KCNB1-related disorder is a rare genetic disorder caused by variations in the KCNB1 gene, with a wide range of symptoms including seizures, developmental delay and speech impairment, among others.
Introduction
KCNB1-related disorder or KCNB1 encephalopathy is a rare autosomal dominant genetic disorder caused by variations in the KCNB1 gene located on chromosome 20 (locus 10q13.3). Early-onset developmental delay, speech, language impairment, and seizures are the most typical symptoms of this disorder, with other possible symptoms including hypotonia, delayed motor skills, involuntary movements, vision changes, and sleep disturbances, among others [1]. Today, individuals with KCNB1-related disorder manage their symptoms by working with a range of specialists, such as physical, occupational, speech, and behavioral therapists. These treatments differ depending on the prevalence, frequency, and severity of symptoms [2] [3].
This disorder was first identified in 2014 and since then 119 patients have been diagnosed worldwide [2]. Due to the novelty of this rare disease, clinical information is limited and research towards a targeted therapeutic is still in the early stages of development.
Tell Me About This Rare Disease
Genetic basis: This disorder is caused by a pathogenic mutation in the KCNB1 gene, on human chromosome 20q13.3, which encodes for a voltage-gated potassium channel called Kv2.1 [4]. Kv2.1 allows potassium ions to flow in and out of cells (Figure 1). A mutation in KCNB1 usually leads to a decrease in activity of the affected potassium channels. Kv2.1 is prevalent in the brain and plays an important role in controlling neuronal excitability. If it becomes mutated this can cause epilepsy or serious neurological problems for patients [3] [4] [5]. Most of these mutations occur “de novo,” meaning they are typically not inherited, but in rare cases can be due to dominant inheritance [1] [2]. Most mutations are missense variants (Figure 2) [6]. Seizures are more likely to occur in people who have KCNB1 missense variants than in those who have KCNB1 truncating variants [2].
As of 2024, there are 55 unique identified mutations identified in KCNB1 in patients of encephalopathic epilepsy, infantile epilepsy, autism spectrum disorder, and neurodevelopmental disorders [4].
Clinical Presentation: While all KCNB1-related disorders are caused by variations in the KCNB1 gene, symptom progression and severity vary widely among patients [2] [7]. The first signs of this disorder typically appear in infancy or early childhood and may be seen as neurodevelopmental delays or seizures [3]. However, in some cases, individuals may start experiencing symptoms later in childhood [3] [7]. The seizure types caused by KCNB1 variations may include infantile spasms, focal onset, clonic, myoclonic, tonic, tonic-clonic, atonic, drop attacks, or absence seizures [1] [3] [8]. While 87% of patients experience some type of seizure, there are still some individuals who do not experience them [2] [8].
Additional neurological symptoms of this disorder include cognitive impairment, including language and speech delays/impairment, abnormal EEG patterns, sleep disorders, movement disorders such as ataxia, dystonia, or chorea, and behavioral disturbances such as hyperactivity, aggression, and characteristics of autism spectrum disorder (ASD) [1] [2] [3] [7] [8].
In addition to neurological impacts, some patients also experience hypotonia, which can cause delayed motor development to achieve milestones such as crawling, sitting, and walking [8]. This may require walking and mobility aids for some, but most patients are able to walk independently by age two [2] [8].
KCNB1 variants have not been found to cause structural abnormalities or contractile dysfunction by ECHO, however more research is needed regarding the effect of all variants on cardiac arrhythmia [9]. Since KCNB1-related disorders are newly identified, this list of symptoms may not be all encompassing.
Incidence: As of 2024, 119 patients have been identified in clinics worldwide [2].
Brief history:
2014: KCNB1-related disorder was first identified in three patients [1] [2]
2017: Largest patient cohort of 26 patients was published [1]
2017: The KCNB1 Association was created by a group of families in France [10]
2021: The first international conference on KCNB1 gene mutations was organized [11]
2024: 119 people with KCNB1-related disorder have been identified [2]
What is it like to be a patient with this disease?
Who are the patients? Patients have been identified in all sexes/genders and in ages ranging from 5 months old to those in their thirties [12] [13]. More research is needed to determine how life expectancy may be affected by different KCNB1 pathogenic variants, however some symptoms of KCNB1-related disorder can be life-threatening [14] [15].
What do current treatment options look like? As of October 2024, there are no medications or targeted treatments to cure KCNB1-related disorders. Instead, patients use symptom management strategies such as physical, occupational, speech, and behavioral therapy in addition to different seizure medications depending on relevance and type [2] [3]. Implantation devices such as vagus nerve stimulation (VNS) or responsive neurostimulation (RNS) may be considered for more severe seizures, along with dietary changes such as switching to a ketogenic diet, which may be helpful in reducing symptoms in some cases [3].
Are there advocacy groups? Yes, there are several small advocacy organizations across the globe including KCNB1.org and Association KCNB1 France [16] [17]. These groups work to share information on KCNB1-related disorder including current research, patient stories, and fundraising [16] [17].
