KCNQ2 Gene Mutation and Epilepsy

By:  Clara O’Hara

Photo Credit: www.depositphotos.com

KCNQ2 Gene

KCNQ2 gene is a voltage-gated potassium channel gene on chromosome 2-0q13.3,  responsible for the regulation of neuronal excitability. They encode for a protein called Kv7.2, which is a subunit of a type of potassium ion channel known as the M-channel, having a crucial role in regulating the electrical excitability of neurons, particularly in the brain. When the Kv7.2 protein combines with other subunits, such as Kv7.3, it forms functional M-channels. They are located in the membranes of neurons and are responsible for controlling the flow of potassium ions across the cell membrane. Each subunit of KCNQ2 consists of heteromultimeric channels with six transmembrane domains, with different voltage sensors that build on ion channel pore domain and long C-terminal region. C-terminal tail will contain two helical domains, A and B, which bind to calmodulin, a calcium sensor. Mutations in the CaM domain have been reported to impair interaction with calmodulin molecules, to impair surface expression of potassium channels, which increased action potential firing and hyperexcitability.

Etiology of Epilepsy in KCNQ2

Mutations of the gene can manifest in certain types of various neurological disorders such as infantic epilepsy – specifically, benign familial neonatal convulsion (BFNC), a rare seizure disorder that occurs in children who typically have a normal psychomotor development. It will be inherited as an autosomal dominant trait to KCNQ2 early-onset epileptic encephalopathy as mostly the result of a de novo pathogenic variant; however, it can also be mosaic inherited. Under both genetic mutations, patients present with severe seizures and severe neurological outcomes. A loss or gain of KCNQ2 gene function is presumed to be the major mechanism for KCNQ-2 associated-neonatal-onset of epileptic encephalopathy. This is presented by, specifically, mutations in the CaM domain where reported impairment to interaction with calmodulin molecules, impairing surface expression of potassium channels, which increased action potential firing and hyperexcitability.

The percentage of neonates and children with KCNQ2-associated epilepsy is unknown, as findings remain inconsistent. In one study of the 8,565 patients enrolled, about 163 (1.9%) with epilepsy and neurodevelopmental disorders had detectable KCNQ2 mutations. However, in another study examining its prevalence, it reported that 11, being 13% of its patients were among 84 patients with neonatal-onset epileptic encephalopathy. In another study, it reported that 12 (5%) of 239 patient cases of KCNQ2-associated epilepsy, however, were not consistent but depended upon the type of patient, diagnosing and promptly stopping time to improve patient outcomes.


In KCNQ2-developmental and epileptic encephalopathy, some symptoms include seizures that are often tonic and stiffening, associated with jerking movements and changes in breathing or heart rate. They are often associated with characteristic patterns on the EEG and may be difficult to control with anti-seizure medications. They are typically experienced to have developmental milestone delays and associated cognitive impairment, ranging in severity from moderate to severe. Among children with KCNQ2-developmental and epileptic encephalopathy, they may have low core muscle tone, increased muscle tone in their limbs, and features of autism spectrum disorder. Although seizures will mostly disappear in childhood – there is a possibility of further cognitive impairment and other neurological complications beyond.

Self-limited (benign) neonatal epilepsy symptoms may be less severe, in comparison to KCNQ2-developmental and epileptic encephalopathy. In KCNQ2-related self-limited neonatal epilepsy, it is characterized by seizures that begin within the first week of life. Seizures usually respond well to anti-seizure medications and often stop by age 2. Typically, development is achieved on-time, and long-term development as well as cognition are not affected. Seizures are called “self-limited” because they typically will resolve on their own with no need for ongoing anti-seizure medications. In rare families, they will have associated abnormal, involuntary muscle movements called myokymia.


For neonates, the diagnosis is further supported by clinical features, EEG findings, age seizure onset, and family history, where it can be, then, confirmed using a genetic study. This will focus on the child’s and family’s medical history. Genetic testing is also essential for confirming the diagnosis of KCNQ2-related epilepsy, where gene sequencing will occur to identify the mutation; selection of the gene can be performed using family members.


In regard to treating children with KCNQ2-related epilepsy, it will depend on the type and severity of the seizures:

A combination of seizure medications is typically used to control the different seizure types. No particular anti-seizure medication has been more effective in treating the type of epilepsy.

A different set of medications, known as rescue therapies, may be given to help stop or shorten clusters of seizures when they occur.

Implantable devices such as vagus nerve stimulation (VNS) or responsive neurostimulation (RNS) may be considered when medications are not effective in controlling seizures.

A dietary therapy, such as a ketogenic diet, may be helpful in some cases.

Different therapies and training may also be supportive in a successful epilepsy treatment plan. Physical, occupational, and speech therapy, and with early intervention support services, may be helpful in cognitive and developmental delays or autism spectrum disorder associated with KCNQ2-developmental and epileptic encephalopathy. Family training and support in teaching parents as well as caregivers to watch out for as well as respond to seizures is necessary. Care may also be provided by a developmental pediatrician.


The KCNQ2 gene, located on chromosome 20q13.3, encodes the Kv7.2 protein, a subunit of potassium ion channels crucial for regulating neuronal excitability in the brain by controlling potassium ion flow across neuron membranes. Mutations in the KCNQ2 gene, particularly in the calmodulin-binding domain, can impair the interaction with calmodulin molecules, leading to decreased surface expression of potassium channels, increased action potential firing, and hyperexcitability in neurons. The mutations will be classified under two conditions: mosaic or de novo inherited. The rates of KCNQ2-gene epilepsy among children is undefined. Diagnosis will be based on genetic testing using familial genes. Treatment may be followed up with a combination of seizure medications; rescue therapies; implantable devices; dietary therapy; physical, occupational, and speech therapy; and family training and support.


Philadelphia, T. C. H. of. (2020, February 19). KCNQ2-Related Epilepsies. Www.chop.edu. https://www.chop.edu/conditions-diseases/kcnq2-related-epilepsies.

Portale, A., Comella, M., Salomone, G., Di Nora, A., Marino, L., Leonardi, R., Praticò, A. D., & Falsaperla, R. (2021). The Spectrum of KCNQ2- and KCNQ3-Related Epilepsy. Journal of Pediatric Neurology. https://doi.org/10.1055/s-0041-1727099.

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