Benign Familial Neonatal Seizures Research Articles

Lipophilic compounds restore function to neurodevelopmental-associated KCNQ3 mutations

A major driver of neuronal hyperexcitability is dysfunction of K+ channels, including voltage-gated KCNQ2/3 channels. Their hyperpolarized midpoint of activation and slow activation and deactivation kinetics produce a current that regulates membrane potential and impedes repetitive firing. Inherited mutations in KCNQ2 and KCNQ3 are linked to a wide spectrum of neurodevelopmental disorders (NDDs), ranging from benign familial neonatal seizures to severe epileptic encephalopathies and autism spectrum disorders. However, the impact of these variants on the molecular mechanisms underlying KCNQ3 channel function remains poorly understood and existing treatments have significant side effects. Here, we use voltage clamp fluorometry, molecular dynamic simulations, and electrophysiology to investigate NDD-associated variants in KCNQ3 channels. We identified two distinctive mechanisms by which loss– and gain–of function NDD-associated mutations in KCNQ3 affect channel gating: one directly affects S4 movement while the other changes S4-to-pore coupling. MD simulations and electrophysiology revealed that polyunsaturated fatty acids (PUFAs) primarily target the voltage-sensing domain in its activated conformation and form a weaker interaction with the channel’s pore. Consistently, two such compounds yielded partial and complete functional restoration in R227Q- and R236C-containing channels, respectively. Our results reveal the potential of PUFAs to be developed into therapies for diverse KCNQ3-based channelopathies.

Novel KCNQ2 missense variant expands the genotype spectrum of DEE7.

KCNQ is a voltage-gated K + channel that controls neuronal excitability and is mutated in epilepsy and autism spectrum disorder (ASD). We focus on the KV7.2 voltage-gated potassium channel gene (KCNQ2), which is known for its association with developmental delay and various seizures (including self-limited benign familial neonatal epilepsy and epileptic encephalopathy). But the pathogenicity of many variants remains unproven, potentially leading to misinterpretation of their functional consequences. In this study, we studied a patient who visited Nanhua Hospital. Targeted next-generation sequencing and Sanger sequencing were used to identify the pathogenic variants. Meanwhile, computational models, including hydrogen bonding and docking analyses, suggest that variants cause functional impairment. In addition, functional validation was performed in the drosophila to further evaluate the missense variant in the KCNQ2 gene as the cause of this patient. A new missense variant in the KCNQ2 gene was identified: NM_172107.4:c.1007C > A(p.ALa336Glu), which resulted in the change from alanine to glutamate at amino acid position 336 in the KCNQ2 gene. After computational modeling, including hydrogen bond analysis and docking analysis, it is indicated that the variants cause functional impairment. Furthermore, RNAi-mediated KCNQ knockout in flies led to the onset of epileptic behavior, lifespan and climbing capacity were affected, expression of the normal human KCNQ2 rescues the in flies RNAi-mediated KCNQ knockout behavioral abnormalities. Our findings expands the genetic profile of KCNQ2 and enhances the genotype - phenotype link.

MLe-KCNQ2: An Artificial Intelligence Model for the Prognosis of Missense KCNQ2 Gene Variants.

Despite the increasing availability of genomic data and enhanced data analysis procedures, predicting the severity of associated diseases remains elusive in the absence of clinical descriptors. To address this challenge, we have focused on the KV7.2 voltage-gated potassium channel gene (KCNQ2), known for its link to developmental delays and various epilepsies, including self-limited benign familial neonatal epilepsy and epileptic encephalopathy. Genome-wide tools often exhibit a tendency to overestimate deleterious mutations, frequently overlooking tolerated variants, and lack the capacity to discriminate variant severity. This study introduces a novel approach by evaluating multiple machine learning (ML) protocols and descriptors. The combination of genomic information with a novel Variant Frequency Index (VFI) builds a robust foundation for constructing reliable gene-specific ML models. The ensemble model, MLe-KCNQ2, formed through logistic regression, support vector machine, random forest and gradient boosting algorithms, achieves specificity and sensitivity values surpassing 0.95 (AUC-ROC > 0.98). The ensemble MLe-KCNQ2 model also categorizes pathogenic mutations as benign or severe, with an area under the receiver operating characteristic curve (AUC-ROC) above 0.67. This study not only presents a transferable methodology for accurately classifying KCNQ2 missense variants, but also provides valuable insights for clinical counseling and aids in the determination of variant severity. The research context emphasizes the necessity of precise variant classification, especially for genes like KCNQ2, contributing to the broader understanding of gene-specific challenges in the field of genomic research. The MLe-KCNQ2 model stands as a promising tool for enhancing clinical decision making and prognosis in the realm of KCNQ2-related pathologies.

