Benign familial neonatal epilepsy

Alternate names

Benign familial neonatal convulsions; Benign familial neonatal seizures; BFNS

Definition

Benign familial neonatal epilepsy (BFNE) is a rare genetic epilepsy syndrome characterized by the occurrence of afebrile seizures in otherwise healthy newborns with onset in the first few days of life.

Epidemiology

Prevalence is currently unknown since this disorder is possibly overlooked. About 100 families have been reported to date.

Cause

• Mutations in two genes, KCNQ2 and KCNQ3, have been found to cause BFNS.
• Mutations in the KCNQ2 gene are a much more common cause of the condition than mutations in the KCNQ3 gene.
• The KCNQ2 and KCNQ3 genes provide instructions for making proteins that interact to 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.
• Channels made with the KCNQ2 and KCNQ3 proteins are active in nerve cells (neurons) in the brain, where they transport potassium ions out of cells. These channels transmit a particular type of electrical signal called the M-current, which prevents the neuron from continuing to send signals to other neurons.
• The M-current ensures that the neuron is not constantly active, or excitable.

Gene muatations

• Mutations in the KCNQ2 or KCNQ3 gene result in a reduced or altered M-current, which leads to excessive excitability of neurons.
• Seizures develop when neurons in the brain are abnormally excited.
• It is unclear why the seizures stop around the age of 4 months.
• It has been suggested that potassium channels formed from the KCNQ2 and KCNQ3 proteins play a major role in preventing excessive excitability of neurons in newborns, but other mechanisms develop during infancy.
• About 70 percent of people with BFNS have a mutation in either the KCNQ2 or the KCNQ3 gene.
• Researchers are working to identify other gene mutations involved in this condition.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

• Transmission is autosomal dominant with incomplete penetrance.
• Genetic counseling should be offered to affected families informing them of the 50% chance the offspring has of inheriting the disease-causing mutation and therefore being affected with the disorder.
• Rare cases are due to de novo mutations.

Signs and symptoms

• The seizures begin around day 3 of life and usually go away within 1 to 4 months.
• The seizures can involve only one side of the brain (focal seizures) or both sides (generalized seizures).
• This condition is often associated with generalized tonic-clonic seizures (also known as grand mal seizures).
• This type of seizure involves both sides of the brain and affects the entire body, causing a combination of seizure types: tonic seizures, which are characterized by uncontrolled muscle stiffness and rigidity, and clonic seizures, which are characterized by uncontrolled jerking of the muscles.
• Seizure episodes in infants with BFNS typically begin with tonic stiffness and pauses in breathing (apnea) followed by clonic jerking.
• A test called an electroencephalogram (EEG) is used to measure the electrical activity of the brain.
• Abnormalities on an EEG test, measured during no seizure activity, can indicate a risk for seizures.
• However, infants with BFNS usually have normal EEG readings.
• In some affected individuals, the EEG shows a specific abnormality called the theta pointu alternant pattern.
• By age 2, most affected individuals who had EEG abnormalities have a normal EEG reading.
• Typically, seizures are the only symptom of BFNS, and most people with this condition develop normally.
• However, some affected individuals develop intellectual disability that becomes noticeable in early childhood.
• A small percentage of people with BFNS also have a condition called myokymia, which is an involuntary rippling movement of the muscles.
• In addition, in about 15 percent of people with BFNS, recurrent seizures (epilepsy) will come back later in life after the seizures associated with BFNS have gone away.
• The age that epilepsy begins is variable.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Focal EEG discharges with secondary generalization
• Focal tonic seizure

30%-79% of people have these symptoms

• Apnea
• Circumoral cyanosis(Bluish lips)
• Clonus
• Focal autonomic seizure
• Focal clonic seizure
• Generalized tonic seizure
• Limb myoclonus

5%-29% of people have these symptoms

• Facial tics(Cramping of facial muscles)
• Gastroesophageal reflux(Acid reflux)
• Muscular hypotonia of the trunk(Low muscle tone in trunk)
• Simple febrile seizure

1%-4% of people have these symptoms

• Increased theta frequency activity in EEG
• Status epilepticus(Repeated seizures without recovery between them)

Diagnosis

• Electroclinical events are suggestive of the disorder.
• Asymmetric tonic posturing associated with apnea and followed by focal or bilateral clonic jerking is the typical seizure type.
• In BFNE, neonates are neurologically normal and neurocognitive development is normal.
• Ictal electroencephalogram (EEG) may show focal interictal abnormalities, mainly over the central regions, but otherwise the EEG background is normal.
• The diagnosis is confirmed by genetic testing.

Antenatal diagnosis

Prenatal diagnosis is possible if the disease-causing mutation has already been identified in the family.

Treatment

• The use of anticonvulsant therapy (e.g. phenobarbital, phenytoin, valproate, carbamazepine) is needed in most cases to stop seizures in the neonatal period, particularly in cases with very frequent seizures or status epilepticus.
• Usually, patients require treatment for the first 6-12 months of life.
• However, it is important for clinicians and family to be aware that some patients require treatment beyond 12 months of age.

Prognosis

• Prognosis is good.
• Seizures normally disappear during the first year of life and patients do not display any neurological sequelae.
• Later seizures have been reported, including occasional febrile seizures and idiopathic epilepsy syndromes in childhood, in particular Rolandic epilepsy.

NIH genetic and rare disease info

• NIH info on Benign familial neonatal epilepsy

Benign familial neonatal epilepsy is a rare disease.

Benign familial neonatal epilepsy Resources
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