NORD gratefully acknowledges Sunita Misra, MD, PhD, Pediatric Epilepsy Attending Physician, Instructor of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, and KCNB1.org for assistance in the preparation of this report.
KCNB1 encephalopathy is a rare autosomal dominant genetic disorder caused by a change in the KCNB1 gene. Patients have developmental delay starting in infancy or early childhood, often with prominent language impairment. Most children develop multiple types of seizures that can be frequent and hard to control with standard treatments. However, a few patients do not have seizures but may still have abnormal patterns on EEG. Some children may have features of autism or Rett syndrome or have a diagnosis of Lennox-Gastaut syndrome. Broadly patients with KCNB1 encephalopathy may be classified as having a developmental and epileptic encephalopathy since features of developmental delay and epilepsy are the most common.
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).
Due to the recent identification of the syndrome and limited number of patients with detailed clinical characterization, the full extent of symptoms has yet to be described. To date, the largest patient cohort was published in 2017 and including 26 patients. All 26 patients had developmental delay with speech/language more affected than other aspects of development. About half of children with KCNB1 encephalopathy have features of autism, abnormal behavior, or attention deficit/hyperactivity disorder (ADHD). A little less than half of patients have hypotonia, or low muscle tone that may contribute to delayed motor skills. A few patients have movement disorders or involuntary movements, vision changes (either strabismus or cortical visual impairment), GI issues, and sleep disturbances. Some patients also have borderline long QT and/or autonomic nervous system abnormalities. 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 cases. The autonomic nervous system is important for regulating unconscious body functions including heart rate, blood pressure, breathing rate, sweating, and digestion. The specific changes to the autonomic nervous system function have not been well described yet.
With regard to epilepsy, the majority of patients with KCNB1 encephalopathy also have difficult to control epilepsy with seizure onset usually in late infancy to early childhood. Most patients have multiple seizure types including myoclonic, atonic, generalized tonic-clonic, infantile spasms, tonic, drop attacks, absence, and focal dyscognitive seizures. The initial seizure type may be focal dyscognitive seizures that are subtle and difficult to recognize especially in young children. Up to one quarter of patients, including those without discrete seizures may have an abnormal pattern on EEG during sleep called continuous spike wave during slow-wave sleep (CSWS) or electrical status epilepticus during slow-wave sleep (ESES). This EEG pattern can be seen in patients with other genetic changes and is sometimes associated with developmental regression or expressive language difficulties (see Landau-Kleffner in Related Disorders section).
KCNB1 encephalopathy is caused by a change (variant/mutation) in one copy of the KCNB1 gene that prevents it from working properly. Genetic variation affecting the coding sequence of this gene in the general or unaffected population is extremely rare. KCNB1 is the gene that codes for KV2.1, an ion channel that helps potassium (K) flow out of the cell and has a role in the cell’s ability to make and transmit electrical signals. KCNB1 is a voltage gated potassium channel meaning that it opens based on the charge around it. Variants in a few other potassium channels are also associated with epilepsy and developmental delay (see Related Disorders section for KCNQ2).
Two types of KCNB1 variants have been identified in patients with KCNB1 encephalopathy. The most common are point mutations, single base pair changes in the DNA sequence that result in a different amino acid in the KV2.1 protein. There are a few specific point mutations that have occurred in different, unrelated patients and the clinical features of these patients can be different. A few patients also have the same location of the point mutation but with a different substitution resulting in different proteins and different clinical features. Less commonly, there are truncating or frameshift variants that stop the protein product early and often cause a nonfunctional potassium channel. Most of the KCNB1 encephalopathy associated variants cause a loss of potassium channel function by affecting a few different aspects of channel function. A few variants cause little to no change in channel function and are associated with a milder clinical symptoms (phenotype).
KCNB1 encephalopathy is an autosomal dominant genetic condition meaning that only one non-working copy of the gene leads to disease. The non-working variant can either be inherited from either parent or be a new change (de novo) in the affected child. The risk of a patient passing the non-working gene to an offspring is 50% for each pregnancy. The risk of disease is the same for males and females.
KCNB1 encephalopathy is a very rare disorder. About 35 patients have been described in the literature and about 65 cases are known worldwide. 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 gender. 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.
The diagnosis of KCNB1 encephalopathy is made by molecular genetic testing. This is usually done with an epilepsy gene panel looking at a number of genes associated with epilepsy or by whole exome sequencing.
Clinical Testing and Work-Up
Seizures are a clinical feature in the majority of patients. An EEG is highly recommended to help evaluate and guide treatment of seizures. Even in patients who do not have a diagnosis of seizures, an overnight EEG capturing non-REM sleep can be helpful to look for frequent epileptiform activity (as in continuous spike wave in slow-wave sleep and electrical status epilepticus in slow wave sleep).
A few patients have borderline QT interval. Screening with an EKG or Holter monitor may be recommended.
Treatment often requires a team of specialists including pediatricians, child neurologists or pediatric epileptologists, developmental pediatricians, and/or other healthcare professionals.
For children with seizures/epilepsy, anticonvulsant medications may be helpful in decreasing seizure frequency. There is no clear anticonvulsant medication that has been shown to be most helpful in patients with KCNB1 encephalopathy. In some patients, if seizures are not controlled with medication, other treatments including diet therapy (ketogenic diet, modified Atkins diet), surgically implanted devices, or epilepsy surgery may be considered. In some patients without discrete seizures but who have abnormal EEG activity during sleep, anticonvulsant medications may be recommended.
For children with features of autism spectrum disorder, developmental pediatricians may be involved in the diagnosis and may recommend Applied Behavioral Analysis (ABA) or other therapies.
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Contact for additional information about KCNB1 encephalopathy:
Sunita Misra, MD, PhD
Instructor of Pediatrics, Division of Neurology & Epilepsy
Ann & Robert H. Lurie Children’s Hospital of Chicago
Northwestern University Feinberg School of Medicine
Jennifer Kearney, PhD
Associate Professor of Pharmacology
Northwestern University Feinberg School of Medicine
Torkamani, A., et al. De novo KCNB1 mutations in epileptic encephalopathy. Ann Neurol 2014;76(4): 529-540.
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).
Kang, S.K., et al. High throughput Characterization of KCNB1 variants Associated with Developmental and Epileptic Encephalopathy. BioRxiv 2019.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Epileptic Encephalopathy, Early Infantile, 26;EIEE26. Entry No: 616056. Last edited: 10/20/2014. http://www.omim.org/entry/616056 Accessed June 18, 2019.
National Institute of Mental Health (NIMH). Autism Spectrum Disorder. Last edited: March 2018. https://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-asd/index.shtml Accessed June 18, 2019.
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