Continuous spike-wave of slow sleep in a patient with KCNB1-related epilepsy responsive to highly purified cannabidiol: a case report and comparison with literature.

KCNB1-associated encephalopathy is characterized by intellectual disability (ID), autism spectrum disorder and epilepsy. Specific treatments are still lacking. We describe a 12-year-old boy with severe ID and treatment-resistant seizures due to a pathogenic KCNB1 variant. His EEG showed a CSWS pattern. Aged 11, he started treatment with highly purified cannabidiol (CBD) and has been seizure free for 18 months, with significant EEG and social skills improvements. This suggests CBD may benefit CSWS, likely due to its anti-inflammatory properties. Some preclinical studies also indicate CBDs interact with voltage-gated channels, leading us to speculate its possible role for treating KCNB1 related encephalopathy.

Adaptive behavior and psychiatric comorbidities in KCNB1 encephalopathy.

AIM: KCNB1 encephalopathy encompasses a broad phenotypic spectrum associating intellectual disability, behavioral disturbances, and epilepsies of various severity. Using standardized parental questionnaires, we aimed to capture the heterogeneity of the adaptive and behavioral features in a series of patients with KCNB1 pathogenic variants. METHODS: We included 25 patients with a KCNB1 encephalopathy, aged from 3.2 to 34.1 years (median = 10 years). Adaptive functioning was assessed in all patients using the French version of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) questionnaire. We screened global behavior with the Childhood Behavioral Check-List (CBCL, Achenbach) and autism spectrum disorder (ASD) with the Social Communication Questionnaire (SCQ). We used a cluster analysis to identify subgroups of adaptive profiles. RESULTS: VABS-II questionnaire showed pathological adaptive behavior in all participants with a severity of adaptive deficiency ranging from mild in 8/20 to severe in 7/20. Eight out of 16 were at risk of Attention Problems at the CBCL and 13/18 were at risk of autism spectrum disorder (ASD). The adaptive behavior composite score significantly decreased with age (Spearman's Rho=-0.72, p<0.001) but not the equivalent ages, suggesting stagnation and slowing but no regression over time. The clustering analysis identified two subgroups of patients, one showing more severe adaptive behavior. The severity of the epilepsy phenotype predicted the severity of the behavioral profile with a sensitivity of 70% and a specificity of 90.9%. CONCLUSION: This study confirms the deleterious consequences of early-onset epilepsy in addition to the impact of the gene dysfunction in patients with KCNB1 encephalopathy. ASD and attention disorders are frequent. Parental questionnaires should be considered as useful tools for early screening and care adaptation.

Molecular, Cellular and Functional Changes in the Retinas of Young Adult Mice Lacking the Voltage-Gated K+ Channel Subunits Kv8.2 and K2.1.

Cone Dystrophy with Supernormal Rod Response (CDSRR) is a rare autosomal recessive disorder leading to severe visual impairment in humans, but little is known about its unique pathophysiology. We have previously shown that CDSRR is caused by mutations in the KCNV2 (Potassium Voltage-Gated Channel Modifier Subfamily V Member 2) gene encoding the Kv8.2 subunit, a modulatory subunit of voltage-gated potassium (Kv) channels. In a recent study, we validated a novel mouse model of Kv8.2 deficiency at a late stage of the disease and showed that it replicates the human electroretinogram (ERG) phenotype. In this current study, we focused our investigation on young adult retinas to look for early markers of disease and evaluate their effect on retinal morphology, electrophysiology and immune response in both the Kv8.2 knockout (KO) mouse and in the Kv2.1 KO mouse, the obligate partner of Kv8.2 in functional retinal Kv channels. By evaluating the severity of retinal dystrophy in these KO models, we demonstrated that retinas of Kv KO mice have significantly higher apoptotic cells, a thinner outer nuclear cell layer and increased activated microglia cells in the subretinal space. Our results indicate that in the murine retina, the loss of Kv8.2 subunits contributes to early cellular and physiological changes leading to retinal dysfunction. These results could have potential implications in the early management of CDSRR despite its relatively nonprogressive nature in humans.

Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature.

Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel Kv 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of Kv 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less-severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.

KCNB1 gene polymorphisms and related indel as predictor biomarkers of treatment response for colorectal cancer - toward a personalized medicine.

The KCNB1 gene variants were differentially associated with cancers. However, their association with colorectal cancer has not yet been explored. We investigated the contribution of the KCNB1 gene variants rs3331, rs1051295, and indel (insertion/deletion) rs11468831 Polymorphism as predictors of the treatment response in colorectal cancer patients. A retrospective study, which involved 291 Tunisian colorectal cancer patients (aged 60.0 ± 13.1 years), who were stratified into responder and non-responder groups, according to TNM stages and their responsiveness to chemotherapy based on fluorouracil. KCNB1 genotyping was performed with amplification-refractory mutation system-polymerase chain reaction, and was confirmed by Sanger sequencing. Sex-specific response was found and colorectal cancer females are less likely to achieve a positive response during the chemotherapy strategy, compared to males. Weight and body mass index, tumor size, and tumor localization are considered as predictive factors to treatment responsiveness. Carriage of rs11468831 Ins allele was significantly associated with successful therapy achievement (p adjusted < 0.001). Stratification of colorectal cancer patients' response according to tumor localization and TNM stages reveals negative association of rs3331 Major allele to treatment response among the patients with advanced cancer stages (subgroup G2). The presence of rs3331 (homozygous minor) C/C genotype was positively associated with decline in carcino-embryonic antigen (p = 0.043) and CA19-9 (p = 0.014) serum levels. On the other hand, the presence of rs1051295 (homozygous minor) A/A genotype was correlated with marked decline in CA19-9 serum levels. KCNB1 haplotype did not reveal any association between haplotypes and treatment response. The results obtained suggest that gender-specific strategies for screening treatment and prevention protocols as well as KCNB1 variants may constitute an effective model for ongoing personalization medicine.

Western influenced lifestyle and Kv2.1 association as predicted biomarkers for Tunisian colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most diagnosed malignancy worldwide. The global burden is expected to increase along with ongoing westernized behaviors and lifestyle. The etiology of CRC remains elusive and most likely combines environmental and genetic factors. The Kv2.1 potassium channel encoded by KCNB1 plays a collection of roles in malignancy of cancer and may be a key factor of CRC susceptibility. Our study provides baseline association between Tunisian CRC and interactions between KCNB1 variants and lifestyle factors. METHODS: A case-control study involving 300 CRC patients, and 300 controls was conducted Patients were carefully phenotyped and followed till the end of study. KCNB1 genotyping was confirmed by Sanger sequencing. Bivariate and multivariable logistic regression analyses were used to assess the clinical status, lifestyle and study polymorphisms association with CRC. RESULTS: We noted significant gender association with CRC occurrence. Moreover, CRC risk increases with high meat and fat consumption, alcohol use and physical activity (PA). Carriage of rs1051296 A/G and both rs11468831 ins/del and del/del genotypes (p < 0.001) were significantly associated with CRC risk. Analysis according to gender reveals correlation of rs1051295 A/G, rs11468831 non ins/ins (p = 0.01) with CRC susceptibility regardless of patients' gender while rs3331 T/C (p = 0.012) was associated with females. Stratification study according to malignancy site; Rectal Cancer (RC) and Colon Cancer (CC), reveals increasing RC risk by gender and high meat and fat consumption, alcohol use and PA. However, additional association with high brine consumption was noted for CC. The rs1051295 A/G (p = 0.01) was associated with RC risk. Increased CC risk was associated with carriage of rs1051295 A/G, rs11168831 (del/del) and (ins/del) genotypes. CONCLUSION: The risk of CRC increases with modifiable factors by Western influences on Tunisian lifestyle such as alcohol use, high fat consumption and possibly inadequate intake of vegetables. In addition, KCNB1 polymorphisms also markedly influence CRC susceptibility. Our study establishes key elements of a baseline characterization of clinical state, Western influenced lifestyle and KCNB1 variants associated with Tunisian CRC.

