KCNB1 Encephalopathy

Disease Overview

Summary

KCNB1 encephalopathy is a rare genetic disorder characterized by developmental delay starting in infancy or early childhood, often with severe t language impairment. Most children develop multiple types of seizures that can be frequent and hard to control with standard treatments. However, a few people do not have seizures but may still have abnormal patterns on EEG (electroencephalogram), a non-invasive medical test that measures the electrical activity of the brain and records brain waves, which are the patterns of electrical impulses generated by neurons.

Diagnosis is made by a genetic test identifying a change (variant) in the KCNB1 gene. Inheritance is autosomal dominant.

Treatment is based on the symptoms that the affected person has, and may include antiseizure medication, behavioral therapy and others.

Introduction

KCNB1 encephalopathy was first identified in 2014 in three patients with severe early onset seizures and developmental delay. Over the last few years, with increasing availability of genetic testing, additional patients have been identified with a broader range of clinical features (see the Signs & Symptoms section for further explanation). Some children may have features of autism or Rett syndrome or have a diagnosis of Lennox-Gastaut syndrome. People with KCNB1 encephalopathy may be classified as having a developmental and epileptic encephalopathy since features of developmental delay and epilepsy are the most common.

Developmental and epileptic encephalopathy (DEE) is a group of rare brain disorders that begin in infancy or childhood. Children with DEE often have frequent seizures and unusual patterns on brain tests (EEGs). These seizures and brain activity can affect how the brain grows and develops, sometimes leading to delays or even a loss of skills (regression) the child has already learned. When DEE is caused by problems with ion channels, it’s called a channelopathy.

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Synonyms

early infantile epileptic encephalopathy (EIEE26)
KCNB1-related epilepsy

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Signs & Symptoms

Because KCNB1 encephalopathy is a newly identified condition and only a small number of people have been diagnosed so far, not all symptoms that can be found in people with this condition are fully known. Based on studies published to date, the signs and symptoms may include:

Developmental delays and cognitive impairment, which range in severity from mild to severe
- Speech and language development may be more significantly affected than motor development
Behavioral and social challenges (occurred in about half of the children reported with this condition)
- Features of autism spectrum disorder
- Attention deficit/hyperactivity disorder (ADHD)
- Aggressive behavior
Low muscle tone (hypotonia), which can worsen delays in motor skills like sitting, crawling or walking

Movement disorders or involuntary movements
Vision problems such as:
Strabismus (lazy eyes or eye misalignment)
Cortical visual impairment (a vision problem that arises from damage to the parts of the brain responsible for processing visual information, rather than the eyes themselves) which can result in low vision, trouble seeing things like faces or moving objects and other problems
Gastrointestinal (GI) issues
Sleep problems
Heart problems:
- Borderline long QT
  - The QT interval represents the time it takes for the heart ventricles to squeeze and relax
    - A long QT interval is associated with an increased risk of abnormal heart rhythms and even sudden cardiac death in some people
      - Heart rhythm issues could increase the risk for serious arrhythmias or sudden cardiac events
    - Problems with the autonomic nervous system which controls heart rate, breathing, blood pressure, sweating and digestion (Note: The exact nature of these autonomic problems isn’t well understood yet.)
    - Seizures and epilepsy: Most people with KCNB1 encephalopathy also have epilepsy that can be hard to control
    - Seizures usually begin in late infancy to early childhood
    - Multiple seizure types are common including:
      - Myoclonic (brief muscle jerks)
      - Atonic (sudden loss of muscle strength)
      - Generalized tonic-clonic (also known as grand mal seizures)
      - Infantile spasms
      - Tonic (muscle stiffening)
      - Drop attacks (sudden falls due to loss of muscle control)
      - Absence seizures (brief lapses in awareness)
      - Focal dyscognitive seizures (starting in one area of the brain with impaired awareness) which can be the first sign of this condition
        
        Focal dyscognitive seizures can be subtle and easy to miss in young children, especially at the beginning.
      - Specific abnormal EEG pattern during sleep with no obvious seizures known as CSWS (continuous spike-wave during slow-wave sleep) or ESES (electrical status epilepticus during slow-wave sleep) which may be linked with:
        
        Developmental regression
        
        Inability to speak words clearly (expressive language difficulties)

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Causes

KCNB1 encephalopathy is caused by a change (variant) in one copy of the KCNB1 gene. This gene normally helps make a potassium channel (KV2.1) that controls electrical signals in brain cells (neurons).

KCNB1 is a type of voltage-gated potassium channel, which means it opens and closes in response to changes in the electrical charge around it. Potassium channels help move potassium ions in and out of cells, which are essential for generating and transmitting electrical signals, including those used by neurons the brain cells. Potassium channels represent the most numerous and complex family of ion channels. These channels are critical to many cellular processes, play an essential role in epilepsy and are effective for targeted therapy.

Variants in KCNB1 gene can disrupt this process, leading to various neurological problems such as epilepsy, developmental delays and intellectual disabilities.

In simpler terms, KCNB1 is a gene that helps regulate how electrical signals are sent through cells in the body, and when it’s not working correctly it can lead to neurological problems.

Most variants in the KCNB1 gene lead to a loss of function in the potassium channel, though a few variants result in mild symptoms with nearly normal channel function.

KCNB1 encephalopathy is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

KCNB1 Patients are from families with various ethnic backgrounds in the USA and European countries. At this time, there does not appear to be a difference based on sex. Typically features of the disease present in infancy or childhood. Until recently, the KCNB1 gene was not screened in standard diagnostic sequencing. Now that KCNB1 is included on more epilepsy gene panels, more patients will likely be identified.