“Fifth‐day fits” revisited: A literature review of benign idiopathic neonatal seizures and comparison with KCNQ2‐ and KCNQ3‐associated benign familial epilepsy syndromes

AbstractBenign idiopathic neonatal seizures (BINS), colloquially referred to as the “fifth‐day fits,” is a clinical neonatal epilepsy syndrome associated with early, spontaneous resolution of seizures and favorable developmental outcome. Although this disease entity was first described over four decades ago, the etiopathogenesis remains unknown, and it is unclear if the syndrome represents a single, cohesive disorder or a common manifestation of various unrelated neonatal neurological disturbances. As such, there are no standardized approaches to diagnostic workup and management. Benign familial neonatal seizures (BFNS) is a well‐characterized genetic syndrome associated with KCNQ2 and KCNQ3 pathogenic variants, which also manifests clinically with self‐resolving seizures in the neonatal period. While it remains unclear if there is any shared pathogenesis between these two disorders, the exceedingly similar phenotypic presentations and natural history raise the question of whether consensus management approaches used in genetic BFNS can also be applied to BINS. Here, we present a topical and historical review of BINS and BFNS literature and propose specific treatment recommendations based on extrapolation of limited existing clinical data.

Point mutations in the voltage-gated potassium channel Kv7.2/7.3, and their possible involvement in epilepsy and channel gating.

Benign familial neonatal epilepsy (BFNE) is a genetic disorder that causes seizures, starting during the 3rd - 7th day after birth. Most of the causes of this condition are associated with a malfunction of the M-channel, a heteromeric potassium channel consisting of Kv7.2 and Kv7.3 subunits. The demand for better antiepileptic drugs has made this channel an important target to be explored, equally to treat BFNE as well as some other forms of epilepsy. Understanding in detail the function of this channel in health and disease is fundamental to develop new and more effective drug treatments. Using a combination of mutagenesis, concatemers, molecular modeling, and two-electrode voltage clamp electrophysiology we have characterized some functional aspects of mutations, identified on the ClinVar database as pathogenic or likely pathogenic. The identity and location of these mutations, and how they affect channel function, may guide us to a deeper understanding of the severity of this disease. These mutations also suggest which biophysical properties are important for normal gating and stability in the membrane. Here we describe a significant reduction in the magnitude of the current as a direct consequence of the mutations and discuss some of the possible mechanistic reasons for this reduction.

Heterozygous Deletion of Epilepsy Gene KCNQ2 Has Negligible Effects on Learning and Memory.

Neuronal Kv7/Potassium Voltage-Gated Channel Subfamily Q (KCNQ) potassium channels underlie M-current that potently suppresses repetitive and burst firing of action potentials (APs). They are mostly heterotetramers of Kv7.2 and Kv7.3 subunits in the hippocampus and cortex, the brain regions important for cognition and behavior. Underscoring their critical roles in inhibiting neuronal excitability, autosomal dominantly inherited mutations in Potassium Voltage-Gated Channel Subfamily Q Member 2 (KCNQ2) and Potassium Voltage-Gated Channel Subfamily Q Member 3 (KCNQ3) genes are associated with benign familial neonatal epilepsy (BFNE) in which most seizures spontaneously remit within months without cognitive deficits. De novo mutations in KCNQ2 also cause epileptic encephalopathy (EE), which is characterized by persistent seizures that are often drug refractory, neurodevelopmental delay, and intellectual disability. Heterozygous expression of EE variants of KCNQ2 is recently shown to induce spontaneous seizures and cognitive deficit in mice, although it is unclear whether this cognitive deficit is caused directly by Kv7 disruption or by persistent seizures in the developing brain as a consequence of Kv7 disruption. In this study, we examined the role of Kv7 channels in learning and memory by behavioral phenotyping of the KCNQ2+/− mice, which lack a single copy of KCNQ2 but dos not display spontaneous seizures. We found that both KCNQ2+/− and wild-type (WT) mice showed comparable nociception in the tail-flick assay and fear-induced learning and memory during a passive inhibitory avoidance (IA) test and contextual fear conditioning (CFC). Both genotypes displayed similar object location and recognition memory. These findings together provide evidence that heterozygous loss of KCNQ2 has minimal effects on learning or memory in mice in the absence of spontaneous seizures.

