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1.
Int J Mol Sci ; 20(3)2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30717422

RESUMO

Bisoprolol (BIS) is a selective antagonist of ß1 adrenergic receptors. We examined the effects of BIS on M-type K⁺ currents (IK(M)) or erg-mediated K⁺ currents (IK(erg)) in pituitary GH3, R1220 cells, and hippocampal mHippoE-14 cells. As GH3 cells were exposed to BIS, amplitude of IK(M) was suppressed with an IC50 value of 1.21 µM. The BIS-induced suppression of IK(M) amplitude was not affected by addition of isoproterenol or ractopamine, but attenuated by flupirtine or ivabradine. In cell-attached current, BIS decreased the open probability of M-type K⁺ (KM) channels, along with decreased mean opening time of the channel. BIS decreased IK(erg) amplitude with an IC50 value of 6.42 µM. Further addition of PD-118057 attenuated BIS-mediated inhibition of IK(erg). Under current-clamp conditions, BIS depolarization increased the firing of spontaneous action potentials in GH3 cells; addition of flupirtine, but not ractopamine, reversed BIS-induced firing rate. In R1220 cells, BIS suppressed IK(M); subsequent application of ML-213(Kv7.2 channel activator) reversed BIS-induced suppression of the current. In hippocampal mHippoE-14 neurons, BIS inhibited IK(M) to a greater extent compared to its depressant effect on IK(erg). This demonstrated that in pituitary cells and hippocampal neurons the presence of BIS is capable of directly and differentially suppressing IK(M) and IK(erg), despite its antagonism of ß1-adrenergic receptors.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Bisoprolol/farmacologia , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Hipófise/citologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Canal de Potássio KCNQ2/genética , Canal de Potássio KCNQ2/metabolismo , Canal de Potássio KCNQ3/genética , Canal de Potássio KCNQ3/metabolismo , Camundongos , Ratos , Canais de Potássio Shaw/genética , Canais de Potássio Shaw/metabolismo
2.
Medicine (Baltimore) ; 97(50): e13565, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30558019

RESUMO

Dravet syndrome is considered to be one of the most severe types of genetic epilepsy. Mutations in SCN1A gene have been found to be responsible for at least 80% of patients with Dravet syndrome, and 90% of these mutations arise de novo. The variable clinical phenotype is commonly observed among these patients with SCN1A mutations, suggesting that genetic modifiers may influence the phenotypic expression of Dravet syndrome. In the present study, we described the clinical, pathological, and molecular characteristics of 13 Han Chinese pedigrees clinically diagnosed with Dravet syndrome. By targeted-exome sequencing, bioinformatics analysis and Sanger sequencing verification, 11 variants were identified in SCN1A gene among 11 pedigrees including 7 missense mutations, 2 splice site mutations, and 2 frameshift mutations (9 novel variants and 2 reported mutations). Particularly, 2 of these Dravet syndrome patients with SCN1A variants also harbored SCN9A, KCNQ2, or SLC6A8 variants. In addition, 2 subjects were failed to detect any pathogenic mutations in SCN1A and other epilepsy-related genes. These data suggested that SCN1A variants account for about 84.6% of Dravet syndrome in our cohort. This study expanded the mutational spectrum for the SCN1A gene, and also provided clinical and genetic evidence for the hypothesis that genetic modifiers may contribute to the variable manifestation of Dravet syndrome patients with SCN1A mutations. Thus, targeted-exome sequencing will make it possible to detect the interactions of epilepsy-related genes and reveal their modification on the severity of SCN1A mutation-related Dravet syndrome.


Assuntos
Epilepsias Mioclônicas/genética , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Linhagem , Análise de Sequência/métodos , Grupo com Ancestrais do Continente Asiático/genética , Pré-Escolar , China , Feminino , Mutação da Fase de Leitura/genética , Humanos , Lactente , Canal de Potássio KCNQ2/genética , Masculino , Mutação de Sentido Incorreto/genética , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Isoformas de Proteínas/genética
3.
Epileptic Disord ; 20(6): 541-544, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530441