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Disorders with Similar Symptoms

Some medical conditions have symptoms that overlap with KCNB1 encephalopathy, which can make diagnosis challenging.

Early infantile epileptic encephalopathy (EIEE)/ Developmental and epileptic encephalopathy (DEE): EIEE/DEE are umbrella terms that include many genetic causes (e.g., KCNQ2, SCN1A, FOXG1, SLC6A1), not just KCNB1. Like KCNB1 encephalopathy, these conditions involve multiple types of seizures and developmental delays. Both may start in infancy and include difficult-to-control epilepsy. The specific seizure types and severity can differ depending on the gene involved.

Lennox-Gastaut syndrome (LGS): Children with both LGS and KCNB1 encephalopathy may have multiple seizure types that do not improve with medications. Cognitive impairment and specific EEG abnormalities are common to both. However, LGS is diagnosed based on a set of clinical and EEG criteria, while KCNB1 encephalopathy is confirmed through genetic testing. KCNB1 gene variants are one of many possible causes of LGS, and not all people with KCNB1 encephalopathy meet the criteria for an LGS diagnosis.

Rett syndrome: Both conditions can involve developmental delays, movement problems, features of autism and loss of previously acquired skills. Breathing abnormalities and difficulty swallowing can also appear in both. Rett syndrome mostly affects girls and is typically caused by variants in the MECP2 gene. KCNB1 encephalopathy may resemble a mild or “atypical” form of Rett syndrome but has a distinct genetic cause.

Landau-Kleffner syndrome: Children with either condition may show a unique EEG pattern during sleep called CSWS (continuous spike wave during slow-wave sleep) or ESES (electrical status epilepticus in sleep) and both conditions can involve sudden loss of speech and language comprehension. However, Landau-Kleffner syndrome is primarily defined by its language regression and EEG findings, even in the absence of frequent seizures and in KCNB1 encephalopathy, this EEG pattern is one feature among many, and not all children experience language regression.

Genetic testing is essential for an accurate diagnosis.

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Diagnosis

The diagnosis of KCNB1 encephalopathy is made by molecular genetic testing. This is usually done with an epilepsy gene panel looking at several genes associated with epilepsy or by whole exome sequencing.

Clinical Testing and Work-Up
Since seizures are common in this condition, an EEG (electroencephalogram) is strongly recommended to help plan treatment. Even in children without diagnosed seizures, an overnight EEG (done during non-REM sleep) can check for unusual brain activity patterns.

Some children may also have a borderline QT interval. A heart test like an EKG or a Holter monitor might be recommended.

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Standard Therapies

People with KCNB1 encephalopathy often need a team of doctors and specialists including pediatricians, child neurologists and developmental pediatricians, among others.

Anti-seizure (anticonvulsant) medications can help reduce seizures, but the seizures are very hard to treat, and no single medicine has been proven to work best for this condition. Recent studies have shown that a combination of valproate and lamotrigine may represent a reliable option for treatment of this condition. Other options may include:

Special diets (like the ketogenic diet, a very low-carbohydrate, high-fat diet that forces the body to switch to burning fat for energy instead of carbohydrates or the modified Atkins diet, a low-carbohydrate diet designed for weight loss, where individuals focus on consuming mostly fat and protein while limiting carbohydrate intake)
Implanted devices that work by stimulating nerve cells to release substances that change how the cells act or help them go back to their normal state, aiming to stop the seizures
Surgery which can involve removing the part of the brain that is causing seizures

In children who don’t have visible seizures but have abnormal brain activity on EEG, medication may still be helpful.

If a child shows signs of autism, developmental pediatricians can help with diagnosis and may recommend therapies such as Applied Behavioral Analysis (ABA) or others to support development.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Ren Y, Hu W, Gao Z, Shi J, Liu Y, Zhang H. De novo KCNB1 missense variant causing developmental and epileptic encephalopathy: Two case reports. Medicine (Baltimore). 2025;104(2):e41236. doi:10.1097/MD.0000000000041236

Xiong J, Liu Z, Chen S, et al. Correlation Analyses of Clinical Manifestations and Variant Effects in KCNB1-Related Neurodevelopmental Disorder. Front Pediatr. 2022;9:755344. Published 2022 Jan 5. doi:10.3389/fped.2021.755344

Bar C, Barcia G, Jennesson M, et al. Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature. Hum Mutat. 2020;41(1):69-80. doi:10.1002/humu.23915

Kang, S.K., et al. High throughput Characterization of KCNB1 variants Associated with Developmental and Epileptic Encephalopathy. BioRxiv 2019; May 14. doi: https://doi.org/10.1101/637041

de Kovel, C.G.F, et al. Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes. JAMA Neurol 2017:74(10):1228-1236.

Marini, C., et al. Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations. Neurol Genet 2017:3(6).

Torkamani, A., et al. De novo KCNB1 mutations in epileptic encephalopathy. Ann Neurol 2014;76(4): 529-540.

INTERNET
Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University. Epileptic Encephalopathy, Early Infantile, 26; EIEE26. Entry No: 616056. Last edited: 10/12/2020. https://www.omim.org/entry/616056 Accessed June 25, 2025.

National Institute of Mental Health (NIMH). Autism Spectrum Disorder. Last edited: December 2024. https://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-asd/index.shtml Accessed June 25, 2025.

KCNB1. Simon Searchlight. 2024. June 25, 2025.

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