KCNQ2-Related Epilepsies

Pathogenic variants (“mutations”) in the KCNQ2 gene cause a range of neonatal-onset epilepsy syndromes, including severe early-onset epilepsies (developmental and epileptic encephalopathies) and milder presentations that are typically referred to as self-limited (benign) neonatal epilepsies, which may run in families. The symptoms a child experiences and the severity of the disorder can vary widely and will depend on the particular KCNQ2-related epilepsy the child has.

KCNQ2 is not the name of a medical condition but is rather the name of the gene that is affected. When epilepsy is traced back to a disease-causing (pathogenic) variant in the KCNQ2 gene, it is called a KCNQ2-related disorder.

KCNQ2-related epilepsies fall into two broad categories, although some children have presentations that may overlap between these categories:

• KCNQ2-developmental and epileptic encephalopathy (DEE)
• Self-limited neonatal epilepsy

Seizures beginning shortly after birth may be the first indication of a KCNQ2-related epilepsy. However, the associated symptoms and outcomes can vary widely, depending on the particular KCNQ2-related epilepsy the child has.

KCNQ2-Developmental and Epileptic Encephalopathy

Encephalopathy refers to a disease that affects the functioning of the brain. Children with KCNQ2-developmental and epileptic encephalopathy typically experience multiple daily seizures that begin within the first week of life. These seizures are often tonic (stiffening) seizures and may be associated with jerking movements and changes in breathing or heart rate. Seizures are often associated with characteristic patterns on EEG and may be difficult to control with anti-seizure medications initially. Children with KCNQ2-developmental and epileptic encephalopathy have delays in reaching developmental milestones and associated cognitive impairment, ranging in severity from moderate to severe.

Children with KCNQ2-developmental and epileptic encephalopathy may also have:

• Low core muscle tone (hypotonia)
• Increased muscle tone in their limbs (spasticity)
• Features of autism spectrum disorder

In most children with KCNQ2-developmental and epileptic encephalopathy, seizures disappear in childhood. However, cognitive impairment and other neurological complications persist.

Self-limited (benign) Neonatal Epilepsy

Self-limited neonatal epilepsy (formerly called benign familial neonatal seizures) is less severe than KCNQ2-developmental and epileptic encephalopathy. This type of KCNQ2-related epilepsy is characterized by seizures that begin within the first week of life in an otherwise well neonate. Often there is a positive family history of seizures in infancy in a parent or other family member. Seizures usually respond well to anti-seizure medications and often stop by age 2. Developmental milestones are typically achieved on time, and long-term development and 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. Rare families have been described with associated abnormal, involuntary muscle movements called myokymia.

Seizures that begin shortly after birth may suggest a KCNQ2-related epilepsy. A positive family history of seizures may suggest a diagnosis of a milder familial KCNQ2-related epilepsy. Characteristic EEG patterns, such as a burst-suppression pattern, in conjunction with neonatal seizures may indicate a diagnosis of KCNQ2-developmental and epileptic encephalopathy. However, a diagnosis of a KCNQ2-related epilepsy cannot be made based on clinical features alone.

Genetic testing is required to confirm a diagnosis.

Additional tests may also be done, including:

• Electroencephalogram (EEG) to look for evidence of abnormal brain activity and seizures
• Magnetic resonance imaging (MRI) to look for structural brain abnormalities

Many children with KCNQ2-developmental and epileptic encephalopathy are also diagnosed with specific epilepsy syndromes based on the types of seizures they have experienced and features of their EEG. Some of these epilepsy syndromes include:

• Ohtahara syndrome
• West syndrome
• Lennox-Gastaut syndrome

In these cases, the epilepsy syndrome diagnosis is a description of the types of seizures the child is having, but the genetic diagnosis of KCNQ2-developmental and epileptic encephalopathy is the primary diagnosis that explains why a child has developed epilepsy.

All children with KCNQ2-related epilepsy have a pathogenic variant (“mutation”) in the gene KCNQ2, which encodes the instructions to make a protein in the brain called a potassium channel. Pathogenic variants that affect the KCNQ2 potassium channel impair the flow of potassium ions in the brain.

KCNQ2-Developmental and Epileptic Encephalopathy

In children with KCNQ2-developmental and epileptic encephalopathy, the pathogenic variant may affect the KCNQ2 potassium channel in different ways. In most cases, the KCNQ2 mutation leads to decreased activity of the ion channel; in other cases, the mutation leads to over activity of the ion channel. Changes in the flow of potassium ions in the brain causes epilepsy and associated developmental differences.

In most children with KCNQ2-developmental and epileptic encephalopathy, the pathogenic KCNQ2 variant occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic KCNQ2 variant has been passed on from an asymptomatic parent due to parental mosaicism. Just like a mosaic piece of art, in which each tile is different, a mosaic parent has distinct cell types. Most cells of a mosaic parent do not carry the pathogenic KCNQ2 variant. However, a small proportion of cells do carry the pathogenic KCNQ2 variant in very low levels that may be difficult or impossible to detect.

Self-Limited Neonatal Epilepsy

In children with self-limited neonatal epilepsy due to a pathogenic KCNQ2 variant, the flow of potassium ions in the brain is disrupted, but to a lesser extent than in children with KCNQ2-developmental and epileptic encephalopathy. This difference likely explains why these children have less severe disorders than children with KCNQ2-developmental and epileptic encephalopathy.

In most children with self-limited neonatal epilepsy, the pathogenic KCNQ2 variant was inherited from a parent who also had seizures as an infant. However, in some cases, the pathogenic KCNQ2 variant occurred spontaneously (de novo) and was not inherited from either parent.

Treatment for KCNQ2-related epilepsy 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 shown to be more effective than others.
• 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.
• Dietary therapy, such as the ketogenic diet, may be helpful in some cases.

Family training and support is a key element in a successful epilepsy treatment plan. Parents and caregivers must know how to watch for and respond to seizures.
Cognitive and developmental delays or autism spectrum disorder associated with KCNQ2-developmental and epileptic encephalopathy are treated with physical, occupational and speech therapy, and with the support of early intervention services. Care may be provided by a developmental pediatrician.

Families come to our ENGIN Clinic from all over the world. Children with KCNQ2-related epilepsy who are cared for at CHOP will receive cutting-edge genetic testing to confirm the underlying cause of their condition, as well as parental testing to confirm the diagnosis and inform recurrence risk with a subsequent pregnancy. Through ENGIN, your child will have access to any other medical specialists they may need. They will also have access to the full range of epilepsy therapies provided through CHOP’s Pediatric Epilepsy Program, including epilepsy management, dietary treatment and epilepsy surgery, as well as cutting edge research, clinical trials and ongoing follow-up care.

All individuals seen in the ENGIN Clinic are offered the opportunity to participate in research studies. ENGIN providers are collaborators on the NIH-funded Channelopathy-Associated Epilepsy Research Center, the goal of which is to understand how variation in ion channel genes including KCNQ2 leads to epilepsy and to advance the development of novel therapeutics.

ENGIN integrates genetic testing into the diagnosis and treatment of children with difficult-to-treat or unexplained epilepsies, genetic epilepsy syndromes and other genetic neurodevelopmental disorders. We combine cutting-edge clinical care and advanced genetic testing with innovative research to identify the underlying cause of a child’s epilepsy and develop an individualized approach to treatment and management.

• KCNQ2 Cure Alliance
• Jack Pribaz Foundation
• Beyond the Ion Channel | Dr. Helbig’s Blog for The ILAE Genetics Commission