RESUMO

A male neonate presented with seizures at 18 hours of life, characterized by tonic posturing with eye deviation to the right, apnoea, bradycardia, and oxygen desaturation. Initial structural, metabolic, and infectious work-up was unremarkable. He continued to have seizures refractory to a variety of antiepileptic medications. A phenobarbital coma was trialled, leading to cessation of clinical seizures but continuation of electrographic status epilepticus. On EEG, ictal discharges originated from both the right and left hemispheres, migrating to the opposite hemisphere, consistent with encephalopathy of infancy with migrating focal seizures. At this time, he developed septic shock and was trialled on a ketamine infusion and ketogenic diet. Due to his poor prognosis, a goals of care discussion was carried out with the family, leading to withdrawal of care and his subsequent death at one month and seven days. A posthumous genetic panel revealed a de novo KCNQ2 p.Ser247Leu variant, considered likely to be pathogenic. This is the third reported case of a KCNQ2 mutation associated with an encephalopathy of infancy with migrating focal seizures phenotype. We discuss potential cellular mechanisms underlying this unique KCNQ2 phenotype, as well as future therapeutic considerations.


Assuntos
Canal de Potássio KCNQ2/genética , Mutação , Convulsões/genética , Espasmos Infantis/genética , Encéfalo/fisiopatologia , Análise Mutacional de DNA , Eletroencefalografia , Humanos , Recém-Nascido , Masculino , Prognóstico , Convulsões/fisiopatologia , Espasmos Infantis/fisiopatologia
4.
Epilepsia ; 59(2): 358-368, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29265344

RESUMO

OBJECTIVES: Antiseizure drugs are the leading therapeutic choice for treatment of epilepsy, but their efficacy is limited by pharmacoresistance and the occurrence of unwanted side effects. Here, we examined the therapeutic efficacy of KCNQ channel activation by retigabine in preventing seizures and neurocardiac dysfunction in 2 potassium channelopathy mouse models of epilepsy with differing severity that have been associated with increased risk of sudden unexpected death in epilepsy (SUDEP): the Kcna1-/- model of severe epilepsy and the Kcnq1A340E/A340E model of mild epilepsy. METHODS: A combination of behavioral, seizure threshold, electrophysiologic, and gene expression analyses was used to determine the effects of KCNQ activation in mice. RESULTS: Behaviorally, Kcna1-/- mice exhibited unexpected hyperexcitability instead of the expected sedative-like response. In flurothyl-induced seizure tests, KCNQ activation decreased seizure latency by ≥50% in Kcnq1 strain mice but had no effect in the Kcna1 strain, suggesting the influence of genetic background. However, in simultaneous electroencephalography and electrocardiography recordings, KCNQ activation significantly reduced spontaneous seizure frequency in Kcna1-/- mice by ~60%. In Kcnq1A340E/A340E mice, KCNQ activation produced adverse cardiac effects including profound bradycardia and abnormal increases in heart rate variability and atrioventricular conduction blocks. Analyses of Kcnq2 and Kcnq3 mRNA levels revealed significantly elevated Kcnq2 expression in Kcna1-/- brains, suggesting that drug target alterations may contribute to the altered drug responses. SIGNIFICANCE: This study shows that treatment strategies in channelopathy may have unexpected outcomes and that effective rebalancing of channel defects requires improved understanding of channel interactions at the circuit and tissue levels. The efficacy of KCNQ channel activation and manifestation of adverse effects were greatly affected by genetic background, potentially limiting KCNQ modulation as a way to prevent neurocardiac dysfunction in epilepsy and thereby SUDEP risk. Our data also uncover a potential role for KCNQ2-5 channels in autonomic control of chronotropy.


Assuntos
Anticonvulsivantes/farmacologia , Carbamatos/farmacologia , Epilepsia/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Canais de Potássio KCNQ/agonistas , Canal de Potássio KCNQ1/genética , Canal de Potássio Kv1.1/genética , Fenilenodiaminas/farmacologia , Animais , Bloqueio Atrioventricular , Comportamento Animal , Bradicardia , Canalopatias , Morte Súbita , Modelos Animais de Doenças , Resistência a Medicamentos , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/genética , Eletroencefalografia , Epilepsia/genética , Perfilação da Expressão Gênica , Canal de Potássio KCNQ2/genética , Canal de Potássio KCNQ3/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Farmacogenética , Testes Farmacogenômicos , RNA Mensageiro/metabolismo , Transcriptoma
5.
Curr Med Chem ; 25(23): 2637-2660, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29022505

