KCNB1-Related Developmental and Epileptic Encephalopathy

Mendelian MONDO:0014477 Pathograph 12 Show in embeddings browser Neurodevelopmental Disorder Epileptic Encephalopathy

A developmental and epileptic encephalopathy caused by de novo heterozygous variants in KCNB1, which encodes the alpha subunit of the Kv2.1 delayed-rectifier voltage-gated potassium channel, the major delayed-rectifier K+ conductance of cortical and hippocampal pyramidal neurons. Most pathogenic variants cluster in the pore/selectivity-filter and voltage-sensor regions and act through more than one mechanism: dominant-negative suppression of the delayed-rectifier K+ current (mutant subunits co-assemble with wild-type subunits into dysfunctional heterotetramers), loss of K+ selectivity that converts the channel into an aberrant depolarizing cation conductance, and disruption of Kv2.1's non-conducting structural role in surface clustering and endoplasmic reticulum-plasma-membrane junction organization. The net effect is disturbed neuronal excitability and cortical network function. Affected individuals present in infancy or early childhood along a spectrum from severe developmental and epileptic encephalopathy (DEE) with infantile-onset seizures to developmental encephalopathy with later-onset or no epilepsy, and virtually all have developmental delay with frequently severe-to-profound intellectual disability, autistic features, and behavioral problems.

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1
Mappings
1
Inheritance
6
Pathophys.
8
Phenotypes
2
Gaps
12
Pathograph
1
Genes
3
Medical Actions
2
Differentials
1
Models
6
References
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Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
Channelopathy
neurological channelopathy
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Mappings

MONDO
MONDO:0014477 developmental and epileptic encephalopathy, 26
skos:exactMatch MONDO
Primary MONDO disease term for this entry; MONDO:0014477 cross-references OMIM:616056 (developmental and epileptic encephalopathy 26).
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Inheritance

1
Autosomal Dominant (De Novo) HP:0000006
Nearly all cases arise from de novo heterozygous KCNB1 variants. A single variant allele is sufficient to cause disease, acting through dominant-negative suppression of the Kv2.1 channel and/or a gain of aberrant channel function.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:25164438 SUPPORT Human Clinical
"we identified 2 additional patients with epileptic encephalopathy and de novo KCNB1 missense mutations that cause a similar pattern of KV 2.1 dysfunction."
Establishes the de novo heterozygous genetic basis of KCNB1 epileptic encephalopathy across multiple unrelated patients.
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Discussions and Knowledge Gaps

2
Does KCNB1-related encephalopathy produce seizures through net neuronal hyperexcitability (dominant-negative and gain-of-function loss of the repolarizing delayed-rectifier current with an aberrant depolarizing cation conductance) or through reduced repetitive pyramidal-neuron firing that destabilizes cortical circuits, and is the dominant route determined by variant class (selectivity-filter versus voltage-sensor variants)?
CONTROVERSY OPEN gap_kcnb1_hyperexcitability_vs_reduced_firing
Attached to
pathophysiology#Dominant-Negative Loss of Delayed-Rectifier K+ Current pathophysiology#Neuronal Hyperexcitability and Hypersynchrony
Heterologous expression of pore/selectivity-filter variants shows loss of K+ selectivity plus dominant-negative and gain-of-function defects predicted to depolarize neurons and increase excitability. In contrast, neuronal studies of other variants report that mutants inhibit repetitive firing of pyramidal neurons, so that insufficient firing disturbs circuit development and stability. These are mechanistically opposite accounts of how the same channel defect produces epilepsy and encephalopathy, and reconciling them, potentially by variant class or by excitatory-versus-inhibitory cell-type effects, is prerequisite to rational, mechanism-matched therapy.
Proposed experiments
KCNB1 variant-class neuronal excitability comparison
neuronal electrophysiology allelic-series experiment Relation: this experiment is of type this experiment type This experiment is of type neuronal electrophysiology allelic-series experiment.
exp_kcnb1_variant_class_excitability
Express an allelic series of KCNB1 variants (selectivity-filter, other pore, and voltage-sensor classes) in patient-derived or isogenic human iPSC neurons and in pyramidal versus interneuron backgrounds, and measure resting membrane potential, repetitive firing, and network activity to determine whether the net effect is hyperexcitability or reduced firing and whether it tracks with variant class or cell type.
Perturbations
KCNB1 variant-class expression
pathophysiology#Dominant-Negative Loss of Delayed-Rectifier K+ Current
Introduce selectivity-filter, pore, and voltage-sensor KCNB1 variants in a shared neuronal background, in excitatory and inhibitory neuron types.
KCNB1 hgnc:6231 HUGO Gene Nomenclature Committee (hgnc) Relation: this perturbation targets this gene This perturbation targets KCNB1 (hgnc:6231). hgnc:6231 is a gene from the HUGO Gene Nomenclature Committee.
Readouts
Neuronal excitability and network activity
pathophysiology#Neuronal Hyperexcitability and Hypersynchrony
regulation of membrane potential GO:0042391 Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on abnormal regulation of membrane potential (GO:0042391). GO:0042391 is a biological process from the Gene Ontology. ⚠ ABNORMAL
patch-clamp recording Relation: this readout is measured by this assay This readout is measured by patch-clamp recording. multielectrode array recording Relation: this readout is measured by this assay This readout is measured by multielectrode array recording.
Direction: POSITIVE
Controls
Wild-type KCNB1
Wild-type Kv2.1 expressed in the same neuronal backgrounds.
Variant-class comparison groups
Selectivity-filter, pore, and voltage-sensor groups compared with one another.
Decision criterion
Net hyperexcitability is supported if variants depolarize neurons and increase network firing; the reduced-firing account is supported if variants suppress repetitive firing, and a variant-class or cell-type dependence would reconcile the two.
Would support
pathophysiology#Dominant-Negative Loss of Delayed-Rectifier K+ Current pathophysiology#Neuronal Hyperexcitability and Hypersynchrony
Show evidence (3 references)
PMID:25164438 SUPPORT In Vitro
"These gain-of-function and dominant-negative functional defects are predicted to result in depolarized resting membrane potential and impaired membrane repolarization, with increased cellular excitability as a net consequence."
Supports the net-hyperexcitability account arising from selectivity-filter/pore variants.
PMID:26477325 SUPPORT In Vitro
"Both mutants inhibited repetitive neuronal firing through preventing production of deep interspike voltages."
Supports the competing reduced-firing account, in which impaired repetitive firing destabilizes circuits.
PMID:25164438 SUPPORT Model Organism
"Reduction of delayed rectifier potassium current by Kcnb1 deletion in mice results in reduced thresholds to induced seizures, but not spontaneous seizures."
The Kcnb1-deletion mouse is the explicit loss-of-function counterweight to the human gain-of-function/dominant-negative result: pure loss of Kv2.1 current lowers induced-seizure threshold but does not reproduce spontaneous epileptic encephalopathy, sharpening the open question of which mechanism drives the human disease.
How much of KCNB1-related encephalopathy is driven by loss of Kv2.1's non-conducting structural role in surface clustering and endoplasmic reticulum-plasma-membrane junction organization, as opposed to the conduction defect, and does disrupting this scaffolding function alone produce disease-relevant neuronal dysfunction?
KNOWLEDGE GAP OPEN gap_kcnb1_nonconducting_role_contribution
Attached to
pathophysiology#Disrupted Kv2.1 Clustering and ER-Plasma-Membrane Junction Organization
Kv2.1 has a well-established conductance-independent role in forming ER-plasma-membrane junctions that serve as membrane-trafficking and Ca2+-signaling hubs, and disease variants alter Kv2.1 expression and subcellular localization. It is not yet resolved whether the encephalopathy phenotype depends on this scaffolding defect in addition to the conduction defect, which matters for whether therapies must restore channel gating, channel localization/clustering, or both.
Proposed experiments
KCNB1 conduction-versus-clustering separation-of-function test
separation-of-function structure-function experiment Relation: this experiment is of type this experiment type This experiment is of type separation-of-function structure-function experiment.
exp_kcnb1_clustering_separation_of_function
Using engineered Kv2.1 alleles that separate conduction from clustering (a conduction-dead but clustering-competent channel and a conducting but clustering-deficient channel), test in human iPSC neurons whether disrupting the clustering/ER-plasma-membrane-junction role alone impairs neuronal Ca2+ signaling, trafficking, and network maturation independent of the current defect.
Perturbations
Conduction versus clustering separation-of-function alleles
pathophysiology#Disrupted Kv2.1 Clustering and ER-Plasma-Membrane Junction Organization
Express clustering-deficient and conduction-dead Kv2.1 variants to isolate the scaffolding role from the conduction role.
KCNB1 hgnc:6231 HUGO Gene Nomenclature Committee (hgnc) Relation: this perturbation targets this gene This perturbation targets KCNB1 (hgnc:6231). hgnc:6231 is a gene from the HUGO Gene Nomenclature Committee.
Readouts
ER-plasma-membrane junction integrity and network maturation
pathophysiology#Impaired Neurodevelopment and Cortical Network Maturation
organelle localization by membrane tethering GO:0140056 Gene Ontology (GO) Relation: this readout reports on this biological process This readout reports on abnormal organelle localization by membrane tethering (GO:0140056). GO:0140056 is a biological process from the Gene Ontology. ⚠ ABNORMAL
total internal reflection fluorescence microscopy Relation: this readout is measured by this assay This readout is measured by total internal reflection fluorescence microscopy. multielectrode array recording Relation: this readout is measured by this assay This readout is measured by multielectrode array recording.
Direction: NEGATIVE
Controls
Wild-type KCNB1
Wild-type Kv2.1 expressed in the same neuronal background.
Conduction-only defect allele
A clustering-competent, conduction-impaired allele as comparator.
Decision criterion
An independent contribution of the scaffolding role is supported if a clustering-deficient but conducting allele impairs junction integrity and network maturation, and is refuted if only conduction-impairing alleles produce neuronal dysfunction.
Would support
pathophysiology#Disrupted Kv2.1 Clustering and ER-Plasma-Membrane Junction Organization
Show evidence (2 references)
PMID:25908859 SUPPORT In Vitro
"Kv2.1 localizes to dense, cell-surface clusters that contain non-conducting channels, indicating that they have a function that is unrelated to membrane-potential regulation."
Establishes the conductance-independent structural role whose disease contribution is the open question.
PMID:26503721 SUPPORT In Vitro
"Striking cell background-dependent differences in expression and subcellular localization of the V378A mutation were observed in heterologous cells."
Shows a disease variant disrupts Kv2.1 localization, the scaffolding arm whose phenotypic weight is unresolved.
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Pathophysiology

