormality in cerebral electrical activity recorded along the scalp by electroencephalography (EEG).

Focal-onset seizure · Very frequent (99-80%)

A focal-onset seizure is a type of seizure originating within networks limited to one hemisphere. They may be discretely localized or more widely distributed, and may originate in subcortical structures.

Bilateral tonic-clonic seizure · Frequent (79-30%)

A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.

Interictal EEG abnormality · Frequent (79-30%)

Interictal refers to a period of time between epileptic seizures. Electroencephalographic (EEG) patterns are important in the differential diagnosis of epilepsy, and the EEG is almost always abnormal during a seizure. Some persons with seizures may show EEG abnormalities between seizures, while others do not. In some cases, multiple interictal EEGs must be recorded before an abnormality is observed. In most cases the electrographic pattern of seizure onset is completely different from the activity recorded during interictal discharge.

Nocturnal seizures · Frequent (79-30%)

Seizures that occur while the affected individual is sleeping.

Atypical behavior · Occasional (29-5%)

Atypical behavior is an abnormality in a person's actions that can be controlled or modulated by the will of the individual. While abnormal behaviors can be difficult to control, they are distinct from other abnormal actions that cannot be affected by the individual's will.

Auditory hallucinations · Occasional (29-5%)

Perception of sounds without auditory stimulus.

Autistic behavior · Occasional (29-5%)

Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.

Other findings in the same source

From: Orphanet

Additional reported features include Cognitive impairment (Occasional (29-5%)); Deja vu (Occasional (29-5%)); Flushing (Occasional (29-5%)); Focal aware seizure (Occasional (29-5%)); Focal cortical dysplasia (Occasional (29-5%)); Focal impaired awareness seizure (Occasional (29-5%)); Infantile spasms (Occasional (29-5%)); Intellectual disability (Occasional (29-5%)); Motor aphasia (Occasional (29-5%)); Multifocal epileptiform discharges (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Familial focal epilepsy with variable foci is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Familial focal epilepsy with variable foci. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.