RESUMO

BACKGROUND: The Kv7 (KCNQ) subfamily of voltage-gated potassium channels consists of 5 members (Kv7.1-5) each showing characteristic tissue distribution and physiological roles. Given their functional heterogeneity, Kv7 channels represent important pharmacological targets for the development of new drugs for neuronal, cardiovascular and metabolic diseases. OBJECTIVE: In the present manuscript, we focus on describing the pharmacological relevance and potential therapeutic applications of drugs acting on neuronally-expressed Kv7.2/3 channels, placing particular emphasis on the different chemotypes, and highlighting their pharmacodynamic and, whenever possible, pharmacokinetic peculiarities. METHODS: The present work is based on an in-depth search of the currently available scientific literature, and on our own experience and knowledge in the field of neuronal Kv7 channel pharmacology. Space limitations impeded to describe the full pharmacological potential of Kv7 channels; thus, we have chosen to focus on neuronal channels composed of Kv7.2 and Kv7.3 subunits, and to mainly concentrate on their involvement in epilepsy. RESULTS: An astonishing heterogeneity in the molecular scaffolds exploitable to develop Kv7.2/3 modulators is evident, with important structural/functional peculiarities of distinct compound classes. CONCLUSION: In the present work we have attempted to show the current status and growing potential of the Kv7 pharmacology field. We anticipate a bright future for the field, and express our hopes that the efforts herein reviewed will result in an improved treatment of hyperexcitability (or any other) diseases.


Assuntos
Canal de Potássio KCNQ2/metabolismo , Canal de Potássio KCNQ3/metabolismo , Neurônios/metabolismo , Animais , Carbamatos/química , Carbamatos/metabolismo , Carbamatos/farmacologia , Epilepsia/metabolismo , Epilepsia/patologia , Humanos , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Canal de Potássio KCNQ2/química , Canal de Potássio KCNQ2/genética , Canal de Potássio KCNQ3/química , Canal de Potássio KCNQ3/genética , Moduladores de Transporte de Membrana/química , Moduladores de Transporte de Membrana/metabolismo , Neurônios/efeitos dos fármacos , Fenilenodiaminas/química , Fenilenodiaminas/metabolismo , Fenilenodiaminas/farmacologia , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/metabolismo , Piridinas/química , Piridinas/metabolismo , Piridinas/farmacologia
6.
Brain Dev ; 40(1): 69-73, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28687180

RESUMO

BACKGROUND: The potassium voltage-gated channel subfamily Q member 2 (KCNQ2) gene has been reported to be associated with various types of epilepsy, including benign familial neonatal seizure (BFNS), early infantile epileptic encephalopathy (EIEE), and unclassified early onset encephalopathies. We herein report a patient with early myoclonic encephalopathy (EME) caused by a KCNQ2 mutation. CASE REPORT: A male infant started to exhibit erratic myoclonus several days after birth and apnea attacks lasting for seconds with desaturation. One month after birth, his myoclonuses worsened in frequency. Electroencephalogram (EEG) showed a burst and suppression pattern, and myoclonuses occurred in the burst phase with diffuse polyspikes on EEG. At five months, inter-ictal EEG revealed hypsarrhythmia, but his attacks were still only myoclonuses. ACTH treatment was effective and the myoclonus frequency markedly decreased. At one year of age, whole-exome sequencing revealed a heterozygous mutation of the KCNQ2 gene (NM_172107.2): c.601C>T; p.(Arg201Cys), which was confirmed as de novo by Sanger sequencing. This mutation lies within the extracellular portion of the S4 voltage sensor. CONCLUSION: Most patients with a KCNQ2 mutation present with seizures starting in the neonatal period with varying severity, ranging from BFNS to Ohtahara syndrome. Furthermore, KCNQ2 appears to be a causative gene for EME.