Kv2.1 voltage-gated potassium channels in developmental perspective.

Kv2.1 voltage-gated potassium channels consist of two types of α-subunits: (a) electrically-active Kcnb1 α-subunits and (b) silent or modulatory α-subunits plus ß-subunits that, similar to silent α-subunits, also regulate electrically-active subunits. Voltage-gated potassium channels were traditionally viewed, mainly by electrophysiologists, as regulators of the electrical activity of the plasma membrane in excitable cells, a role that is performed by transmembrane protein domains of α-subunits that form the electric pore. Genetic studies revealed a role for this region of α-subunits of voltage-gated potassium channels in human neurodevelopmental disorders, such as epileptic encephalopathy. The N- and C-terminal domains of α-subunits interact to form the cytoplasmic subunit of heterotetrameric potassium channels that regulate electric pores. Subsequent animal studies revealed the developmental functions of Kcnb1-containing voltage-gated potassium channels and illustrated their role during brain development and reproduction. These functions of potassium channels are discussed in this review in the context of regulatory interactions between electrically-active and regulatory subunits.

Functional antagonism of voltage-gated K+ channel α-subunits in the developing brain ventricular system.

The brain ventricular system is essential for neurogenesis and brain homeostasis. Its neuroepithelial lining effects these functions, but the underlying molecular pathways remain to be understood. We found that the potassium channels expressed in neuroepithelial cells determine the formation of the ventricular system. The phenotype of a novel zebrafish mutant characterized by denudation of neuroepithelial lining of the ventricular system and hydrocephalus is mechanistically linked to Kcng4b, a homologue of the 'silent' voltage-gated potassium channel α-subunit Kv6.4. We demonstrated that Kcng4b modulates proliferation of cells lining the ventricular system and maintains their integrity. The gain of Kcng4b function reduces the size of brain ventricles. Electrophysiological studies suggest that Kcng4b mediates its effects via an antagonistic interaction with Kcnb1, the homologue of the electrically active delayed rectifier potassium channel subunit Kv2.1. Mutation of kcnb1 reduces the size of the ventricular system and its gain of function causes hydrocephalus, which is opposite to the function of Kcng4b. This demonstrates the dynamic interplay between potassium channel subunits in the neuroepithelium as a novel and crucial regulator of ventricular development in the vertebrate brain.

Clinician's guide to genes associated with Rett-like phenotypes-Investigation of a Danish cohort and review of the literature.

The differential diagnostics in Rett syndrome has evolved with the development of next generation sequencing-based techniques and many patients have been diagnosed with other syndromes or variants in newly described genes where the associated phenotype(s) is yet to be fully explored. The term Rett-like refers to phenotypes with distinct overlapping features of Rett syndrome where the clinical criteria are not completely fulfilled. In this study we have combined a review of Rett-like disorders with data from a Danish cohort of 35 patients with Rett-like phenotypes emphasizing the diagnostic overlap with Pitt-Hopkins syndrome, Cornelia de Lange syndrome with SMC1A variants, and epileptic encephalopathies, for example, due to STXBP1 variants. We also found a patient with a pathogenic variant in KCNB1, which has not been previously linked to a Rett-like phenotype. This study underlines the clinical and genetic heterogeneity of a Rett syndrome spectrum, and provides an overview of the Rett syndrome-related genes described to date, and hence serves as a guide for diagnosing patients with Rett-like phenotypes.

A novel autism-associated KCNB1 mutation dramatically slows Kv2.1 potassium channel activation, deactivation and inactivation.

