Epilepsy of infancy with migrating focal seizures

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Epilepsy of infancy with migrating focal seizures (EIMFS) is a form of recurrent seizures (epilepsy) that begins early in life. Seizures typically start before the age of 6 months. Babies with this condition can reach early developmental milestones, such as the ability to follow movement with their eyes or control their head movement. However, as seizure activity develops, children with EIMFS typically stop developing new skills and may experience a gradual loss of existing skills (developmental regression).

Focal motor seizures are the most common type of seizure seen in children with EIMFS. Focal motor seizures start in one area of the brain and affect muscle (motor) activity on one side of the body. Affected individuals may have more than one focal seizure at a time, and seizure activity can spread (migrate) from one brain region to another during an episode.

Although the seizures that are associated with EIMFS may be relatively infrequent at first, the seizure frequency increases rapidly. Affected individuals often experience several seizures per day; in some cases, the seizures may seem almost continuous. Children with EIMFS may also have individual seizures that last for several minutes (status epilepticus). After a year or more of persistent seizures, the episodes may become less frequent.

In children with EIMFS, seizures can affect the growth of the brain, leading to a small head size (microcephaly). The problems with brain development can also cause significant developmental delays and intellectual disabilities. Many affected individuals do not learn to walk or talk. Additional signs and symptoms of EIMFS may include weak muscle tone (hypotonia), abnormal tensing of the muscles (spasticity), and abnormal involuntary muscle movements.

EIMFS is one of a group of severe epilepsies called developmental and epileptic encephalopathies (DEEs). These disorders are characterized by significant developmental delays and seizures that begin early in life and may be difficult to treat.

Though some people with EIMFS have had milder signs and symptoms, many affected individuals do not survive past early childhood because of the serious health problems that are associated with this condition.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

The cause of EIMFS is not always known. Variants (also called mutations) in one of several different genes cause EIMFS in approximately 70 percent of cases. Researchers are studying how the features of EIMFS and the responses to various treatments differ in affected individuals depending on the particular gene involved.

Variants in the KCNT1 gene are the most common genetic cause of EIMFS. The KCNT1 gene provides instructions for making a protein that helps form potassium channels. Potassium channels, which transport positively charged atoms (ions) of potassium into and out of cells, play a key role in a cell's ability to generate and transmit electrical signals. The potassium channels made with the KCNT1 protein are active in nerve cells (neurons) in the brain. This flow of ions is involved in generating currents that activate (excite) neurons and send signals in the brain.

The KCNT1 gene variants that cause EIMFS typically lead to the substitution of one protein building block (amino acid) for another in the KCNT1 protein. This altered protein disrupts the function of the potassium channel. In most cases, the KCNT1 variants are described as “gain-of-function variants” because they increase the flow of potassium ions through the channel. The increased flow of potassium ions likely leads to the excitation of neurons and the repeated seizures seen in people with EIMFS.

Variants in genes that provide instructions for making proteins that form sodium channels have also been found to cause EIMFS. These sodium channels transport sodium ions into cells, which helps cells generate and transmit electrical signals. The SCN2A gene provides instructions for making a protein that helps form part of the sodium channel, and variants in this gene are the second most common genetic cause of EIMFS.

Sodium channels that are made with the SCN2A protein are active in neurons. Variants in the SCN2A gene can alter the structure and function of this protein. Researchers are working to learn more about the complex ways in which SCN2A gene variants affect the activity of sodium channels in the brain and how this change in activity results in the repeated seizures seen in children with EIMFS.

In some cases, EIMFS has been associated with a group of disorders called congenital disorders of glycosylation (CDGs). CDGs are genetic conditions that affect a process called glycosylation, in which proteins are modified by adding sugar molecules. Glycosylation is necessary for the normal function of many different proteins.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

EIMFS can be caused by variants in one of several different genes. The pattern of inheritance depends on the particular gene involved.

In many cases, EIMFS results from new (de novo) variants in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or during early embryonic development. These affected individuals typically have no history of the disorder in their family.

In some cases, EIMFS can be inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In a few families with a variant in the KCNT1 gene, some people who inherit the altered gene have not developed the features of the condition (reduced penetrance) or the affected individuals have had different signs and symptoms (variable expressivity).

EIMFS can also be inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

When EIMFS is caused by a gene on the X chromosome, it is inherited in an X-linked pattern. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), a variant in the only copy of the gene in each cell is typically sufficient to cause the condition. In females (who have two copies of the X chromosome), one altered copy of the gene may or may not cause the condition. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

EIMFS is estimated to occur in approximately 1 in 900,000 children.

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.

Cognitive impairment · Very frequent (99-80%)

Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.

Developmental regression · Very frequent (99-80%)

Loss of developmental skills, as manifested by loss of developmental milestones.

Inability to walk · Very frequent (99-80%)

Incapability to ambulate.

Multifocal epileptiform discharges · Very frequent (99-80%)

An abnormality in cerebral electrical activity recorded along the scalp by electroencephalography (EEG) and being identified at multiple locations (foci).

Neurodevelopmental delay · Very frequent (99-80%)

Neurodevelopmental delay (NDD) refers to delays in the maturation of the brain and central nervous system; infants and young children with NDD may experience delays in the development of one or more skills including gross motor abilities, fine-motor coordination, language abilities and ability to solve increasingly complex problems.

Functional motor deficit · Very frequent (99-80%)

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.

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

A bilateral tonic-clonic seizure with focal onset is a focal-onset seizure which progresses into a bilateral tonic-clonic phase.

Other findings in the same source

From: Orphanet

Additional reported features include Cerebral atrophy (Frequent (79-30%)); Focal emotional seizure with laughing (Frequent (79-30%)); Focal hemiclonic seizure (Frequent (79-30%)); Focal impaired awareness seizure (Frequent (79-30%)); Hypotonia (Frequent (79-30%)); Microcephaly (Frequent (79-30%)); Myoclonic seizure (Frequent (79-30%)); Abnormal corpus callosum morphology (Occasional (29-5%)); Aortopulmonary collateral arteries (Occasional (29-5%)); Delayed myelination (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 Epilepsy of infancy with migrating focal seizures 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

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

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.