Assuntos
Epilepsias Mioclônicas/genética , Canal de Potássio KCNQ2/genética , Canal de Potássio KCNQ2/metabolismo , Eletroencefalografia , Epilepsia/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Convulsões/genética , Espasmos Infantis
7.
Brain Dev ; 40(1): 65-68, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28728838

RESUMO

KCNQ2 encephalopathy is characterized by severely abnormal EEG, neonatal-onset epilepsy and developmental delay. It is caused by mutations (typically missense) in the KCNQ2 gene, encoding the voltage gated potassium channel Kv7.2 and leading to a negative-dominant effect. We present one case experiencing recurrent neonatal seizures with changing hemispheres of origin, reminiscent of epilepsy of infancy with migrating focal seizures. At 9months of age the patient is still seizure-free on carbamazepine, although he is developing a spastic-dystonic tetraplegia with severe dysphagia. He harbors a de novo deletion (c.913_915del [p.Phe305del)]), only described once in a couple of severely affected twins, and leading to the deletion of a phenylalanine residue in the pore domain of the channel. In conclusion, our case is the second described with encephalopathy due to this specific deletion (the one and only deletion so far reported in KCNQ2 encephalopathy). Thus, deletion is a newly described mechanism highlighting how not only missense mutations but also deletions in the channel hot spots can lead to a severe phenotype. Furthermore he presented ictal EEG features similar to epilepsy of infancy with migrating focal seizures not previously described.


Assuntos
Epilepsia/genética , Canal de Potássio KCNQ2/genética , Encefalopatias/genética , Encefalopatias/metabolismo , Deficiências do Desenvolvimento/genética , Eletroencefalografia/métodos , Predisposição Genética para Doença/genética , Humanos , Lactente , Canal de Potássio KCNQ2/metabolismo , Masculino , Mutação de Sentido Incorreto/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Convulsões/genética , Deleção de Sequência/genética
8.
J Hum Genet ; 63(1): 9-18, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29215089

RESUMO

Benign familial epilepsies that present themselves in the first year of life include benign familial neonatal epilepsy (BFNE), benign familial neonatal-infantile epilepsy (BFNIE) and benign familial infantile epilepsy (BFIE). We used Sanger sequencing and targeted next-generation sequencing to detect gene mutations in a Chinese cohort of patients with these three disorders. A total of 79 families were collected, including 4 BFNE, 7 BFNIE, and 68 BFIE. Genetic testing led to the identification of gene mutations in 60 families (60 out of 79, 75.9%). A total of 42 families had PRRT2 mutations, 9 had KCNQ2 mutations, 8 had SCN2A mutations, and 1 had a GABRA6 mutation. In total three of four BFNE families were detected with KCNQ2 mutations. Mutations were detected in all BFNIE families, including 3 KCNQ2 mutations, 3 SCN2A mutations, and 1 PRRT2 mutation. Gene mutations were identified in 50 out of 68 BFIE families (73.5%), including 41 PRRT2 mutations (41 out of 68, 60.3%), 5 SCN2A mutations, 3 KCNQ2 mutations, and 1 GABRA6 mutation. Our results confirmed that mutations in KCNQ2, SCN2A, and PRRT2 are major genetic causes of benign familial epilepsy in the first year of life in the Chinese population. KCNQ2 is the major gene related to BFNE. PRRT2 is the main gene responsible for BFIE.


Assuntos
Epilepsia Neonatal Benigna/genética , Testes Genéticos , Canal de Potássio KCNQ2/genética , Proteínas de Membrana/genética , Mutação , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Proteínas do Tecido Nervoso/genética , Receptores de GABA-A/genética , Grupo com Ancestrais do Continente Asiático , China , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
9.
J Child Neurol ; 32(14): 1123-1124, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29129156

RESUMO

The differential diagnosis of fever-induced movement disorders in childhood is broad. Whole exome sequencing has yielded new insights into those cases with a suspected genetic basis. We report the case of an 8-year-old boy with a history of neonatal seizures who presented with near-continuous hyperkinetic movements of his limbs during a febrile illness. Initial diagnostic testing did not explain his abnormalities; however, given the suspicion for a channelopathy, whole exome sequencing was performed and it demonstrated a de novo pathogenic heterozygous variant in KCNQ2. There is an expanding phenotypic spectrum of heterozygous alterations in KCNQ2; however, this report provides the first description of a pathogenic KCNQ2 variant fever-induced hyperkinetic movement disorder in childhood. We also review the literature of cases previously published with the same pathogenic variant.