6
KCNB1 Variant and Altered Kv2.1 Channel Function
De novo heterozygous KCNB1 variants, most located in the pore/selectivity-filter and voltage-sensor regions of the channel, alter the function of Kv2.1, the alpha subunit of the delayed-rectifier voltage-gated potassium channel that is the major delayed-rectifier K+ current of cortical and hippocampal pyramidal neurons and an important regulator of neuronal excitability. This is the upstream molecular trigger of the disorder.
pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology.
delayed rectifier potassium channel activity GO:0005251 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal delayed rectifier potassium channel activity (GO:0005251). GO:0005251 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Dominant-Negative Loss of Delayed-Rectifier K+ Current
Disrupted Kv2.1 Clustering and ER-Plasma-Membrane Junction Organization
Show evidence (2 references)
PMID:25164438 SUPPORT Human Clinical
"KCNB1 encodes the alpha subunit of the KV2.1 voltage-gated potassium channel, a delayed rectifier potassium channel that is an important regulator of neuronal excitability."
Identifies KCNB1/Kv2.1 as the delayed-rectifier channel whose de novo variants trigger the disorder.
PMID:26477325 SUPPORT Human Clinical
"The voltage-gated Kv2.1 potassium channel encoded by KCNB1 produces the major delayed rectifier potassium current in pyramidal neurons."
Establishes Kv2.1 as the major delayed-rectifier current of pyramidal neurons, the channel altered by the variant.
Dominant-Negative Loss of Delayed-Rectifier K+ Current
Mutant Kv2.1 subunits co-assemble with wild-type subunits into heterotetrameric channels, so a single variant allele suppresses the delayed-rectifier K+ current in a dominant-negative fashion. Pore-domain variants can selectively abolish the endogenous Kv2 current, while selectivity-filter variants additionally cause loss of K+ selectivity, rendering the channel a nonselective, depolarizing cation conductance. Loss of the repolarizing delayed-rectifier current, together with an aberrant inward cation current, is predicted to depolarize the resting membrane potential and impair membrane repolarization.
pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology.
regulation of membrane potential GO:0042391 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of membrane potential (GO:0042391). GO:0042391 is a biological process from the Gene Ontology. ⚠ ABNORMAL
delayed rectifier potassium channel activity GO:0005251 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased delayed rectifier potassium channel activity (GO:0005251). GO:0005251 is a molecular function from the Gene Ontology. ↓ DECREASED voltage-gated potassium channel activity GO:0005249 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased voltage-gated potassium channel activity (GO:0005249). GO:0005249 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Excitation-Inhibition Imbalance
Show evidence (4 references)
PMID:26477325 SUPPORT In Vitro
"the mutation in the channel pore domain (p.G401R) selectively abolished endogenous Kv2 currents in transfected pyramidal neurons, indicating a dominant-negative effect."
Demonstrates the dominant-negative suppression of the Kv2 delayed-rectifier current by a pore-domain variant.
PMID:25164438 SUPPORT In Vitro
"All three mutants exhibited loss of K+ selectivity"
Shows loss of potassium selectivity for selectivity-filter/pore variants, the basis for an aberrant depolarizing cation conductance.
PMID:25164438 SUPPORT In Vitro
"These gain-of-function and dominant-negative functional defects are predicted to result in depolarized resting membrane potential and impaired membrane repolarization, with increased cellular excitability as a net consequence."
Links the dominant-negative and gain-of-function defects to impaired repolarization and increased excitability.
+ 1 more reference
Disrupted Kv2.1 Clustering and ER-Plasma-Membrane Junction Organization
Beyond conducting current, Kv2.1 localizes to dense surface clusters of largely non-conducting channels that play a direct structural role in forming stable endoplasmic reticulum-plasma-membrane junctions, which serve as membrane-trafficking and Ca2+-signaling hubs. Disease variants perturb Kv2.1 expression and subcellular localization and reciprocally alter the trafficking of co-assembled wild-type subunits, so this non-conducting scaffolding role is an independent, conductance-separable arm of the pathophysiology.
pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology.
organelle localization by membrane tethering GO:0140056 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal organelle localization by membrane tethering (GO:0140056). GO:0140056 is a biological process from the Gene Ontology. ⚠ ABNORMAL
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Excitation-Inhibition Imbalance
Impaired Neurodevelopment and Cortical Network Maturation
Show evidence (3 references)
PMID:25908859 SUPPORT In Vitro
"Kv2.1 localizes to dense, cell-surface clusters that contain non-conducting channels, indicating that they have a function that is unrelated to membrane-potential regulation."
Establishes the non-conducting clustered pool of Kv2.1 with a function independent of current conduction.
PMID:25908859 SUPPORT In Vitro
"the clustered Kv2.1 plays a direct structural role in the induction of stable ER-plasma-membrane junctions in both transfected HEK 293 cells and cultured hippocampal neurons."
Demonstrates the direct structural role of clustered Kv2.1 in organizing ER-plasma-membrane junctions.
PMID:26503721 SUPPORT In Vitro
"we suggest that defects in expression and subcellular localization of Kv2.1 V378A channels could contribute to the pathophysiology of this KCNB1 variant."
Links disease-variant defects in Kv2.1 expression and localization directly to the pathophysiology.
Excitation-Inhibition Imbalance
Loss of the repolarizing delayed-rectifier current and an aberrant depolarizing cation conductance disturb the excitability of cortical and hippocampal neurons. In heterologous studies the dominant-negative and gain-of-function defects predict depolarized resting potential and increased cellular excitability, whereas neuronal studies of some variants show impaired repetitive firing of pyramidal cells; both routes converge on a disturbed balance between excitatory and inhibitory signaling in cortical networks.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
regulation of membrane potential GO:0042391 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of membrane potential (GO:0042391). GO:0042391 is a biological process from the Gene Ontology. ⚠ ABNORMAL
neocortex UBERON:0001950 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in neocortex (UBERON:0001950). UBERON:0001950 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Neuronal Hyperexcitability and Hypersynchrony
Show evidence (1 reference)
PMID:25164438 SUPPORT In Vitro
"These gain-of-function and dominant-negative functional defects are predicted to result in depolarized resting membrane potential and impaired membrane repolarization, with increased cellular excitability as a net consequence."
Directly supports increased neuronal excitability as the net functional consequence of the channel defect, shifting the excitation-inhibition balance.
Neuronal Hyperexcitability and Hypersynchrony
The net excitatory bias produces a hyperexcitable, hypersynchronous cortical and hippocampal network state that converts the altered excitability into paroxysmal discharges, manifesting clinically as infantile-onset seizures with high-amplitude spike-and-wave electroencephalographic discharges.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
action potential GO:0001508 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased action potential (GO:0001508). GO:0001508 is a biological process from the Gene Ontology. ↑ INCREASED
neocortex UBERON:0001950 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in neocortex (UBERON:0001950). UBERON:0001950 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Developmental and Epileptic Encephalopathy
Epileptic Spasms
Show evidence (1 reference)
PMID:26477325 SUPPORT Human Clinical
"novel de novo heterozygous missense KCNB1 mutations in two patients showing psychomotor developmental delay and severe infantile generalized seizures with high-amplitude spike-and-wave electroencephalogram discharges."
Documents the electroclinical seizure phenotype produced by the hypersynchronous network excitability disturbance.
Impaired Neurodevelopment and Cortical Network Maturation
Abnormal excitability and disturbed activity-dependent signaling during a critical developmental window impair maturation and stability of cortical neuronal circuits. Insufficient or dysregulated pyramidal-neuron firing is predicted to disturb both the development and the stability of neuronal networks, producing developmental delay in essentially all patients, with frequently severe-to-profound intellectual disability, autistic features, and behavioral problems that are partly independent of seizure burden.
pyramidal neuron CL:0000598 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pyramidal neuron (CL:0000598). CL:0000598 is a cell type from the Cell Ontology.
nervous system development GO:0007399 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal nervous system development (GO:0007399). GO:0007399 is a biological process from the Gene Ontology. ⚠ ABNORMAL
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Global Developmental Delay
Severe to Profound Intellectual Disability
Autistic Behavior
Show evidence (2 references)
PMID:26477325 SUPPORT In Vitro
"insufficient firing of pyramidal neurons would disturb both development and stability of neuronal circuits, leading to the disease phenotypes."
Links the neuronal firing defect to disturbed circuit development, the basis of the neurodevelopmental phenotype.
PMID:32954514 SUPPORT Human Clinical
"showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56%"
Quantifies the near-universal developmental delay and severe-to-profound intellectual disability that define the neurodevelopmental outcome.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for KCNB1-Related Developmental and Epileptic Encephalopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25164438 SUPPORT Human Clinical
"Individual ID9 is a 9-year-old female with epileptic encephalopathy, hypotonia, developmental delays, cognitive impairment, and intermittent agitation."
A molecularly confirmed KCNB1 patient presenting with hypotonia, documenting it within the phenotypic spectrum.
Nervous System 6
Seizures VERY_FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28806457 SUPPORT Human Clinical
"Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age."
Quantifies seizures as a frequent feature of KCNB1-related neurodevelopmental disorder.
Epileptic Spasms FREQUENT HP:0011097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic spasm (HP:0011097). HP:0011097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28806457 SUPPORT Human Clinical
"9 patients (36%) starting with epileptic spasms between 3 and 18 months of age."
Documents epileptic spasms as an infantile-onset seizure type in a defined fraction of patients.
Global Developmental Delay OBLIGATE HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28806457 SUPPORT Human Clinical
"All patients had developmental delay, with 17 (65%) experiencing severe developmental delay"
Establishes developmental delay as a universal feature, severe in most.
Severe to Profound Intellectual Disability FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe to profound intellectual disability, annotated with Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32954514 SUPPORT Human Clinical
"severe to profound intellectual disability in 67% (n = 41/61)"
Quantifies severe-to-profound intellectual disability across the pooled cohort.
Autistic Behavior FREQUENT HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32954514 SUPPORT Human Clinical
"autistic features in 56% (n = 32/57)."
Quantifies autistic features as a frequent neurodevelopmental comorbidity.
Behavioral Abnormalities Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Behavioral problems, annotated with Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28806457 SUPPORT Human Clinical
"14 (82%) with severe delay had behavioral problems."
Documents behavioral problems as a frequent feature, especially with severe developmental delay.
Other 1
Developmental and Epileptic Encephalopathy FREQUENT HP:0200134 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32954514 SUPPORT Human Clinical
"Twenty patients (56%) had DEE with infantile onset seizures"
Documents developmental and epileptic encephalopathy with infantile-onset seizures as the predominant presentation.
🧬