Phenotypic Spectrum in a Family Sharing a Heterozygous KCNQ3 Variant.

Mutations in KCNQ3 have classically been associated with benign familial neonatal and infantile seizures and more recently identified in patients with neurodevelopmental disorders and abnormal electroencephalogram (EEG) findings. We present 4 affected patients from a family with a pathogenic mutation in KCNQ3 with a unique constellation of clinical findings. A family of 3 affected siblings and mother sharing a KCNQ3 pathogenic variant are described, including clinical history, genetic results, and EEG and magnetic resonance imaging (MRI) findings. This family shows a variety of clinical manifestations, including neonatal seizures, developmental delays, autism spectrum disorder, and anxiety. One child developed absence epilepsy, 2 children have infrequent convulsive seizures that have persisted into childhood, and their parent developed adult-onset epilepsy. An underlying c.1091G>A (R364H) variant in KCNQ3 was found in all affected individuals. The phenotypic variability of KCNQ3 channelopathies continues to expand as more individuals and families are described, and the variant identified in this family adds to the understanding of the manifestations of KCNQ3-related disorders.

A novel KCNQ2 missense variant in non-syndromic intellectual disability causes mild gain-of-function of Kv7.2 channel

BackgroundHeterozygous variants of KCNQ2 can cause KCNQ2 associated neurodevelopmental disorder, mainly are benign (familial) neonatal or infantile epilepsy (B(F)NE or B(F)IE) and developmental epileptic encephalopathy(DEE). Moreover, some intermediate phenotypes, including intellectual disability (ID), and myokymia are related to the gene. MethodsWe collected a non-syndromic ID male patient with a novel KCNQ2 missense variant. Whole cell electrophysiology, western blotting, and immunofluorescence were adopted to analyze the variant’s functional alterations. ResultsThe patient presented with global developmental delay since his infancy. He still had profound ID but did not have epilepsy at the adolescence. The de novo KCNQ2 variant p.R75C (NM_172107) in the NH2 domain identified here showed a slightly hyperpolarized shift of activation curves and larger current density in homomeric configurations, which could be abolished in co-expression with Kv7.2 or Kv7.3 wild-type. Western blotting and immunocytochemistry supported that the expression of variant p.R75C is lower than the Kv7.2 wild-type. The findings indicated variant p.R75C causes mild gain-of-function (GOF) of Kv7.2 channel. ConclusionsWe report a non-syndromic ID patient with a KCNQ2 mild GOF variant, adding evidence for this rare clinical phenotype in the disorder. We propose that individuals with KCNQ2 GOF variants are prone to have cognitive impairments.

Cannabidiol differentially modulates Kv7 channelopathy-related phenotypes

Mutations in members of voltage-gated potassium channel family 7 (Kv7) modify electrophysiological properties and cause distinct clinical presentations. Mutations of the M-channel (Kv7.2/3 heterotetramer) underlying the neuronal M-current cause benign familial neonatal epilepsy (BFNE). Mutations in the Kv7.1 or KCNE1 subunit of the Kv7.1/KCNE1 heteromultimer underlying the ventricular repolarization current IKS cause Long-(L)QT-syndrome. The phytocannabinoid cannabidiol (CBD) is an FDA-approved anticonvulsant.

Biophysical and molecular studies of an epilepsy related single-point mutant in the S4-S5 linker of the kv7.3 subunit of M-channel

Benign familial neonatal epilepsy (BFNE) is a form of childhood epilepsy, occurring along the first days of life, and can be prolonged for months and in some cases even for years. Many forms of BFNE are associated to mutations in a type of slowly opening and closing voltage-dependent potassium channel called the “M-channel”. The M-channel is a hetero-tetramer containing two different members of the Kv7 family: Kv7.2/Kv7.3 or Kv7.3/Kv7.5. It plays an important role in setting the membrane resting potential in sympathetic neurons, but it is also expressed widely in the brain.

Distinctive mechanisms of epilepsy-causing mutants discovered by measuring S4 movement in KCNQ2 channels

Neuronal KCNQ voltage-gated potassium channels mediate the muscarine-regulated M-current, which contributes to maintaining the resting membrane potential and is a key regulator in preventing hyperexcitability in neurons. Mutations within KCNQ2 alter channel function and result in devastating diseases such as benign familial neonatal seizures (BFNS) and epileptic encephalopathies, conditions that currently affect 50 million people worldwide. The impact that mutations have on channel function remain poorly defined, largely because of our limited understanding of the voltage sensing mechanisms that trigger channel gating.

Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations.

In the central nervous system, the M-current plays a critical role in regulating subthreshold electrical excitability of neurons, determining their firing properties and responsiveness to synaptic input. The M-channel is mainly formed by subunits Kv7.2 and Kv7.3 that co-assemble to form a heterotetrametric channel. Mutations in Kv7.2 and Kv7.3 are associated with hyperexcitability phenotypes including benign familial neonatal epilepsy (BFNE) and neonatal epileptic encephalopathy (NEE). SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), increases M-current density in neurons, leading to reduced excitability and protection against seizures. Herein, using two-electrode voltage clamp on Xenopus laevis oocytes, we demonstrate that SGK1.1 selectively activates heteromeric Kv7 subunit combinations underlying the M-current. Importantly, activated SGK1.1 increases M-channel activity in the presence of two different epilepsy mutations found in Kv7.2, R207W and A306T. In addition, proximity ligation assays in the N2a cell line allowed us to address the effect of these mutations on Kv7-SGK1.1-Nedd4 molecular associations, a proposed pathway underlying augmentation of M-channel activity by SGK1.1

Early initial video-electro-encephalography combined with variant location predict prognosis of KCNQ2-related disorder

BackgroundThe clinical features of KCNQ2-related disorders range from benign familial neonatal seizures 1 to early infantile epileptic encephalopathy 7. The genotype-phenotypic association is difficult to establish.ObjectiveTo explore potential factors in neonatal period that can predict the prognosis of neonates with KCNQ2-related disorder.MethodsInfants with KCNQ2-related disorder were retrospectively enrolled in our study in Children’s Hospital of Fudan University in China from Jan 2015 to Mar 2020. All infants were older than age of 12 months at time of follow-up, and assessed by Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III) or Wechsler preschool and primary scale of intelligence-fourth edition (WPPSI-IV), then divided into three groups based on scores of BSID-III or WPPSI-IV: normal group, mild impairment group, encephalopathy group. We collected demographic variables, clinical characteristics, neuroimaging data. Considered variables include gender, gestational age, birth weight, age of the initial seizures, early interictal VEEG, variant location, delivery type. Variables predicting prognosis were identified using multivariate ordinal logistic regression analysis.ResultsA total of 52 infants were selected in this study. Early interictal video-electro-encephalography (VEEG) (β = 2.77, 1.20 to 4.34, P = 0.001), and variant location (β = 2.77, 0.03 to 5.5, P = 0.048) were independent risk factors for prognosis. The worse the early interictal VEEG, the worse the prognosis. Patients with variants located in the pore-lining domain or S4 segment are more likely to have a poor prognosis.ConclusionsThe integration of early initial VEEG and variant location can predict prognosis. An individual whose KCNQ2 variant located in voltage sensor, the pore domain, with worse early initial VEEG background, often had an adverse outcome.

Neonatal Seizures: An Overview of Genetic Causes and Treatment Options.

Seizures are the most frequent neurological clinical symptoms of the central nervous system (CNS) during the neonatal period. Neonatal seizures may be ascribed to an acute event or symptomatic conditions determined by genetic, metabolic or structural causes, outlining the so-called ‘Neonatal Epilepsies’. To date, three main groups of neonatal epilepsies are recognised during the neonatal period: benign familial neonatal epilepsy (BFNE), early myoclonic encephalopathy (EME) and ‘Ohtahara syndrome’ (OS). Recent advances showed the role of several genes in the pathogenesis of these conditions, such as KCNQ2, KCNQ3, ARX, STXBP1, SLC25A22, CDKL5, KCNT1, SCN2A and SCN8A. Herein, we reviewed the current knowledge regarding the pathogenic variants most frequently associated with neonatal seizures, which should be considered when approaching newborns affected by these disorders. In addition, we considered the new possible therapeutic strategies reported in these conditions.

Differential Functional Changes of Nav1.2 Channel Causing SCN2A-Related Epilepsy and Status Epilepticus During Slow Sleep.