KCNB1, on human chromosome 20q13.3, encodes the alpha subunit of the Kv2.1 voltage gated potassium channel. Kv2.1 is ubiquitously expressed throughout the brain and is critical in controlling neuronal excitability, including in the hippocampus and pyramidal neurons. Human KCNB1 mutations are known to cause global development delay or plateauing, epilepsy, and behavioral disorders. Here, we report a sibling pair with developmental delay, absence seizures, autism spectrum disorder, hypotonia, and dysmorphic features. Whole exome sequencing revealed a heterozygous variant of uncertain significance (c. 342 C>A), p. (S114R) in KCNB1, encoding a serine to arginine substitution (S114R) in the N-terminal cytoplasmic region of Kv2.1. The siblings' father demonstrated autistic features and was determined to be an obligate KCNB1 c. 342 C>A carrier based on familial genetic testing results. Functional investigation of Kv2.1-S114R using cellular electrophysiology revealed slowing of channel activation, deactivation, and inactivation, resulting in increased net current after longer membrane depolarizations. To our knowledge, this is the first study of its kind that compares the presentation of siblings each with a KCNB1 disorder. Our study demonstrates that Kv2.1-S114R has profound cellular and phenotypic consequences. Understanding the mechanisms underlying KCNB1-linked disorders aids clinicians in diagnosis and treatment and provides potential therapeutic avenues to pursue.

Ion channels in neurodevelopment: lessons from the Integrin-KCNB1 channel complex.

Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes. Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide. Epilepsies are triggered by an imbalance between excitatory and inhibitory conductances. However, pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function variants, all able to trigger epilepsy. Furthermore, certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype. This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought. Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox. The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes, including neuronal migration, neurite outgrowth, and synapse formation. Thus, pathogenic channel mutants can not only cause epileptic disorders by altering excitability, but further, by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.

Stress-induced translation of KCNB1 contributes to the enhanced synaptic transmission of the lateral habenula.

The lateral habenula (LHb) is a well-established brain region involved in depressive disorders. Synaptic transmission of the LHb neurons is known to be enhanced by stress exposure; however, little is known about genetic modulators within the LHb that respond to stress. Using recently developed molecular profiling methods by phosphorylated ribosome capture, we obtained transcriptome profiles of stress responsive LHb neurons during acute physical stress. Among such genes, we found that KCNB1 (Kv2.1 channel), a delayed rectifier and voltage-gated potassium channel, exhibited increased expression following acute stress exposure. To determine the roles of KCNB1 on LHb neurons during stress, we injected short hairpin RNA (shRNA) against the kcnb1 gene to block its expression prior to stress exposure. We observed that the knockdown of KCNB1 altered the basal firing pattern of LHb neurons. Although KCNB1 blockade did not rescue despair-like behaviors in acute learned helplessness (aLH) animals, we found that KCNB1 knockdown prevented the enhancement of synaptic strength in LHb neuron after stress exposure. This study suggests that KCNB1 may contribute to shape stress responses by regulating basal firing patterns and neurotransmission intensity of LHb neurons.

KCNB1 frameshift variant caused inherited intellectual disability, developmental delay, and seizure.

Potassium voltage-gated channel subfamily B member 1 (KCNB1) encodes Kv2.1 potassium channel. KCNB1 mutations are known to cause global developmental delay, behavioral disorders, and various epilepsies. Most variants occur de novo and are rarely inherited. Here, we report a 14-year-old male patient who was admitted to our clinic with seizures, developmental delay history, and intellectual disability. Brain magnetic resonance image (MRI) was normal and electroencephalogram (EEG) showed spike and sharp-wave complexes emerging in the left hemisphere parietooccipital areas, which were paroxysmally generalized. We performed whole exome sequence analysis (WES) and identified a heterozygous frameshift mutation c.522delA in exon 1 of KCNB1 (NM_004975.4) predicting a premature stop codon p.Lys174Asnfs*20 in the proband. Sanger sequencing confirmed the heterozygous c.522delA mutation in the proband and his mother who also had epilepsy and learning difficulties. His 45 year old mother had used antiepileptic drugs for 9 years after a seizure episode at 12 years old. Also, his mother's uncle's son is nonverbal and has developmental delay and epilepsy. Our study shows that frameshift mutation cytoplasmic domain of KCNB1 gene can cause intrafamilial phenotypic variability and relatively mild clinical findings in these patients.