Genetic Associations

1
KCNB1 (De Novo Variants)
Gene: KCNB1 hgnc:6231 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KCNB1 (hgnc:6231). hgnc:6231 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Autosomal Dominant (De Novo)
Show evidence (2 references)
PMID:28806457 SUPPORT Human Clinical
"20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6."
Documents the concentration of pathogenic missense variants in the pore-forming ion-channel domain.
PMID:32954514 SUPPORT Human Clinical
"Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants."
Establishes the genotype-phenotype correlation between variant class and epilepsy severity.
💊

Medical Actions

3
Antiseizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: levetiracetam CHEBI:6437 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levetiracetam (CHEBI:6437). CHEBI:6437 is a therapeutic agent from Chemical Entities of Biological Interest.
Seizures are managed with antiseizure medications, but epilepsy is frequently treatment-resistant and no agent corrects the underlying Kv2.1 channel defect. Agents such as levetiracetam are used, with variable and often incomplete response.
Mechanism Target:
INHIBITS Neuronal Hyperexcitability and Hypersynchrony — Antiseizure medications such as levetiracetam act symptomatically to dampen the hyperexcitable, hypersynchronous network discharges rather than correcting the upstream Kv2.1 channel defect, giving variable and often incomplete seizure control.
Show evidence (1 reference)
PMID:25164438 SUPPORT Human Clinical
"Rare GTCS are controlled with levetiracetam and clonazepam, but other seizure types have been poorly controlled with multiple therapies that were ineffective or limited by side effects"
Levetiracetam partially controls some seizure types, consistent with symptomatic suppression of the hyperexcitable network state, but does not address the underlying channel defect.
Show evidence (1 reference)
PMID:25164438 SUPPORT Human Clinical
"Rare GTCS are controlled with levetiracetam and clonazepam, but other seizure types have been poorly controlled with multiple therapies that were ineffective or limited by side effects"
Documents levetiracetam use with partial seizure control and frequent treatment resistance in a KCNB1 patient.
Supportive and Developmental Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Multidisciplinary developmental therapies and supportive care are the mainstay given the severe neurodevelopmental impairment; targeted disease-modifying therapies are not yet available and are much needed.
Show evidence (1 reference)
PMID:32954514 SUPPORT Human Clinical
"Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis."
Highlights the current absence of targeted therapy and reliance on supportive management.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling addresses the de novo dominant mechanism and the generally low recurrence risk, with attention to the rare possibility of parental mosaicism.
🔬