Assuntos
Saúde da Família , Febre/complicações , Canal de Potássio KCNQ2/genética , Transtornos dos Movimentos/etiologia , Transtornos dos Movimentos/genética , Mutação/genética , Criança , Eletroencefalografia , Humanos , Masculino
10.
Epilepsia ; 58(12): 2073-2084, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29067685

RESUMO

OBJECTIVE: Kv7 channels mediate the voltage-gated M-type potassium current. Reduction of M current due to KCNQ2 mutations causes early onset epileptic encephalopathies (EOEEs). Mutations in STXBP1 encoding the syntaxin binding protein 1 can produce a phenotype similar to that of KCNQ2 mutations, suggesting a possible link between STXBP1 and Kv7 channels. These channels are known to be modulated by syntaxin-1A (Syn-1A) that binds to the C-terminal domain of the Kv7.2 subunit and strongly inhibits M current. Here, we investigated whether STXBP1could prevent this inhibitory effect of Syn-1A and analyzed the consequences of two mutations in STXBP1 associated with EOEEs. METHODS: Electrophysiologic analysis of M currents mediated by homomeric Kv7.2 or heteromeric Kv7.2/Kv7.3 channels in Chinese hamster ovary (CHO) cells coexpressing Syn-1A and/or STXBP1 or mutants STXBP1 p.W28* and p.P480L. Expression and interaction of these different proteins have been investigated using biochemical and co-immunoprecipitation experiments. RESULTS: Syn-1A decreased M currents mediated by Kv7.2 or Kv7.2/Kv7.3 channels. STXBP1 had no direct effects on M current but dampened the inhibition produced by Syn-1A by abrogating Syn-1A binding to Kv7 channels. The mutation p.W28*, but not p.P480L, failed to rescue M current from Syn-1A inhibition. Biochemical analysis showed that unlike the mutation p.W28*, the mutation p.P480L did not affect STXBP1 expression and reduced the interaction of Syn-1A with Kv7 channels. SIGNIFICANCE: These data indicate that there is a functional link between STXBP1 and Kv7 channels via Syn-1A, which may be important for regulating M-channel activity and neuronal excitability. They suggest also that a defect in Kv7 channel activity or regulation could be one of the consequences of some STXBP1 mutations associated with EOEEs. Furthermore, our data reveal that STXBP1 mutations associated with the Ohtahara syndrome do not necessarily result in protein haploinsufficiency.


Assuntos
Canal de Potássio KCNQ2/genética , Proteínas Munc18/genética , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/efeitos dos fármacos , Espasmos Infantis/genética , Sintaxina 1/farmacologia , Animais , Biotinilação , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Eletroencefalografia , Humanos , Canal de Potássio KCNQ1/antagonistas & inibidores , Canal de Potássio KCNQ1/genética , Canal de Potássio KCNQ3/antagonistas & inibidores , Canal de Potássio KCNQ3/genética
12.
Neonatology ; 112(4): 387-393, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28926830

RESUMO

BACKGROUND: Recurrent and prolonged seizures are harmful for the developing brain, emphasizing the importance of early seizure recognition and effective therapy. Amplitude-integrated electroencephalography (aEEG) has become a valuable tool to diagnose epileptic seizures, and, in parallel, genetic etiologies are increasingly being recognized, changing the paradigm of the workup and management of neonatal seizures. OBJECTIVE: To report the ictal aEEG pattern in neonates with KCNQ2-related epilepsy. SUBJECTS AND METHODS: In this multicenter descriptive study, clinical data and aEEG findings of 9 newborns with KCNQ2 mutations are reported. RESULTS: Refractory seizures occurred in the early neonatal period with similar seizure type, including tonic features, apnea, and desaturation. A distinct aEEG seizure pattern, consisting of a sudden rise of the lower and upper margin of the aEEG, followed by a marked depression of the aEEG amplitude, was found in 8 of the 9 patients. Prompt recognition of this pattern led to early treatment with carbamazepine in the 2 most recent cases. CONCLUSION: Early recognition of the electroclinical phenotype by using aEEG may direct genetic testing and a precision medicine approach with sodium channel blockers in neonates with KCNQ2 mutations.