A KCNB1 gain of function variant causes developmental delay and speech apraxia but not seizures.

Objective: Numerous pathogenic variants in KCNB1, which encodes the voltage-gated potassium channel, KV2.1, are linked to developmental and epileptic encephalopathies and associated with loss-of-function, -regulation, and -expression of the channel. Here we describe a novel de novo variant (P17T) occurring in the KV2.1 channel that is associated with a gain-of-function (GoF), with altered steady-state inactivation and reduced sensitivity to the selective toxin, guanxitoxin-1E and is clinically associated with neurodevelopmental disorders, without seizures. Methods: The autosomal dominant variant was identified using whole exome sequencing (WES). The functional effects of the KCNB1 variant on the encoded KV2.1 channel were investigated using whole-cell patch-clamp recordings. Results: We identified a de novo missense variant in the coding region of the KCNB1 gene, c.49C>A which encodes a p.P17T mutation in the N-terminus of the voltage-gated, KV2.1 potassium channel. Electrophysiological studies measuring the impact of the variant on the functional properties of the channel, identified a gain of current, rightward shifts in the steady-state inactivation curve and reduced sensitivity to the blocker, guanxitoxin-1E. Interpretation: The clinical evaluation of this KCNB1 mutation describes a novel variant that is associated with global developmental delays, mild hypotonia and joint laxity, but without seizures. Most of the phenotypic features described are reported for other variants of the KCNB1 gene. However, the absence of early-onset epileptic disorders is a much less common occurrence. This lack of seizure activity may be because other variants reported have resulted in loss-of-function of the encoded KV2.1 potassium channel, whereas this variant causes a gain-of-function.

Correlation Analyses of Clinical Manifestations and Variant Effects in KCNB1-Related Neurodevelopmental Disorder.

Objective: Vitro functional analyses of KCNB1 variants have been done to disclose possible pathogenic mechanisms in KCNB1-related neurodevelopmental disorder. "Complete or partial loss of function (LoF)," "dominant-negative (DN) effect" are applied to describe KCNB1 variant's molecular phenotypes. The study here aimed to investigate clinical presentations and variant effects associations in the disorder. Methods: We reported 10 Chinese pediatric patients with KCNB1-related neurodevelopmental disorder here. Functional experiments on newly reported variants, including electrophysiology and protein expression, were performed in vitro. Phenotypic, functional, and genetic data in the cohort and published literature were collected. According to their variants' molecular phenotypes, patients were grouped into complete or partial LoF, and DN effect or non-dominant-negative (non-DN) effect to compare their clinical features. Results: Nine causative KCNB1 variants in 10 patients were identified in the cohort, including eight novel and one reported. Epilepsy (9/10), global developmental delay (10/10), and behavior issues (7/10) were common clinical features in our patients. Functional analyses of 8 novel variants indicated three partial and five complete LoF variants, five DN and three non-DN effect variants. Patient 1 in our series with truncated variants, whose functional results supported haploinsufficiency, had the best prognosis. Cases in complete LoF group had earlier seizure onset age (64.3 vs. 16.7%, p = 0.01) and worse seizure outcomes (18.8 vs. 66.7%, p = 0.03), and patients in DN effect subgroup had multiple seizure types compared to those in non-DN effect subgroup (65.5 vs. 30.8%, p = 0.039). Conclusion: Patients with KCNB1 variants in the Asian cohort have similar clinical manifestations to those of other races. Truncated KCNB1 variants exhibiting with haploinsufficiency molecular phenotype are linked to milder phenotypes. Individuals with complete LoF and DN effect KCNB1 variants have more severe seizure attacks than the other two subgroups.