Diagnosis

3
KCNB1 Molecular Diagnosis
Diagnosis is established by identifying a heterozygous pathogenic or likely pathogenic KCNB1 variant, typically de novo, in a child with a developmental and epileptic encephalopathy or developmental encephalopathy. Parental testing confirms de novo status.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: A heterozygous pathogenic KCNB1 variant establishes the diagnosis.
Show evidence (1 reference)
PMID:25164438 SUPPORT Human Clinical
"We identified a de novo missense mutation in KCNB1 that encodes the KV 2.1 voltage-gated potassium channel."
Molecular identification of a de novo KCNB1 variant established the genetic diagnosis.
EEG and Seizure Phenotyping
EEG documents the encephalopathic background and epilepsy syndrome, including high-amplitude spike-and-wave discharges, and guides antiseizure treatment.
electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Results: Epileptiform discharges support the epileptic encephalopathy diagnosis.
Show evidence (1 reference)
PMID:26477325 SUPPORT Human Clinical
"severe infantile generalized seizures with high-amplitude spike-and-wave electroencephalogram discharges."
Documents the characteristic EEG discharges used in electroclinical phenotyping.
Brain MRI
Brain MRI is used to exclude structural causes of epileptic encephalopathy; findings in KCNB1-related encephalopathy are frequently normal or nonspecific.
magnetic resonance imaging procedure NCIT:C16809 NCI Thesaurus (NCIT)
Results: Usually normal or nonspecific; used mainly to exclude structural causes.
📈

Progression

2
Infancy to Early Childhood
In the DEE presentation, seizures begin in infancy (often with epileptic spasms) alongside emerging developmental delay; the developmental encephalopathy presentation may have later-onset or no epilepsy.
Show evidence (1 reference)
PMID:32954514 SUPPORT Human Clinical
"Twenty patients (56%) had DEE with infantile onset seizures"
Documents the infantile-onset seizure course in the DEE subgroup.
Childhood to Adulthood
Epilepsy course is variable, but long-term cognitive, psychiatric, and behavioral outcome is poor for most individuals.
Show evidence (1 reference)
PMID:32954514 SUPPORT Human Clinical
"Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome."
Documents the poor long-term neurodevelopmental outcome.
📊

Prevalence

1
Worldwide
Unknown Rare
KCNB1-related encephalopathy is a rare single-gene developmental and epileptic encephalopathy identified in a growing number of patients through exome sequencing, but a precise population prevalence has not been established.
Show evidence (1 reference)
PMID:32954514 SUPPORT Human Clinical
"Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports)"
Indicates that the disorder is individually rare, with cohorts assembled only through international collaboration and literature review.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from KCNB1-Related Developmental and Epileptic Encephalopathy:

Other potassium- and sodium-channel developmental and epileptic encephalopathies
Overlapping Features DEEs caused by other neuronal ion-channel genes (e.g. KCNQ2, KCNA2, SCN2A, SCN8A, HCN1) overlap through early-onset epilepsy and developmental impairment and are distinguished by molecular testing.
Distinguishing Features
  • A de novo heterozygous KCNB1 variant favors this disorder.
  • A pathogenic variant in another channel gene favors the corresponding channelopathy.
Other early-onset developmental and epileptic encephalopathies
Overlapping Features Non-channel DEE genes (e.g. STXBP1, CDKL5, SYNGAP1, CHD2) can present with early-onset epilepsy and severe developmental impairment and are distinguished by genetic testing.
Distinguishing Features
  • A pathogenic KCNB1 variant favors this disorder.
  • A causal variant in another DEE gene favors that diagnosis.
🐁

Animal Models

1
Kcnb1 deletion (loss of function) Mouse (Mus musculus)
Kcnb1-deletion mice, which lose the delayed-rectifier K+ current carried by Kv2.1, show reduced thresholds to induced seizures but not spontaneous seizures. This pure loss-of-function model recapitulates only a modest hyperexcitability/seizure-susceptibility phenotype and does not reproduce the severe spontaneous epileptic encephalopathy of humans, providing the explicit loss-of-function counterweight to the gain-of-function and dominant-negative effects of the human pore/selectivity-filter variants.
Species
Mouse (Mus musculus)
Genotype
Kcnb1 deletion (loss of function)
Show evidence (1 reference)
PMID:25164438 SUPPORT Model Organism
"Reduction of delayed rectifier potassium current by Kcnb1 deletion in mice results in reduced thresholds to induced seizures, but not spontaneous seizures."
Mouse Kcnb1 deletion lowers induced-seizure threshold without spontaneous seizures, showing that pure loss of Kv2.1 function is only modestly proconvulsant and distinguishing it from the human gain-of-function disease.
{ }

