KCNB1-Related Disorders

Pathogenic variants (“mutations”) in the KCNB1 gene cause a spectrum of neurodevelopmental disorders that can include childhood-onset epilepsy, developmental delays and features of autism spectrum disorder. The symptoms a child experiences and the severity of the disorder can vary widely. Because KCNB1-related disorders have been discovered relatively recently, the full extent of symptoms has likely not yet been described.

KCNB1 is not the name of a medical condition but rather is the name of the gene that is affected. When a disorder is traced back to a pathogenic variant in the KCNB1 gene, it is called a KCNB1-related disorder.

In some children with KCNB1-related disorders, seizures are the first sign of the condition. In other children, delays in achieving developmental milestones during infancy or early childhood may be the first indication of a KCNB1-related disorder. In most individuals with KCNB1-related disorders, seizures occur in the first two years of life. However, the age of onset varies widely between individuals, ranging from the first day of life to later in childhood. Characteristic findings on EEG, such as a continuous spike wave during slow-wave sleep (CSWS)/electrical status epilepticus during slow-wave sleep (ESES), are seen in some children with KCNB1-related disorders. Some people with KCNB1-related disorders never develop epilepsy.

All children with KCNB1-related disorders have some degree of developmental delay and cognitive impairment, which ranges in severity from mild to severe. Speech and language development may be more significantly impacted than motor development.

Children with KCNB1-related disorders may develop different types of seizures, which are often difficult to control with anti-seizure medications. Common seizure types may include:

• Generalized tonic-clonic seizures, also called grand mal seizures (in which the body, arms and legs extend, then contract and shake)
• Focal impaired awareness seizures (seizures where children stop their usual behavior and lose consciousness)
• Infantile spasms
• Tonic (stiffening) seizures
• Clonic seizures (jerking movements on one part of the body)
• Myoclonic seizures
• Atypical absence seizures
• Atonic (drop) seizures

Many children with KCNB1-related disorders also have:

• Decreased muscle tone (hypotonia)
• Increased muscle tone (spasticity)
• Movement disorders, particularly ataxia, dystonia or chorea
• Behavior disorders, including aggression, hyperactivity or features of autism spectrum disorder

Delays in reaching developmental milestones in infancy and early childhood combined with seizures is not specific but is consistent with a KCNB1-related disorder. However, there are no typical signs of a KCNB1-related disorder that enable a diagnosis based on clinical features alone.

Genetic testing is required to diagnose a KCNB1-related disorder.

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 changes in brain structure

All children with a KCNB1-related disorder have a pathogenic variant in the gene KCNB1, which encodes the instructions to make a protein in the brain called a potassium channel. Pathogenic variants that affect the KCNB1 potassium channel impair the flow of potassium ions in the brain. In most cases, the KCNB1 mutation leads to decreased activity of the affected ion channel. Changes in the flow of potassium ions in the brain causes epilepsy and associated developmental differences.

In most children with KCNB1-related disorders, the pathogenic KCNB1 variant occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic KCNB1 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 KCNB1 variant. However, a small proportion of cells do carry the pathogenic KCNB1 variant in very low levels that may be difficult or impossible to detect.

Treatment for KCNB1-related disorders will depend on the type and severity of the seizures and associated neurological features.

• 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 KCNB1-related disorders 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 KCNB1-related disorders 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, a 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 medication, 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 KCNB1 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.

• Beyond the Ion Channel | Dr. Helbig’s Blog for the ILAE Genetics Commission