Assuntos
Ondas Encefálicas , Encéfalo/fisiopatologia , Eletroencefalografia , Doenças do Recém-Nascido/genética , Canal de Potássio KCNQ2/genética , Mutação , Convulsões/genética , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Ondas Encefálicas/efeitos dos fármacos , Carbamazepina/uso terapêutico , Análise Mutacional de DNA , Predisposição Genética para Doença , Humanos , Recém-Nascido , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/tratamento farmacológico , Doenças do Recém-Nascido/fisiopatologia , Países Baixos , Fenótipo , Portugal , Valor Preditivo dos Testes , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia , Resultado do Tratamento
13.
Proteomics ; 17(19)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28834300

RESUMO

Voltage-gated Kv7.2 potassium channels regulate neuronal excitability. The gating of these channels is tightly controlled by various mediators and neurotransmitters acting via G protein-coupled receptors; the underlying signaling cascades involve phosphatidylinositol-4,5-bisphosphate (PIP2 ), Ca2+ /calmodulin, and phosphorylation. Recent studies found that the PIP2 sensitivity of Kv7.2 channels is affected by two posttranslational modifications, phosphorylation and methylation, harboured within putative PIP2 -binding domains. In this study, we updated phosphorylation and methylation sites in Kv7.2 either heterologously expressed in mammalian cells or as GST-fusion proteins exposed to recombinant protein kinases by using LC-MS/MS. In vitro kinase assays revealed that CDK5, protein kinase C (PKC) alpha, PKA, p38 MAPK, CamKIIα, and GSK3ß could mediate phosphorylation. Taken together, we provided a comprehensive map of phosphorylation and methylation in Kv7.2 within protein-protein and protein-lipid interaction domains. This may help to interpret the functional roles of individual PTM sites in Kv7.2 channels. All MS data are available via ProteomeXchange with the identifier PXD005567.


Assuntos
Metilação de DNA , Canal de Potássio KCNQ2/metabolismo , Lipídeos/análise , Sequência de Aminoácidos , Células HEK293 , Humanos , Técnicas In Vitro , Canal de Potássio KCNQ2/genética , Fosforilação , Mapas de Interação de Proteínas , Homologia de Sequência , Transdução de Sinais , Espectrometria de Massas em Tandem
14.
Epileptic Disord ; 19(3): 351-356, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28832002

RESUMO

We report the case of an infant with KCNQ2-related neonatal epileptic encephalopathy presenting with intractable seizures beginning on the second day of life, which were resistant to multiple antiepileptic drugs. Continuous EEG recordings starting on the sixth day of life demonstrated a unique pattern of inter-and postictal focal rhythmic pointed theta waves of lambdoid morphology in the immediate postictal period, localizing to the side of the antecedent seizure. Interictal EEG exhibited discontinuous background, including patterns of burst suppression and multifocal discharges, predominantly in the centrotemporal regions, which were aggravated during sleep. MRI demonstrated T1 signal abnormalities in the basal ganglia, bilaterally. Genetic testing revealed a de novo missense mutation in KCNQ2 at position c.545 T>G, encoding a previously unreported substitution (p.Val182Gly). Seizure control was achieved immediately after starting a lidocaine infusion at age 4 weeks. The patient remained largely seizure-free following add-on oral carbamazepine for maintenance therapy and weaning off lidocaine. This is the first report of a patient with KCNQ2-related neonatal epileptic encephalopathy and therapy-refractory seizures aborted by lidocaine, demonstrating a unique EEG pattern of inter- and postictal focal rhythmic pointed theta waves. Whether this pattern could be an early EEG marker for this disorder remains to be confirmed. [Published with video sequences on www.epilepticdisorders.com].