Source YAML

click to show 
name: KCNB1-Related Developmental and Epileptic Encephalopathy
creation_date: "2026-07-25T00:00:00Z"
description: >-
  A developmental and epileptic encephalopathy caused by de novo heterozygous
  variants in KCNB1, which encodes the alpha subunit of the Kv2.1 delayed-rectifier
  voltage-gated potassium channel, the major delayed-rectifier K+ conductance of
  cortical and hippocampal pyramidal neurons. Most pathogenic variants cluster in
  the pore/selectivity-filter and voltage-sensor regions and act through more than
  one mechanism: dominant-negative suppression of the delayed-rectifier K+ current
  (mutant subunits co-assemble with wild-type subunits into dysfunctional
  heterotetramers), loss of K+ selectivity that converts the channel into an
  aberrant depolarizing cation conductance, and disruption of Kv2.1's
  non-conducting structural role in surface clustering and endoplasmic
  reticulum-plasma-membrane junction organization. The net effect is disturbed
  neuronal excitability and cortical network function. Affected individuals present
  in infancy or early childhood along a spectrum from severe developmental and
  epileptic encephalopathy (DEE) with infantile-onset seizures to developmental
  encephalopathy with later-onset or no epilepsy, and virtually all have
  developmental delay with frequently severe-to-profound intellectual disability,
  autistic features, and behavioral problems.
synonyms:
- Developmental and epileptic encephalopathy 26
- DEE26
- Early infantile epileptic encephalopathy 26
- EIEE26
- KCNB1 encephalopathy
category: Mendelian
parents:
- Neurodevelopmental Disorder
- Epileptic Encephalopathy
disease_term:
  preferred_term: KCNB1-related developmental and epileptic encephalopathy
  term:
    id: MONDO:0014477
    label: developmental and epileptic encephalopathy, 26
inheritance:
- name: Autosomal Dominant (De Novo)
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Nearly all cases arise from de novo heterozygous KCNB1 variants. A single
    variant allele is sufficient to cause disease, acting through dominant-negative
    suppression of the Kv2.1 channel and/or a gain of aberrant channel function.
  evidence:
  - reference: PMID:25164438
    reference_title: "De novo KCNB1 mutations in epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified 2 additional patients with epileptic encephalopathy and de novo
      KCNB1 missense mutations that cause a similar pattern of KV 2.1 dysfunction.
    explanation: >-
      Establishes the de novo heterozygous genetic basis of KCNB1 epileptic
      encephalopathy across multiple unrelated patients.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    KCNB1-related encephalopathy is a rare single-gene developmental and epileptic
    encephalopathy identified in a growing number of patients through exome
    sequencing, but a precise population prevalence has not been established.
  evidence:
  - reference: PMID:32954514
    reference_title: "Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series
      and 37 published individuals in nine reports)
    explanation: >-
      Indicates that the disorder is individually rare, with cohorts assembled only
      through international collaboration and literature review.
references:
- reference: PMID:25164438
  title: "De novo KCNB1 mutations in epileptic encephalopathy."
- reference: PMID:26477325
  title: "De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing."
- reference: PMID:26503721
  title: "A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization."
- reference: PMID:25908859
  title: "Induction of stable ER-plasma-membrane junctions by Kv2.1 potassium channels."
- reference: PMID:32954514
  title: "Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome."
- reference: PMID:28806457
  title: "Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes."
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  channelopathy_category:
    classification_value: neurological channelopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014477
      label: developmental and epileptic encephalopathy, 26
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO disease term for this entry; MONDO:0014477 cross-references
      OMIM:616056 (developmental and epileptic encephalopathy 26).
pathophysiology:
- name: KCNB1 Variant and Altered Kv2.1 Channel Function
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Ion Channel and Synaptic Dysfunction"
  description: >-
    De novo heterozygous KCNB1 variants, most located in the pore/selectivity-filter
    and voltage-sensor regions of the channel, alter the function of Kv2.1, the
    alpha subunit of the delayed-rectifier voltage-gated potassium channel that is
    the major delayed-rectifier K+ current of cortical and hippocampal pyramidal
    neurons and an important regulator of neuronal excitability. This is the
    upstream molecular trigger of the disorder.
  role: trigger
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  molecular_functions:
  - preferred_term: delayed rectifier potassium channel activity
    term:
      id: GO:0005251
      label: delayed rectifier potassium channel activity
    modifier: ABNORMAL
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:25164438
    reference_title: "De novo KCNB1 mutations in epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KCNB1 encodes the alpha subunit of the KV2.1 voltage-gated potassium channel,
      a delayed rectifier potassium channel that is an important regulator of
      neuronal excitability.
    explanation: >-
      Identifies KCNB1/Kv2.1 as the delayed-rectifier channel whose de novo variants
      trigger the disorder.
  - reference: PMID:26477325
    reference_title: "De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The voltage-gated Kv2.1 potassium channel encoded by KCNB1 produces the major
      delayed rectifier potassium current in pyramidal neurons.
    explanation: >-
      Establishes Kv2.1 as the major delayed-rectifier current of pyramidal neurons,
      the channel altered by the variant.
  downstream:
  - target: Dominant-Negative Loss of Delayed-Rectifier K+ Current
    causal_link_type: DIRECT
  - target: Disrupted Kv2.1 Clustering and ER-Plasma-Membrane Junction Organization
    causal_link_type: DIRECT
- name: Dominant-Negative Loss of Delayed-Rectifier K+ Current
  description: >-
    Mutant Kv2.1 subunits co-assemble with wild-type subunits into
    heterotetrameric channels, so a single variant allele suppresses the
    delayed-rectifier K+ current in a dominant-negative fashion. Pore-domain
    variants can selectively abolish the endogenous Kv2 current, while
    selectivity-filter variants additionally cause loss of K+ selectivity, rendering
    the channel a nonselective, depolarizing cation conductance. Loss of the
    repolarizing delayed-rectifier current, together with an aberrant inward cation
    current, is predicted to depolarize the resting membrane potential and impair
    membrane repolarization.
  role: central_effector
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  molecular_functions:
  - preferred_term: delayed rectifier potassium channel activity
    term:
      id: GO:0005251
      label: delayed rectifier potassium channel activity
    modifier: DECREASED
  - preferred_term: voltage-gated potassium channel activity
    term:
      id: GO:0005249
      label: voltage-gated potassium channel activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: regulation of membrane potential
    term:
      id: GO:0042391
      label: regulation of membrane potential
    modifier: ABNORMAL
  evidence:
  - reference: PMID:26477325
    reference_title: "De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the mutation in the channel pore domain (p.G401R) selectively abolished
      endogenous Kv2 currents in transfected pyramidal neurons, indicating a
      dominant-negative effect.
    explanation: >-
      Demonstrates the dominant-negative suppression of the Kv2 delayed-rectifier
      current by a pore-domain variant.
  - reference: PMID:25164438
    reference_title: "De novo KCNB1 mutations in epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      All three mutants exhibited loss of K+ selectivity
    explanation: >-
      Shows loss of potassium selectivity for selectivity-filter/pore variants, the
      basis for an aberrant depolarizing cation conductance.
  - reference: PMID:25164438
    reference_title: "De novo KCNB1 mutations in epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These gain-of-function and dominant-negative functional defects are predicted
      to result in depolarized resting membrane potential and impaired membrane
      repolarization, with increased cellular excitability as a net consequence.
    explanation: >-
      Links the dominant-negative and gain-of-function defects to impaired
      repolarization and increased excitability.
  - reference: PMID:26503721
    reference_title: "A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These voltage-activated Kv2.1 V378A currents were nonselective among
      monovalent cations.
    explanation: >-
      Independent confirmation that a disease variant abolishes K+ selectivity,
      producing a nonselective cation current.
  downstream:
  - target: Excitation-Inhibition Imbalance
    causal_link_type: DIRECT
- name: Disrupted Kv2.1 Clustering and ER-Plasma-Membrane Junction Organization
  description: >-
    Beyond conducting current, Kv2.1 localizes to dense surface clusters of
    largely non-conducting channels that play a direct structural role in forming
    stable endoplasmic reticulum-plasma-membrane junctions, which serve as
    membrane-trafficking and Ca2+-signaling hubs. Disease variants perturb Kv2.1
    expression and subcellular localization and reciprocally alter the trafficking
    of co-assembled wild-type subunits, so this non-conducting scaffolding role is
    an independent, conductance-separable arm of the pathophysiology.
  role: effector
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: organelle localization by membrane tethering
    term:
      id: GO:0140056
      label: organelle localization by membrane tethering
    modifier: ABNORMAL