Background: Nav1.2 encoded by the SCN2A gene is a brain-expressed voltage-gated sodium channel known to be associated with neurodevelopment disorders ranging from benign familial neonatal infantile seizures (BFIS) to developmental and epileptic encephalopathy (DEE) and autism spectrum disorder. Interestingly, status epilepticus during slow sleep (ESES), which aggravates cognitive impairment, has been found in SCN2A-related epilepsy. However, the functional features and the relationship between SCN2A and ESES have not been researched.Method: We herein investigated the functional consequences of an unpublished de novo V911A and the other two published variants in patients with SCN2A-related disorder and ESES by whole-cell patch-clamp studies in transfected HEK293T cells.Results: The unpublished V911A and published K1933M variants detected in patients with DEE exhibited a profound gain-of-functional (GOF) change. Another published BFIS variant S863F significantly reduced current density as a loss-of-functional (LOF) change. The refractory epilepsy in the patient with V911A was controlled by using the precise treatment of oxcarbazepine (OXC) since the age of 3 months. ESES was found at 18 months during the seizure-free period. We finally chose an aggressive treatment for eliminating ESES by using methylprednisolone combined with levetiracetam and nitrazepam instead of the precise treatment of OXC.Conclusion: Both GOF and LOF variants in the SCN2A gene can lead to ESES among the phenotypes of DEE and BFIS. We should monitor the electroencephalogram regularly in the patients with SCN2A-related epilepsy even during their seizure-free period.

The Spectrum of KCNQ2- and KCNQ3-Related Epilepsy

Abstract KCNQ genes encode for a family of six transmembrane domains, single pore-loop, and K+ channel α-subunits that have a wide range of physiological correlates. In the brain, KCNQ2 and KCNQ3 heteromultimers are thought to underlie the M-current which is essential in raising the threshold for firing an action potential; mutations in these genes may cause several types of infantile epilepsies. KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes that range from KCNQ2 benign familial neonatal epilepsy (BFNE), a seizure disorder that occur in children who typically have a normal psychomotor development and are inherited as an autosomal dominant trait, to KCNQ2 early-onset epileptic encephalopathy (EOEE) as the result of a de novo pathogenic variant. KCNQ3-related disorders are rarer and include BFNE, benign familial infantile epilepsy and KCNQ3-related epileptic encephalopathy with intellectual disability with or without seizures and/or cortical visual impairment. For both KCNQ2- and KCNQ3-related disorders, it is possible to use several drugs for different classes of mutations (i.e., gain of function vs. loss of function), and usually their effects vary in relation to the clinical presentation and the phenotype of the patient. However, KCNQ2-EOEE patients have a worse response to treatment than KCNQ2-BFNE patients and usually become drug resistant with multiple daily seizures.

Pathogenic variants in KCNQ2 cause intellectual deficiency without epilepsy: Broadening the phenotypic spectrum of a potassium channelopathy.

High-throughput sequencing (HTS) improved the molecular diagnosis in individuals with intellectual deficiency (ID) and helped to broaden the phenotype of previously known disease-causing genes. We report herein four unrelated patients with isolated ID, carriers of a likely pathogenic variant in KCNQ2, a gene usually implicated in benign familial neonatal seizures (BFNS) or early onset epileptic encephalopathy (EOEE). Patients were diagnosed by targeted HTS or exome sequencing. Pathogenicity of the variants was assessed by multiple in silico tools. Patients' ID ranged from mild to severe with predominance of speech disturbance and autistic features. Three of the four variants disrupted the same amino acid. Compiling all the pathogenic variants previously reported, we observed a strong overlap between variants causing EOEE, isolated ID, and BFNS and an important intra-familial phenotypic variability, although missense variants in the voltage-sensing domain and the pore are significantly associated to EOEE (p < 0.01, Fisher test). Thus, pathogenic variants in KCNQ2 can be associated with isolated ID. We did not highlight strong related genotype-phenotype correlations in KCNQ2-related disorders. A second genetic hit, a burden of rare variants, or other extrinsic factors may explain such a phenotypic variability. However, it is of interest to study encephalopathy genes in non-epileptic ID patients.