Assuntos
Encéfalo/fisiopatologia , Canal de Potássio KCNQ2/genética , Espasmos Infantis/fisiopatologia , Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Eletroencefalografia , Feminino , Humanos , Recém-Nascido , Lidocaína/uso terapêutico , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/genética , Resultado do Tratamento
15.
Neurology ; 89(9): 893-899, 2017 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-28733343

RESUMO

OBJECTIVE: Although individual neonatal epilepsy syndromes are rare, as a group they represent a sizable subgroup of neonatal seizure etiologies. We evaluated the profile of neonatal epilepsies in a prospective cohort of newborns with seizures. METHODS: Consecutive newborns with seizures were enrolled in the Neonatal Seizure Registry (an association of 7 US children's hospitals). Treatment and diagnostic testing were at the clinicians' discretion. Neonates with seizures related to epileptic encephalopathies (without structural brain abnormalities), brain malformations, or benign familial epilepsies were included in this analysis. RESULTS: Among 611 consecutive newborns with seizures, 79 (13%) had epilepsy (35 epileptic encephalopathy, 32 congenital brain malformations, 11 benign familial neonatal epilepsy [BFNE], 1 benign neonatal seizures). Twenty-nine (83%) with epileptic encephalopathy had genetic testing and 24/29 (83%) had a genetic etiology. Pathogenic or likely pathogenic KCNQ2 variants (n = 10) were the most commonly identified etiology of epileptic encephalopathy. Among 23 neonates with brain malformations who had genetic testing, 7 had putative genetic etiologies. Six infants with BFNE had genetic testing; 3 had pathogenic KCNQ2 variants and 1 had a pathogenic KCNQ3 variant. Comorbid illnesses that predisposed to acute symptomatic seizures occurred in 3/35 neonates with epileptic encephalopathy vs 10/32 with brain malformations (p = 0.03). Death or discharge to hospice were more common among newborns with brain malformations (11/32) than those with epileptic encephalopathy (3/35, p = 0.01). CONCLUSIONS: Neonatal epilepsy is often due to identifiable genetic causes. Genetic testing is now warranted for newborns with epilepsy in order to guide management and inform discussions of prognosis.


Assuntos
Epilepsia/epidemiologia , Encéfalo/anormalidades , Encéfalo/fisiopatologia , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Hospitais Pediátricos , Humanos , Recém-Nascido , Canal de Potássio KCNQ2/genética , Canal de Potássio KCNQ3/genética , Masculino , Estudos Prospectivos , Sistema de Registros , Convulsões/diagnóstico por imagem , Convulsões/epidemiologia , Convulsões/genética , Convulsões/fisiopatologia , Centros de Atenção Terciária , Estados Unidos/epidemiologia
17.
Epilepsia ; 58(8): 1430-1439, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28575529

RESUMO

OBJECTIVE: Mutations of the KCNQ2 gene, which encodes the Kv 7.2 subunit of voltage-gated M-type potassium channels, have been associated with epilepsy in the neonatal period. This developmental stage is unique in that the neurotransmitter gamma aminobutyric acid (GABA), which is inhibitory in adults, triggers excitatory action due to a reversed chloride gradient. METHODS: To examine whether KCNQ2-related neuronal hyperexcitability involves neonatally excitatory GABA, we examined 1-week-old knockin mice expressing the Kv 7.2 variant p.Tyr284Cys (Y284C). RESULTS: Brain slice electrophysiology revealed elevated CA1 hippocampal GABAergic interneuron activity with respect to presynaptic firing and postsynaptic current frequency. Blockade with the GABAA receptor antagonist bicuculline decreased ictal-like bursting in brain slices with lowered divalent ion concentration, which is consistent with GABA mediating an excitatory function that contributes to the hyperexcitability observed in mutant animals. SIGNIFICANCE: We conclude that excitatory GABA contributes to the phenotype in these animals, which raises the question of whether this special type of neurotransmission has broader importance in neonatal epilepsy than is currently recognized.


Assuntos
Epilepsia/genética , Epilepsia/metabolismo , Canal de Potássio KCNQ2/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Transmissão Sináptica/genética , Ácido gama-Aminobutírico/metabolismo , Animais , Animais Recém-Nascidos , Biofísica , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Modelos Animais de Doenças , Estimulação Elétrica , GABAérgicos/farmacologia , Técnicas In Vitro , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/genética , Interneurônios/efeitos dos fármacos , Interneurônios/fisiologia , Magnésio/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Patch-Clamp , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia
18.
Am J Med Genet A ; 173(8): 2226-2230, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28602030