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:25908859
    reference_title: "Induction of stable ER-plasma-membrane junctions by Kv2.1 potassium channels."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Kv2.1 localizes to dense, cell-surface clusters that contain non-conducting
      channels, indicating that they have a function that is unrelated to
      membrane-potential regulation.
    explanation: >-
      Establishes the non-conducting clustered pool of Kv2.1 with a function
      independent of current conduction.
  - reference: PMID:25908859
    reference_title: "Induction of stable ER-plasma-membrane junctions by Kv2.1 potassium channels."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the clustered Kv2.1 plays a direct structural role in the induction of stable
      ER-plasma-membrane junctions in both transfected HEK 293 cells and cultured
      hippocampal neurons.
    explanation: >-
      Demonstrates the direct structural role of clustered Kv2.1 in organizing
      ER-plasma-membrane junctions.
  - reference: PMID:26503721
    reference_title: "A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we suggest that defects in expression and subcellular localization of Kv2.1
      V378A channels could contribute to the pathophysiology of this KCNB1 variant.
    explanation: >-
      Links disease-variant defects in Kv2.1 expression and localization directly to
      the pathophysiology.
  downstream:
  - target: Excitation-Inhibition Imbalance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Neurodevelopment and Cortical Network Maturation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Excitation-Inhibition Imbalance
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance"
  description: >-
    Loss of the repolarizing delayed-rectifier current and an aberrant depolarizing
    cation conductance disturb the excitability of cortical and hippocampal neurons.
    In heterologous studies the dominant-negative and gain-of-function defects
    predict depolarized resting potential and increased cellular excitability,
    whereas neuronal studies of some variants show impaired repetitive firing of
    pyramidal cells; both routes converge on a disturbed balance between excitatory
    and inhibitory signaling in cortical networks.
  role: amplifier
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: regulation of membrane potential
    term:
      id: GO:0042391
      label: regulation of membrane potential
    modifier: ABNORMAL
  locations:
  - preferred_term: neocortex
    term:
      id: UBERON:0001950
      label: neocortex
  evidence:
  - reference: PMID:25164438
    reference_title: "De novo KCNB1 mutations in epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These gain-of-function and dominant-negative functional defects are predicted
      to result in depolarized resting membrane potential and impaired membrane
      repolarization, with increased cellular excitability as a net consequence.
    explanation: >-
      Directly supports increased neuronal excitability as the net functional
      consequence of the channel defect, shifting the excitation-inhibition balance.
  downstream:
  - target: Neuronal Hyperexcitability and Hypersynchrony
    causal_link_type: DIRECT
- name: Neuronal Hyperexcitability and Hypersynchrony
  conforms_to: "epilepsy_excitation_inhibition_imbalance#Neuronal Hyperexcitability and Hypersynchrony"
  description: >-
    The net excitatory bias produces a hyperexcitable, hypersynchronous cortical
    and hippocampal network state that converts the altered excitability into
    paroxysmal discharges, manifesting clinically as infantile-onset seizures with
    high-amplitude spike-and-wave electroencephalographic discharges.
  role: central_effector
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: action potential
    term:
      id: GO:0001508
      label: action potential
    modifier: INCREASED
  locations:
  - preferred_term: neocortex
    term:
      id: UBERON:0001950
      label: neocortex
  evidence:
  - reference: PMID:26477325
    reference_title: "De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      novel de novo heterozygous missense KCNB1 mutations in two patients showing
      psychomotor developmental delay and severe infantile generalized seizures with
      high-amplitude spike-and-wave electroencephalogram discharges.
    explanation: >-
      Documents the electroclinical seizure phenotype produced by the
      hypersynchronous network excitability disturbance.
  downstream:
  - target: Developmental and Epileptic Encephalopathy
    causal_link_type: DIRECT
  - target: Epileptic Spasms
    causal_link_type: DIRECT
- name: Impaired Neurodevelopment and Cortical Network Maturation
  description: >-
    Abnormal excitability and disturbed activity-dependent signaling during a
    critical developmental window impair maturation and stability of cortical
    neuronal circuits. Insufficient or dysregulated pyramidal-neuron firing is
    predicted to disturb both the development and the stability of neuronal
    networks, producing developmental delay in essentially all patients, with
    frequently severe-to-profound intellectual disability, autistic features, and
    behavioral problems that are partly independent of seizure burden.
  role: effector
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:26477325
    reference_title: "De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      insufficient firing of pyramidal neurons would disturb both development and
      stability of neuronal circuits, leading to the disease phenotypes.
    explanation: >-
      Links the neuronal firing defect to disturbed circuit development, the basis
      of the neurodevelopmental phenotype.
  - reference: PMID:32954514
    reference_title: "Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      showed developmental delay in all with severe to profound intellectual
      disability in 67% (n = 41/61) and autistic features in 56%
    explanation: >-
      Quantifies the near-universal developmental delay and severe-to-profound
      intellectual disability that define the neurodevelopmental outcome.
  downstream:
  - target: Global Developmental Delay
    causal_link_type: DIRECT
  - target: Severe to Profound Intellectual Disability
    causal_link_type: DIRECT
  - target: Autistic Behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Developmental and Epileptic Encephalopathy
  category: Clinical
  description: >-
    A large proportion of patients have a developmental and epileptic
    encephalopathy with infantile-onset seizures; others fall along a spectrum to
    developmental encephalopathy with later-onset or no epilepsy.
  diagnostic: true
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  frequency: FREQUENT
  evidence:
  - reference: PMID:32954514
    reference_title: "Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty patients (56%) had DEE with infantile onset seizures
    explanation: >-
      Documents developmental and epileptic encephalopathy with infantile-onset
      seizures as the predominant presentation.
- name: Seizures
  category: Clinical
  description: >-
    Most patients develop seizures, ranging from infantile-onset generalized
    seizures to later-onset epilepsy; seizure types are variable and often
    treatment-resistant.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:28806457
    reference_title: "Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting
      with epileptic spasms between 3 and 18 months of age.
    explanation: >-
      Quantifies seizures as a frequent feature of KCNB1-related neurodevelopmental
      disorder.
- name: Epileptic Spasms
  category: Clinical
  description: >-
    A substantial subset of patients present with epileptic spasms in infancy,
    typically between 3 and 18 months of age.
  phenotype_term:
    preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
  frequency: FREQUENT
  evidence:
  - reference: PMID:28806457
    reference_title: "Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      9 patients (36%) starting with epileptic spasms between 3 and 18 months of
      age.
    explanation: >-
      Documents epileptic spasms as an infantile-onset seizure type in a defined
      fraction of patients.
- name: Global Developmental Delay
  category: Clinical
  description: >-
    Developmental delay is essentially universal, spanning motor, language, and
    cognitive domains.
  diagnostic: true
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: OBLIGATE
  evidence:
  - reference: PMID:28806457
    reference_title: "Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients had developmental delay, with 17 (65%) experiencing severe
      developmental delay
    explanation: >-
      Establishes developmental delay as a universal feature, severe in most.
- name: Severe to Profound Intellectual Disability
  category: Clinical
  description: >-
    Intellectual disability is frequently severe to profound, and is more marked in
    individuals with the developmental and epileptic encephalopathy end of the
    spectrum.
  phenotype_term:
    preferred_term: Severe to profound intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: FREQUENT
  evidence:
  - reference: PMID:32954514
    reference_title: "Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe to profound intellectual disability in 67% (n = 41/61)
    explanation: >-
      Quantifies severe-to-profound intellectual disability across the pooled
      cohort.
- name: Autistic Behavior
  category: Clinical
  description: >-
    Autistic features are common in KCNB1-related encephalopathy.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  frequency: FREQUENT
  evidence:
  - reference: PMID:32954514
    reference_title: "Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      autistic features in 56% (n = 32/57).
    explanation: >-
      Quantifies autistic features as a frequent neurodevelopmental comorbidity.
- name: Behavioral Abnormalities
  category: Clinical
  description: >-
    Behavioral problems are frequent, particularly in individuals with severe
    developmental delay.
  phenotype_term:
    preferred_term: Behavioral problems
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:28806457