Are there genetic tests? Yes, because KCNB1-related disorder cannot be diagnosed based on clinical symptoms alone, genetic testing is required to diagnose this disorder [8]. Due to the rarity of this disorder, it is important to perform genetic sequencing to rule out other genetic causes and to identify the exact KCNB1 mutation [8] [18].
How do scientists and clinicians study this disease?
Are there good/any model systems scientists can use to develop drugs? To study this disease, researchers are using CRISPR and Cas9 genome editing to model common mutations in mice [7].
A number of mouse models exist for various KCNB1 mutations. Some of the less commonly occurring modeled mutations include G379R (a dominant-negative mutation which affects the pore of the channel and results in a relatively severe phenotype), R312H (which affects trafficking), and complete knockout mice [7] [9].
Additionally, one group recently created a knock-in mouse model to study the recurring mutation p.R306C [7]. This loss of function variant affects the S4 voltage-sensing transmembrane domain. Unlike several of the previous mouse models studied, these model mice had no significant difference in KCNB1 expression and localization compared to the wild type [7]. Despite this, the mice exhibited symptoms like those in humans (including hyperactivity, EEG changes, and seizures). Researchers think this suggests that the symptoms associated with this mutation are primarily due to decreased voltage sensing, unlike other variants that are associated with decreased expression or localization of KCNB1 [7] [24]. Models like this give insight into the physiological changes that lead to symptoms of this disease and may help in the development of a treatment.
In another recent study, knockout zebrafish models were used to study KCNB1-related disorders. Researchers observed altered swimming and epilepsy-like symptoms in these zebrafish, reflective of the symptoms observed in humans and mouse models [19].
Have natural history studies been done? No natural history studies have been done on this disorder specifically, but some patients are included in more general natural history studies on early-life epilepsies [20].
Certain physicians or centers that are experts? Although occurrence is rare, pediatric neurologists may be familiar with treating the symptoms of this disorder. Specifically, Children’s Hospital of Philadelphia which has an Epilepsy Neurogenetics Initiative (ENGIN) that lists KCNB1 as a focus. They can provide genetic testing and treatment for kids and families with this disorder, and they collaborate with the NIH Channelopathy-Associated Epilepsy Research Center to stay up to date on research their patients may be able to participate in [3].
In addition, the Kearny Lab at Northwestern University is conducting laboratory functional studies on three encephalopathies, including KCNB1. They hope to better understand the impact of human mutations on channel function using mice models [2]. Early research like this can serve as a basis for future therapeutic development. To participate in this research, patient families can ask their clinician for more information [21].
What are the major challenges in studying and curing this disease? In general, it has been difficult to selectively target K+-channels. There are a variety of channel subtypes, many of which have a complex structure that is not yet fully resolved. This makes it difficult to create structure-based drugs [25].
Furthermore, these channels have a wide array of roles throughout the body depending on their location and coupled proteins, and so successful therapies must be careful to not alter healthy channels [22]. Currently, many small molecule drugs that have been tested against K+-channels have off-target effects and are not yet safe [25].
Additionally, like many rare diseases, this is a difficult disorder to study due to the small patient population and diverse range of symptoms. KCNB1 is often included in larger studies of encephalopathies, but these disorders have a wide range of genetic causes outside of KCNB1 mutations [20].
The Cure Corner: What is needed for a cure?
What are current therapies and treatments lacking? Current therapies exist to treat symptoms such as seizures, but patients are lacking a targeted treatment option that addresses the underlying cause of the disorder [3].
Are there companies already developing drugs? The n-Lorem Foundation has the KCNB1 gene in their queue with the aim to use allele-selective RNAse H1 activating PS ASOs to treat KCNB1-related disorders [23].
Could an RNA therapeutic fit the need? Individual mutations need to be studied to determine if an RNA therapeutic could be beneficial. For example, an allele-selective ASO may be employed to address single nucleotide mutations to downregulate the pathogenic copy of the gene without perturbing the healthy copy [23]. Other strategies could include steric-blocking ASOs, where an ASO therapeutic can be used to block premature stop codons introduced by mutations and inhibit degradation of the transcript.
Conclusion
Scientists, clinicians, and patient families have only begun to scratch the surface in uncovering the details of this newly identified rare disease. Natural history studies of the disorder must be done to inform patient outcomes and identify targeted strategies for treatment. We are hopeful that in the coming years there will be more definitive information on clinical symptoms and individual mutations so that all patients with KCNB1-related disorders can receive specialized treatment.
