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What is KCNQ2?

The KCNQ2 gene provides instructions for making potassium channels in the brain cells. These channels allow potassium to move outside of the cell, and if the channels are not working properly, brain cells are predisposed to generate excessive electrical signals that may lead to seizures. KCNQ2 pathogenic variants are associated with a wide range of severity of both seizures and development. 

KCNQ2 pathogenic variants that result in symptoms on the mild end of the spectrum, specifically benign familial neonatal epilepsy (BFNE), are typically inherited in an autosomal dominant fashion, meaning that one or the other parent has the same variant. In such cases, there is often a family history of neonatal seizures that spontaneously resolved.

Pathogenic variants that are associated with the more severe developmental and epileptic encephalopathy (DEE) are usually de novo, meaning that the variant is detected only in the affected person and is not in either parent. There are more rare exceptions where the variant may be present in one parent, for example in a mosaic pattern (not present in all cells, but perhaps only in a fraction of cells or just in a fractions of egg cells or sperm cells, so the parent does not show signs of illness).

What types of seizures (and epilepsies) are associated with variants in KCNQ2?

The most common seizures are focal tonic (stiffening of the body, often turning to one side) with autonomic features (changes in breathing, heart rate, color change such as a red or blue face). Seizures typically begin within the first week of life.

Benign Familial Neonatal Epilepsy

Benign familial neonatal epilepsy (BFNE) presents with seizures in the first week of life, which typically disappear spontaneously in the first year of life followed by normal development. BFNE may be inherited from a parent who had the same condition and then went on to have minimal or no long-term symptoms. 

Babies with BFNE will appear normal in between the seizures, and the electroencephalograph (EEG) brain activity between seizures is normal. In contrast, newborns with the severe KCNQ2 DEE will often appear sleepy or less alert than normal and have difficulty feeding between seizures.

Developmental and Epileptic Encephalopathy

Developmental and epileptic encephalopathy (DEE) associated with KCNQ2 variants may present in the newborn period with severe, difficult to control seizures in the first week of life followed by a spectrum of developmental disability that is often severe. 

Babies with KCNQ2-DEE may also have other types of seizures including myoclonic (quick body jerks) and focal clonic (rhythmic jerking on one side of the body). The EEG brain wave activity between seizures is severely abnormal and readily distinguishable from that in BFNE.

Babies with KCNQ2-DEE may have features consistent with or similar to the classic neonatal encephalopathy syndromes, Ohtahara syndrome (early infantile epileptic encephalopathy) and early myoclonic epilepsy (EME).

Rare Presentations

There are a few rare presentations that depend on the specific pathogenic variant in the KCNQ2 gene. These include neonatal seizures followed by myokymia (muscle tremors), severe neonatal myoclonus (body jerks that are not seizures), or specific seizures called infantile spasms that start later in life without preceding neonatal seizures.

What non-seizure symptoms may be seen with KCNQ2 variants?

Individuals with BFNE are typically otherwise normal and do not have any learning problems or other symptoms. Individuals with KCNQ2-DEE, and other individuals on the more severe end of the spectrum, frequently have variable degrees of learning problems (often severe), autism, behavior problems, and sleep disorders. Movement disorders such as dystonia (abnormal limb stiffening and stretching) are also seen with KCNQ2-DEE. Not that in many children presenting the KCNQ2-DEE, the seizures may respond to treatment or resolve after some months or years, but the other symptoms persist and impose have a larger effect on quality of life.

How are KCNQ2 variants diagnosed?

KCNQ2 variants can only be identified by genetic testing. Targeted testing of the KCNQ2 gene specifically is the most direct method of testing an individual when there is a high degree of confidence that a variant in the KCNQ2 gene is likely to be the underlying cause, but this form of testing is being undertaken less commonly over time. Epilepsy gene panels, which involve testing of multiple epilepsy-associated genes, and whole exome sequencing (WES) also detect KCNQ2 variants and are being used more commonly, including rapid testing with these methods applied in the Neonatal ICU setting in order to detect KCNQ2 and other variants.

Genetic counseling prior to genetic testing is an important step in making sure that the best testing strategy is selected and that patients and families understand the risks, benefits, limitations and outcomes of testing.

How is KCNQ2-related epilepsy treated?

Decisions regarding treatment are dependent on the type and severity of epilepsy. Using medications in newborns must be done carefully and only by experienced medical specialists. Most anti-seizure medications are not approved by the FDA for use in neonates, and instead, there are years of experience and agreement among medical specialists on what medications to use.

Many neonates with BFNE will require short-term anti-seizure medication, which may often be slowly discontinued (weaned) after several months of seizure freedom. The most commonly used medications traditionally used in babies include phenobarbital, and in some cases levetiracetam, which are typically used empirically before a genetic diagnosis is made.

Seizures in individuals with KCNQ2-NEE are more likely to continue despite treatment with the traditional medications used in babies. Since KCNQ2 variants were recognized as a specific cause of seizures in babies, there has been growing experience with using medications that all work a certain way (sodium channel blockers – which include carbamazepine, oxcarbazepine and phenytoin or fosphenytoin) which has shown that these stop seizures more effectively in many cases. For a time, ezogabine (a potassium channel opener) was used off-label in some pediatric cases, but this medication was removed from the market because of side effects, including urinary retention and blue discoloration of the retina. Trials are in progress to treat KCNQ2-related epilepsy with other forms of potassium channel openers.

How common is KCNQ2-related epilepsy?

We do not have adequate data to be able to report on how common KCNQ2-related epilepsy may be.

What is the outlook for KCNQ2-related epilepsy?

Disclaimer: This field is rapidly evolving and each individual has his/her own course. We are constantly learning and published data may be slow to come.

Seizures in individuals with BFNE resolve within the first few months of life. Anti-seizure medications may typically be stopped within a few months. Approximately 10% of individuals may have relapse of seizures in later childhood or adolescence, but these seizures typically respond well to anti-seizure medications. Development typically is normal, but learning issues have been reported.

In individuals with KCNQ2-DEE, seizures are typically difficult to control, though many respond to sodium channel blocker medications, such as carbamazepine, oxcarbazepine or phenytoin. Even for individuals with seizures on the severe end of the spectrum, seizures decrease and may even stop by age 3 years. However, the majority of children will still have severe developmental disabilities and other associated health problems.

For more information about KCNQ2

With Gratitude to: Scotty Sims, M Ed; Director KCNQ2 Cure Alliance

Authored By: 
John J. Millichap MD, FAAN, FAAP, FACNS, FAES
Authored Date: 
02/2021
Reviewed By: 
Beth Sheidley MS, CGC
Annapurna Poduri MD, MPH
on: 
Monday, March 1, 2021