AMIGO-Kv2.1 Potassium Channel Complex Is Associated With Schizophrenia-Related Phenotypes.

The enormous variability in electrical properties of neurons is largely affected by a multitude of potassium channel subunits. Kv2.1 is a widely expressed voltage-dependent potassium channel and an important regulator of neuronal excitability. The Kv2.1 auxiliary subunit AMIGO constitutes an integral part of the Kv2.1 channel complex in brain and regulates the activity of the channel. AMIGO and Kv2.1 localize to the distinct somatodendritic clusters at the neuronal plasma membrane. Here we have created and characterized a mouse line lacking the AMIGO gene. Absence of AMIGO clearly reduced the amount of the Kv2.1 channel protein in mouse brain and altered the electrophysiological properties of neurons. These changes were accompanied by behavioral and pharmacological abnormalities reminiscent of those identified in schizophrenia. Concomitantly, we have detected an association of a rare, population-specific polymorphism of KV2.1 (KCNB1) with human schizophrenia in a genetic isolate enriched with schizophrenia. Our study demonstrates the involvement of AMIGO-Kv2.1 channel complex in schizophrenia-related behavioral domains in mice and identifies KV2.1 (KCNB1) as a strong susceptibility gene for schizophrenia spectrum disorders in humans.

Variabilidad de la expresión clínica de la encefalopatía KCNB1 / Variability of the clinical expression of KCNB1 encephalopathy

Introducción: El gen KCNB1 codifica un canal de potasio dependiente del voltaje que regula corrientes transmembrana en las neuronas piramidales. Variantes en heterocigosis se han asociado recientemente con encefalopatías epilépticas de inicio precoz y discapacidad intelectual, pero su caracterización clínica no está completamente definida.Objetivo: Describir el espectro clínico asociado con variantes de KCNB1 en pacientes pediátricos. Pacientes y métodos: Estudio retrospectivo de cuatro pacientes procedentes de tres familias con encefalopatía KCNB1, analizando características clínicas y electroencefalográficas de la epilepsia, manifestaciones neurológicas asociadas y patrón de neurodesarrollo. Resultados: En dos, la mutación en KCNB1 fue de novo; las otras dos, hermanas, heredaron la variante de un progenitor con mosaicismo germinal. Todos presentaban discapacidad intelectual leve-moderada; dos pacientes, trastorno del espectro autista; y otros dos, trastorno por déficit de atención/hiperactividad. Sólo el caso 2 mostro´ alteraciones en la resonancia magnética cerebral: atrofia cortical evolutiva. Tres desarrollaron epilepsia (casos 1-3). Caso 1: inicio a los 9,5 meses con síndrome de West bien controlado con vigabatrina y zonisamida. Caso 2: inicio a los 13 meses con síndrome de West; desarrollo evolutivo de crisis polimorfas (atónicas, hipermotoras, disautonómicas y tónicas) refractarias a 10 fármacos antiepilépticos y corticoides. Asocio´ trastorno del movimiento caracterizado por ataxia, discinesias y temblor. Caso 3: inicio a los 14,5 años con crisis atónicas, patrón multifocal en el electroencefalograma y adecuado control con levetiracetam. Conclusiones: La encefalopatía KCNB1 presenta una evolución natural heterogénea, principalmente respecto a la epilepsia, y se observan desde pacientes con epilepsia refractaria hasta pacientes sin crisis epilépticas...(AU)