    reference_title: "Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      14 (82%) with severe delay had behavioral problems.
    explanation: >-
      Documents behavioral problems as a frequent feature, especially with severe
      developmental delay.
- name: Hypotonia
  category: Clinical
  description: >-
    Hypotonia is a recognized early neurologic feature in KCNB1-related
    encephalopathy.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:25164438
    reference_title: "De novo KCNB1 mutations in epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individual ID9 is a 9-year-old female with epileptic encephalopathy,
      hypotonia, developmental delays, cognitive impairment, and intermittent
      agitation.
    explanation: >-
      A molecularly confirmed KCNB1 patient presenting with hypotonia, documenting
      it within the phenotypic spectrum.
genetic:
- name: KCNB1
  gene_term:
    preferred_term: KCNB1
    term:
      id: hgnc:6231
      label: KCNB1
  association: De Novo Variants
  presence: Positive
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal Dominant (De Novo)
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    De novo heterozygous KCNB1 variants cause the disorder. Missense variants
    concentrate in the ion-channel domain, particularly the S5-S6 pore/selectivity
    filter and the voltage-sensor region, and are associated with more frequent and
    more severe epilepsy; truncating variants tend to produce a milder phenotype.
  evidence:
  - reference: PMID:28806457
    reference_title: "Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a
      concentration of variants in region S5 to S6.
    explanation: >-
      Documents the concentration of pathogenic missense variants in the pore-forming
      ion-channel domain.
  - reference: PMID:32954514
    reference_title: "Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Missense variants were associated with more frequent and more severe epilepsy
      compared to truncating variants.
    explanation: >-
      Establishes the genotype-phenotype correlation between variant class and
      epilepsy severity.
diagnosis:
- name: KCNB1 Molecular Diagnosis
  description: >-
    Diagnosis is established by identifying a heterozygous pathogenic or likely
    pathogenic KCNB1 variant, typically de novo, in a child with a developmental
    and epileptic encephalopathy or developmental encephalopathy. Parental testing
    confirms de novo status.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: KCNB1
        term:
          id: hgnc:6231
          label: KCNB1
  results: A heterozygous pathogenic KCNB1 variant establishes the diagnosis.
  evidence:
  - reference: PMID:25164438
    reference_title: "De novo KCNB1 mutations in epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a de novo missense mutation in KCNB1 that encodes the KV 2.1
      voltage-gated potassium channel.
    explanation: >-
      Molecular identification of a de novo KCNB1 variant established the genetic
      diagnosis.
- name: EEG and Seizure Phenotyping
  description: >-
    EEG documents the encephalopathic background and epilepsy syndrome, including
    high-amplitude spike-and-wave discharges, and guides antiseizure treatment.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  results: Epileptiform discharges support the epileptic encephalopathy diagnosis.
  evidence:
  - reference: PMID:26477325
    reference_title: "De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe infantile generalized seizures with high-amplitude spike-and-wave
      electroencephalogram discharges.
    explanation: >-
      Documents the characteristic EEG discharges used in electroclinical
      phenotyping.
- name: Brain MRI
  description: >-
    Brain MRI is used to exclude structural causes of epileptic encephalopathy;
    findings in KCNB1-related encephalopathy are frequently normal or nonspecific.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  results: Usually normal or nonspecific; used mainly to exclude structural causes.
differential_diagnoses:
- name: Other potassium- and sodium-channel developmental and epileptic encephalopathies
  description: >-
    DEEs caused by other neuronal ion-channel genes (e.g. KCNQ2, KCNA2, SCN2A,
    SCN8A, HCN1) overlap through early-onset epilepsy and developmental impairment
    and are distinguished by molecular testing.
  distinguishing_features:
  - A de novo heterozygous KCNB1 variant favors this disorder.
  - A pathogenic variant in another channel gene favors the corresponding channelopathy.
- name: Other early-onset developmental and epileptic encephalopathies
  description: >-
    Non-channel DEE genes (e.g. STXBP1, CDKL5, SYNGAP1, CHD2) can present with
    early-onset epilepsy and severe developmental impairment and are distinguished
    by genetic testing.
  distinguishing_features:
  - A pathogenic KCNB1 variant favors this disorder.
  - A causal variant in another DEE gene favors that diagnosis.
animal_models:
- species: Mouse (Mus musculus)
  genotype: Kcnb1 deletion (loss of function)
  description: >-
    Kcnb1-deletion mice, which lose the delayed-rectifier K+ current carried by
    Kv2.1, show reduced thresholds to induced seizures but not spontaneous
    seizures. This pure loss-of-function model recapitulates only a modest
    hyperexcitability/seizure-susceptibility phenotype and does not reproduce the
    severe spontaneous epileptic encephalopathy of humans, providing the explicit
    loss-of-function counterweight to the gain-of-function and dominant-negative
    effects of the human pore/selectivity-filter variants.
  evidence:
  - reference: PMID:25164438
    reference_title: "De novo KCNB1 mutations in epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Reduction of delayed rectifier potassium current by Kcnb1 deletion in mice
      results in reduced thresholds to induced seizures, but not spontaneous
      seizures.
    explanation: >-
      Mouse Kcnb1 deletion lowers induced-seizure threshold without spontaneous
      seizures, showing that pure loss of Kv2.1 function is only modestly
      proconvulsant and distinguishing it from the human gain-of-function disease.
progression:
- phase: Infancy to Early Childhood
  notes: >-
    In the DEE presentation, seizures begin in infancy (often with epileptic
    spasms) alongside emerging developmental delay; the developmental encephalopathy
    presentation may have later-onset or no epilepsy.
  evidence:
  - reference: PMID:32954514
    reference_title: "Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty patients (56%) had DEE with infantile onset seizures
    explanation: >-
      Documents the infantile-onset seizure course in the DEE subgroup.
- phase: Childhood to Adulthood
  notes: >-
    Epilepsy course is variable, but long-term cognitive, psychiatric, and
    behavioral outcome is poor for most individuals.
  evidence:
  - reference: PMID:32954514
    reference_title: "Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long-term outcome in 22 individuals older than 12 years (14 in our series and
      eight published individuals) showed poor cognitive, psychiatric, and
      behavioral outcome.
    explanation: >-
      Documents the poor long-term neurodevelopmental outcome.
treatments:
- name: Antiseizure Medication
  description: >-
    Seizures are managed with antiseizure medications, but epilepsy is frequently
    treatment-resistant and no agent corrects the underlying Kv2.1 channel defect.
    Agents such as levetiracetam are used, with variable and often incomplete
    response.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
  evidence:
  - reference: PMID:25164438
    reference_title: "De novo KCNB1 mutations in epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rare GTCS are controlled with levetiracetam and clonazepam, but other seizure
      types have been poorly controlled with multiple therapies that were
      ineffective or limited by side effects
    explanation: >-
      Documents levetiracetam use with partial seizure control and frequent
      treatment resistance in a KCNB1 patient.
  target_mechanisms:
  - target: Neuronal Hyperexcitability and Hypersynchrony
    treatment_effect: INHIBITS
    description: >-
      Antiseizure medications such as levetiracetam act symptomatically to dampen
      the hyperexcitable, hypersynchronous network discharges rather than correcting
      the upstream Kv2.1 channel defect, giving variable and often incomplete
      seizure control.
    evidence:
    - reference: PMID:25164438
      reference_title: "De novo KCNB1 mutations in epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Rare GTCS are controlled with levetiracetam and clonazepam, but other seizure
        types have been poorly controlled with multiple therapies that were
        ineffective or limited by side effects
      explanation: >-
        Levetiracetam partially controls some seizure types, consistent with
        symptomatic suppression of the hyperexcitable network state, but does not
        address the underlying channel defect.
- name: Supportive and Developmental Care
  description: >-
    Multidisciplinary developmental therapies and supportive care are the mainstay
    given the severe neurodevelopmental impairment; targeted disease-modifying
    therapies are not yet available and are much needed.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32954514
    reference_title: "Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further understanding of disease mechanisms should facilitate the development
      of targeted therapies, much needed to improve the neurodevelopmental
      prognosis.
    explanation: >-
      Highlights the current absence of targeted therapy and reliance on supportive
      management.
- name: Genetic Counseling
  description: >-
    Genetic counseling addresses the de novo dominant mechanism and the generally
    low recurrence risk, with attention to the rare possibility of parental
    mosaicism.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
discussions:
- discussion_id: gap_kcnb1_hyperexcitability_vs_reduced_firing
  prompt: >-
    Does KCNB1-related encephalopathy produce seizures through net neuronal