Voltage-Sensing Mechanism of Neuronal KCNQ Channels

The voltage-gated potassium channel KCNQ2/KCNQ3 (KCNQ2/3) mediates the M-current (IKM) in neurons. The IKM channel contributes to maintaining the resting membrane potential and impedes repetitive neuronal firing, therefore playing a crucial role in controlling neuronal excitability. Mutations within the voltage-sensor (S4) of the IKM channel have been linked to Benign Familial Neonatal Seizures (BFNS) and epileptic encephalopathies, conditions that currently affect 50 million people worldwide. However, how KCNQ2/3 channels function remains largely unknown. Here, we use two-electrode voltage clamp and inside-out patch clamp in a Xenopus oocyte expression system to assess external and internal accessibility of S4 cysteine-substituted residues to the membrane-impermeable thiol reagent (MTSET) in homomeric and heteromeric KCNQ channels. We find that in homomeric KCNQ2 (and in KCNQ3) channels, extracellular MTSET labels residues N190C (Q218C) with a similar time course in both closed and open states. By contrast, extracellular MTSET modifies residues A193 to R201 in KCNQ2 (G219-S228 in KCNQ3) at depolarized potentials, but not at hyperpolarized potentials, suggesting that these residues likely lie buried in the membrane in the closed state. We also use voltage clamp fluorometry (VCF) to determine S4 movement in KCNQ2/3 channels. In homomeric KCNQ channels, the time course and voltage dependence of fluorescence F(V) and ionic current G(V) correlate, as if the S4 and the gate motion were directly coupled. Moreover, in KCNQ2, the F(V) follows the voltage dependence of the modification rate of residue A193C. Our data also indicate that the presence of KCNQ3 subunits affects the S4 and gate of KCNQ2 in heteromeric KCNQ2/3 channels.

KCNQ2 Encephalopathy Showing a Distinct Ictal Amplitude-Integrated Electroencephalographic Pattern

KCNQ2 mutations induce a neonatal-onset epileptic encephalopathy of widely varying severity, ranging from benign familial neonatal epilepsy to severe refractory epileptic encephalopathy. Refractory seizures with KCNQ2 mutations have a positive response to sodium-channel blockers. Recently, a distinctive ictal pattern has been reported during amplitude-integrated electroencephalographic (aEEG) monitoring in infants with KCNQ2 encephalopathy. Herein, we describe a case of KCNQ2 encephalopathy with this distinctive ictal aEEG pattern, which was confirmed using conventional electroencephalography (EEG). A 3-day-old female infant presented with neonatal seizures accompanied by cyanosis and desaturation. Her seizure semiology was tonic and focal clonic. Her ictal aEEG demonstrated a sudden rise in amplitude followed by a suppressed background pattern. This pattern was also confirmed on conventional EEG. Her seizures were refractory despite the administration of multiple conventional antiepileptic drugs. Finally, c.794C>T; p. (Ala265Val) mutation was observed in the KCNQ2 gene on genetic testing, and she was diagnosed with KCNQ2 encephalopathy. Identifying this distinctive ictal pattern on aEEG monitoring facilitates the early detection of KCNQ2 encephalopathy and timely targeted treatment in patients with refractory seizures. Keywords: KCNQ2; Mutation; Infant; Seizures; Epilepsy; Electroencephalography

Clinical characteristics of KCNQ2 encephalopathy

PurposeKCNQ2 mutations are associated with benign familial neonatal epilepsy (BFNE) or developmental and epileptic encephalopathy (DEE). In this study, we aimed to delineate the phenotype of KCNQ2 encephalopathy and evaluate the treatment response. MethodsThirteen patients of KCNQ2 encephalopathy were included in the study. Characteristics of KCNQ2 mutations, electroclinical features, clinical course, and response to the treatment were analyzed. ResultsAge range of the thirteen patients was between 3 months and 20.9 years. The onset of seizures in 11 patients ranged from 1 to 3 days of age, while in the other two patients it was 7 and 40 days, respectively. Most common initial seizure types were tonic seizures. Initial EEGs were suppression burst pattern in seven patients and slow and disorganized background with multifocal epileptiform discharges in six patients. Initial epilepsy syndrome was Ohtahara syndrome in seven patients, neonatal focal seizure in five patients, and focal epilepsy beyond neonatal period in one patient. Sodium channel blockers including oxcarbazepine (OXC) (n = 3), lamotrigine (LTG) (n = 3), phenytoin (PHT) (n = 2), topiramate (TPM) (n = 2), and zonisamide (ZNS) (n = 1) were tried and found effective in eleven patients. Ultimately, 12 of 13 patients became seizure-free. However, developmental outcomes were poor. ConclusionsSodium channel blockers are effective in seizure control in these patients with KCNQ2 encephalopathy. Early recognition of KCNQ2 encephalopathy and early use of sodium channel blockers might be helpful in seizure control.