RESUMO

KCNQ2 has been reported as a frequent cause of autosomal dominant benign familial neonatal seizures. De novo likely pathogenic variants in KCNQ2 have been described in neonatal or early infantile onset epileptic encephalopathy patients. Here, we report a three-generation family with six affected patients with a novel likely pathogenic variant (c.628C>T; p.Arg210Cys) in KCNQ2. Four family members, three adults and a child, presented with a childhood seizure onset with variability in the severity of seizures and response to treatment, intellectual disability (ID) as well as behavioral problems. The two youngest affected patients had a variable degree of global developmental delay with no seizures at their current age. This three-generation family with six affected members expands the phenotypic spectrum of KCNQ2 associated encephalopathy to KCNQ2 associated ID and or childhood onset epileptic encephalopathy. We think that KCNQ2 associated epileptic encephalopathy should be included in the differential diagnosis of childhood onset epilepsy and early onset global developmental delay, cognitive dysfunction, or ID. Furthermore, whole exome sequencing in families with ID and history of autosomal dominant inheritance pattern with or without seizures, may further broaden the phenotypic spectrum of KCNQ2 associated epileptic encephalopathy or encephalopathy.


Assuntos
Deficiência Intelectual/genética , Canal de Potássio KCNQ2/genética , Convulsões/genética , Espasmos Infantis/genética , Adulto , Idoso , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Convulsões/fisiopatologia , Espasmos Infantis/fisiopatologia
19.
Neuropediatrics ; 48(3): 199-204, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28420012

RESUMO

Mutations in KCNQ2, encoding for subunits of potassium channels, are known to cause neonatal epileptic encephalopathy (NEE). Therapeutic options for these children are often limited. Recently, there are indications that some patients with KCNQ2 NEE show seizure response to vitamin B6 (VB6) therapy. We present a young infant with severe KCNQ2 encephalopathy resulting from a novel de novo mutation (c.1023G>C; p.(Gln341His)). In our patient, VB6 responsiveness could be demonstrated clearly by remarkable seizure-response to VB6 therapy and seizure exacerbation to discontinuation of VB6 therapy. The pathophysiology of VB6 response in potassium channel mutations is not understood. Some hypothetical mechanisms are currently in discussion. To identify the group of patients who benefits from VB6 therapy, further investigations are necessary.


Assuntos
Epilepsia/tratamento farmacológico , Epilepsia/genética , Canal de Potássio KCNQ2/genética , Fosfato de Piridoxal/uso terapêutico , Vitamina B 6/uso terapêutico , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Mutação , Convulsões/tratamento farmacológico , Convulsões/genética , Convulsões/fisiopatologia
20.
Biomed Mater Eng ; 28(s1): S243-S253, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28372301

RESUMO

BACKGROUND: KCNQ2 plays a key role in the regulation of neuronal excitability. The R214W and Y284C mutants of KCNQ2 channels, which are associated with BFNC, can decrease channel function to cause neuronal hyperexcitability and promote seizures. Previous studies revealed that elevated temperature caused up-regulation of KCNQ2 expression. OBJECTIVE: The present study sought to investigate the impact of temperature elevation on neuronal KCNQ2 ion channel mutants. METHODS: Protein expression of wt KCNQ2 and the R214W, Y284C and truncated selective filter mutants at different temperatures was detected by live-cell confocal fluorescence microscopy and by Western blotting. Whole-cell patch clamp was performed to record the effect of temperature on the electrophysiological activity of KCNQ2 channels. RESULTS: Temperature elevation caused an unexpected increase in voltage-dependent KCNQ2 channel activation but also increased the endoplasmic reticulum (ER) retention of KCNQ2 protein, and the ER retention was greater for mutants associated with BFNC than for wt KCNQ2. Temperature elevation did not increase the fluorescence intensity of cells transfected with a truncated selective filter mutant. CONCLUSIONS: The direct effect of heat on KCNQ2 channels may be involved in excitability regulation of neurons, and the P-loop region is critical for temperature-dependent modulation of the expression and trafficking of KCNQ2 channels.


Assuntos
Retículo Endoplasmático/metabolismo , Canal de Potássio KCNQ2/genética , Canal de Potássio KCNQ2/metabolismo , Retículo Endoplasmático/genética , Células HEK293 , Temperatura Alta , Humanos , Canal de Potássio KCNQ2/análise , Mutação Puntual , Transporte Proteico , Temperatura Ambiente
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