    hyperexcitability (dominant-negative and gain-of-function loss of the
    repolarizing delayed-rectifier current with an aberrant depolarizing cation
    conductance) or through reduced repetitive pyramidal-neuron firing that
    destabilizes cortical circuits, and is the dominant route determined by variant
    class (selectivity-filter versus voltage-sensor variants)?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Dominant-Negative Loss of Delayed-Rectifier K+ Current
  - pathophysiology#Neuronal Hyperexcitability and Hypersynchrony
  rationale: >-
    Heterologous expression of pore/selectivity-filter variants shows loss of K+
    selectivity plus dominant-negative and gain-of-function defects predicted to
    depolarize neurons and increase excitability. In contrast, neuronal studies of
    other variants report that mutants inhibit repetitive firing of pyramidal
    neurons, so that insufficient firing disturbs circuit development and stability.
    These are mechanistically opposite accounts of how the same channel defect
    produces epilepsy and encephalopathy, and reconciling them, potentially by
    variant class or by excitatory-versus-inhibitory cell-type effects, is
    prerequisite to rational, mechanism-matched therapy.
  evidence:
  - reference: PMID:25164438
    reference_title: "De novo KCNB1 mutations in epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These gain-of-function and dominant-negative functional defects are predicted
      to result in depolarized resting membrane potential and impaired membrane
      repolarization, with increased cellular excitability as a net consequence.
    explanation: >-
      Supports the net-hyperexcitability account arising from selectivity-filter/pore
      variants.
  - reference: PMID:26477325
    reference_title: "De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Both mutants inhibited repetitive neuronal firing through preventing
      production of deep interspike voltages.
    explanation: >-
      Supports the competing reduced-firing account, in which impaired repetitive
      firing destabilizes circuits.
  - reference: PMID:25164438
    reference_title: "De novo KCNB1 mutations in epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Reduction of delayed rectifier potassium current by Kcnb1 deletion in mice
      results in reduced thresholds to induced seizures, but not spontaneous
      seizures.
    explanation: >-
      The Kcnb1-deletion mouse is the explicit loss-of-function counterweight to the
      human gain-of-function/dominant-negative result: pure loss of Kv2.1 current
      lowers induced-seizure threshold but does not reproduce spontaneous epileptic
      encephalopathy, sharpening the open question of which mechanism drives the human
      disease.
  proposed_experiments:
  - experiment_id: exp_kcnb1_variant_class_excitability
    name: KCNB1 variant-class neuronal excitability comparison
    description: >-
      Express an allelic series of KCNB1 variants (selectivity-filter, other pore,
      and voltage-sensor classes) in patient-derived or isogenic human iPSC neurons
      and in pyramidal versus interneuron backgrounds, and measure resting membrane
      potential, repetitive firing, and network activity to determine whether the
      net effect is hyperexcitability or reduced firing and whether it tracks with
      variant class or cell type.
    experiment_type:
      preferred_term: neuronal electrophysiology allelic-series experiment
    perturbations:
    - name: KCNB1 variant-class expression
      target: pathophysiology#Dominant-Negative Loss of Delayed-Rectifier K+ Current
      genes:
      - preferred_term: KCNB1
        term:
          id: hgnc:6231
          label: KCNB1
      description: >-
        Introduce selectivity-filter, pore, and voltage-sensor KCNB1 variants in a
        shared neuronal background, in excitatory and inhibitory neuron types.
    readouts:
    - name: Neuronal excitability and network activity
      target: pathophysiology#Neuronal Hyperexcitability and Hypersynchrony
      biological_processes:
      - preferred_term: regulation of membrane potential
        term:
          id: GO:0042391
          label: regulation of membrane potential
        modifier: ABNORMAL
      assays:
      - preferred_term: patch-clamp recording
      - preferred_term: multielectrode array recording
      direction: POSITIVE
    controls:
    - name: Wild-type KCNB1
      description: Wild-type Kv2.1 expressed in the same neuronal backgrounds.
    - name: Variant-class comparison groups
      description: Selectivity-filter, pore, and voltage-sensor groups compared with one another.
    decision_criterion: >-
      Net hyperexcitability is supported if variants depolarize neurons and increase
      network firing; the reduced-firing account is supported if variants suppress
      repetitive firing, and a variant-class or cell-type dependence would reconcile
      the two.
    would_support:
    - pathophysiology#Dominant-Negative Loss of Delayed-Rectifier K+ Current
    - pathophysiology#Neuronal Hyperexcitability and Hypersynchrony
- discussion_id: gap_kcnb1_nonconducting_role_contribution
  prompt: >-
    How much of KCNB1-related encephalopathy is driven by loss of Kv2.1's
    non-conducting structural role in surface clustering and endoplasmic
    reticulum-plasma-membrane junction organization, as opposed to the conduction
    defect, and does disrupting this scaffolding function alone produce
    disease-relevant neuronal dysfunction?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Disrupted Kv2.1 Clustering and ER-Plasma-Membrane Junction Organization
  rationale: >-
    Kv2.1 has a well-established conductance-independent role in forming
    ER-plasma-membrane junctions that serve as membrane-trafficking and
    Ca2+-signaling hubs, and disease variants alter Kv2.1 expression and subcellular
    localization. It is not yet resolved whether the encephalopathy phenotype
    depends on this scaffolding defect in addition to the conduction defect, which
    matters for whether therapies must restore channel gating, channel
    localization/clustering, or both.
  evidence:
  - reference: PMID:25908859
    reference_title: "Induction of stable ER-plasma-membrane junctions by Kv2.1 potassium channels."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Kv2.1 localizes to dense, cell-surface clusters that contain non-conducting
      channels, indicating that they have a function that is unrelated to
      membrane-potential regulation.
    explanation: >-
      Establishes the conductance-independent structural role whose disease
      contribution is the open question.
  - reference: PMID:26503721
    reference_title: "A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Striking cell background-dependent differences in expression and subcellular
      localization of the V378A mutation were observed in heterologous cells.
    explanation: >-
      Shows a disease variant disrupts Kv2.1 localization, the scaffolding arm whose
      phenotypic weight is unresolved.
  proposed_experiments:
  - experiment_id: exp_kcnb1_clustering_separation_of_function
    name: KCNB1 conduction-versus-clustering separation-of-function test
    description: >-
      Using engineered Kv2.1 alleles that separate conduction from clustering (a
      conduction-dead but clustering-competent channel and a conducting but
      clustering-deficient channel), test in human iPSC neurons whether disrupting
      the clustering/ER-plasma-membrane-junction role alone impairs neuronal
      Ca2+ signaling, trafficking, and network maturation independent of the current
      defect.
    experiment_type:
      preferred_term: separation-of-function structure-function experiment
    perturbations:
    - name: Conduction versus clustering separation-of-function alleles
      target: pathophysiology#Disrupted Kv2.1 Clustering and ER-Plasma-Membrane Junction Organization
      genes:
      - preferred_term: KCNB1
        term:
          id: hgnc:6231
          label: KCNB1
      description: >-
        Express clustering-deficient and conduction-dead Kv2.1 variants to isolate
        the scaffolding role from the conduction role.
    readouts:
    - name: ER-plasma-membrane junction integrity and network maturation
      target: pathophysiology#Impaired Neurodevelopment and Cortical Network Maturation
      biological_processes:
      - preferred_term: organelle localization by membrane tethering
        term:
          id: GO:0140056
          label: organelle localization by membrane tethering
        modifier: ABNORMAL
      assays:
      - preferred_term: total internal reflection fluorescence microscopy
      - preferred_term: multielectrode array recording
      direction: NEGATIVE
    controls:
    - name: Wild-type KCNB1
      description: Wild-type Kv2.1 expressed in the same neuronal background.
    - name: Conduction-only defect allele
      description: A clustering-competent, conduction-impaired allele as comparator.
    decision_criterion: >-
      An independent contribution of the scaffolding role is supported if a
      clustering-deficient but conducting allele impairs junction integrity and
      network maturation, and is refuted if only conduction-impairing alleles
      produce neuronal dysfunction.
    would_support:
    - pathophysiology#Disrupted Kv2.1 Clustering and ER-Plasma-Membrane Junction Organization
📚

References & Deep Research

References

6
PMID:25164438
De novo KCNB1 mutations in epileptic encephalopathy.
No top-level findings curated for this source.
PMID:26477325
De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing.
No top-level findings curated for this source.
PMID:26503721
A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization.
No top-level findings curated for this source.
PMID:25908859
Induction of stable ER-plasma-membrane junctions by Kv2.1 potassium channels.
No top-level findings curated for this source.
PMID:32954514
Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome.
No top-level findings curated for this source.
PMID:28806457
Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes.
No top-level findings curated for this source.