[1] KCNB1 Encephalopathy | NORD. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/kcnb1-encephalopathy/
[2] KCNB1-Related Syndrome | Simons Searchlight. https://www.simonssearchlight.org/gene-guide/kcnb1/
[3] KCNB-1 Related Disorders. Children’s Hospital of Philadelphia. https://www.chop.edu/conditions-diseases/kcnb1-related-disorders
[4] Manville RW, Block SD, Illeck CL, Kottmeier J, Sidlow R, Abbott GW. A novel autism-associated KCNB1 mutation dramatically slows Kv2.1 potassium channel activation, deactivation and inactivation. Front Cell Neurosci. 2024;18:1438101. Published 2024 Jul 29. doi:10.3389/fncel.2024.1438101
[5] Key Symptoms/Features. KCBN1.org. http://www.kcnb1.org/key-symptoms.html
[6] 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
[7] Kang S, Hawkins N, Echevarria-Cooper D, Baker E, Dixon C, Speakes N, Kearney J. Altered neurological and neurobehavioral phenotypes in a mouse model of the recurrent KCNB1-p.R306C voltage-sensor variant. BioRxiv. 2023, March 30. doi: 10.1101/2023.03.29.534736
[8] KCNB1 encephalopathy. MedlinePlus. https://medlineplus.gov/genetics/condition/kcnb1-encephalopathy/
[9] Hawkins N, Misra S, Jurado M, Kang S, Vierra N, Nguyen K, Wren L, George A, Trimmer J, Kearney J. Epilepsy and neurobehavioral abnormalities in mice with a dominant-negative KCNB1 pathogenic variant. Neurobiology of Disease. 146. 2021 Jan. Doi: 10.1016/j.nbd.2020.105141.
[10] KCNB1 association: coming together in the face of disease. Imagine Institute. https://www.institutimagine.org/en/kcnb1-association-coming-together-face-disease-203#:~:text=In%20total%2C%208%20families%20came,for%20Rare%20Epilepsies%2C%20was%20launched.
[11] 1ère Conférence internationale sur la mutation du gène KCNB1. Association KCNB1 France. https://kcnb1-france.org/1ere-conference-internationale-sur-la-mutation-du-gene-kcnb1/
[12] Marini C, Romoli M, Parrini E, et al. Clinical features and outcome of 6 new patients carrying de novo KCNB1 gene mutations. Neurol Genet. 2017;3(6):e206. Published 2017 Dec 11. doi:10.1212/NXG.0000000000000206
[13] Bar C, Kuchenbuch M, Barcia G, et al. Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome. Epilepsia. 2020;61(11):2461-2473. doi:10.1111/epi.16679
[14] Jeffrey JS, Leathem J, King C, Mefford HC, Ross K, Sadleir LG. Developmental and epileptic encephalopathy: Personal utility of a genetic diagnosis for families. Epilepsia Open. 2021;6(1):149-159. Published 2021 Jan 19. doi:10.1002/epi4.12458
[15] DEE Challenges. Epilepsy Foundation. https://www.epilepsy.com/what-is-epilepsy/syndromes/dee-challenges
[16] Home. KCBN1.org. http://www.kcnb1.org/
[17] Home. Association KCNB1 France. https://kcnb1-france.org/
[18] Frésard L, Montgomery SB. Diagnosing rare diseases after the exome. Cold Spring Harb Mol Case Stud. 2018;4(6):a003392. Published 2018 Dec 17. doi:10.1101/mcs.a003392
[19] Robichon L, Bar C, Marian A, Lehmann L, Renault S, Kabashi E, Ciura S, Nabbout R. kcnb I loss-of-function in zebrafish causes neurodevelopmental and epileptic disorders asssociated with GABA dysfunction. bioRxiv 2024.07.03.601913; doi: https://doi.org/10.1101/2024.07.03.601913
[20] Current Research Studies. KCBN1.org. http://www.kcnb1.org/current-research-studies.html
[21] Kearney Lab. Northwestern. https://sites.northwestern.edu/kearney/research/
[22] Alam K, Svalastoga P, Martinez A, Glennon J, Haavik J. Potassium channels in behavioral brain disorders. Molecular mechanisms and therapeutic potential: A Narrative Review. Neuroscience and Biohavioral Reviews. 152. 2023 Sept. Doi: https://doi.org/10.1016/j.neubiorev.2023.105301
[23] Crooke ST. Addressing the Challenges of Treating Patients with Heterozygous Gain of Function Mutations. Nucleic Acid Ther. Published online September 23, 2024. doi:10.1089/nat.2024.0060
[24] Kearney, Jennifer, et al. Spectrum of KV2.1 Dysfunction in KCNB1-associated Neurodevelopment Disorders. Annals of Neurology. 2019; 86(6):899-912. Doi: 10.1002/ana/25607.
[25] Alam, Kazi, et al. Potassium channels in behavioral brain disorders. Molecular mechanisms and therapeutic potential: A narrative review. Neuroscience and Biobehavioral Reviews. Published 2023; doi: https://doi.org/10.1016/j.neubiorev.2023.105301.
[26] Gaudet, Pascale, et al. ICEPO: The ion channel electrophysiology ontology. Database: The Journal of Biological Databases and Curation. 2016; doi: 10.1093/database/baw017.
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