Introduction: The KCNB1 gene encodes a voltage-dependent potassium channel that regulates transmembrane currents in pyramidal neurons. Heterozygous variants have recently been associated with early-onset epileptic encephalopathies and intellectual disability, but their clinical characterisation has not yet been fully defined. Aim: To describe the clinical spectrum associated with variants of KCNB1 in paediatric patients. Patients and methods. Retrospective study of four patients from three families with KCNB1 encephalopathy, including an analysis of the clinical and electroencephalographic features of epilepsy, associated neurological manifestations and neurodevelopmental pattern. Results: In two of them, the mutation in KCNB1 was de novo; the other two, who were sisters, inherited the variant from a parent with germline mosaicism. All had mild-to-moderate intellectual disability, two patients had autistic spectrum disorder and two had attention deficit hyperactivity disorder. Only case 2 displayed alterations in the MRI brain scan: progressive cortical atrophy. Three of them developed epilepsy (cases 1-3). Case 1: onset at 9.5 months with West syndrome that was well controlled with vigabatrine and zonisamide. Case 2: onset at 13 months with West syndrome, evolutionary development of polymorphic seizures (atonic, hypermotor, dysautonomic and tonic) that were refractory to 10 antiepileptic drugs and corticosteroids. Accompanied by a movement disorder characterised by ataxia, dyskinesias and tremor. Case 3: onset at 14.5 years with atonic seizures, multifocal EEG pattern and adequate control with levetiracetam.Conclusions: KCNB1 encephalopathy has a heterogeneous natural history, mainly with respect to epilepsy, ranging from patients with refractory epilepsy to patients without any epileptic seizures. All had neurodevelopmental disorders, such as intellectual disability or autism spectrum disorder, independent of epilepsy.(AU)

Specific gene expression patterns of 108 schizophrenia-associated loci in cortex.

The latest genome-wide association study of schizophrenia identified 108 distinct genomic loci that contribute to schizophrenia. Brain development and function depend on the precise regulation of gene expression. The expression of many genes is differentially regulated across brain regions and developmental time points. We investigated the specific gene expression patterns arising from the 108 schizophrenia-associated loci using multiple publicly available databases and multiple regional brain datasets from developing and adult post-mortem human brains. The temporal-spatial expression analysis revealed that the genes in these loci were intensively enriched in the cortex during several developmental stages. These cortex-specific genes were particularly expressed in the fetal brain and adult neocortex.

Deletion of the Kv2.1 delayed rectifier potassium channel leads to neuronal and behavioral hyperexcitability.

The Kv2.1 delayed rectifier potassium channel exhibits high-level expression in both principal and inhibitory neurons throughout the central nervous system, including prominent expression in hippocampal neurons. Studies of in vitro preparations suggest that Kv2.1 is a key yet conditional regulator of intrinsic neuronal excitability, mediated by changes in Kv2.1 expression, localization and function via activity-dependent regulation of Kv2.1 phosphorylation. Here we identify neurological and behavioral deficits in mutant (Kv2.1(-/-) ) mice lacking this channel. Kv2.1(-/-) mice have grossly normal characteristics. No impairment in vision or motor coordination was apparent, although Kv2.1(-/-) mice exhibit reduced body weight. The anatomic structure and expression of related Kv channels in the brains of Kv2.1(-/-) mice appear unchanged. Delayed rectifier potassium current is diminished in hippocampal neurons cultured from Kv2.1(-/-) animals. Field recordings from hippocampal slices of Kv2.1(-/-) mice reveal hyperexcitability in response to the convulsant bicuculline, and epileptiform activity in response to stimulation. In Kv2.1(-/-) mice, long-term potentiation at the Schaffer collateral - CA1 synapse is decreased. Kv2.1(-/-) mice are strikingly hyperactive, and exhibit defects in spatial learning, failing to improve performance in a Morris Water Maze task. Kv2.1(-/-) mice are hypersensitive to the effects of the convulsants flurothyl and pilocarpine, consistent with a role for Kv2.1 as a conditional suppressor of neuronal activity. Although not prone to spontaneous seizures, Kv2.1(-/-) mice exhibit accelerated seizure progression. Together, these findings suggest homeostatic suppression of elevated neuronal activity by Kv2.1 plays a central role in regulating neuronal network function.