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1.
Epilepsy Behav ; 98(Pt A): 19-26, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31299528

RESUMO

OBJECTIVES: The objective of this study was to evaluate the Neurological Disorders Depression Inventory-Epilepsy (NDDI-E) for Youth (NDDI-E-Y) for screening for major depressive disorder (MDD) in French youth with epilepsy (YWE), in order to (1) validate this tool in a separate population; (2) determine whether the 12-item NDDI-E-Y affords advantages over the 6-item adult NDDI-E; (3) measure psychometric performance of each item. METHODS: Youth with epilepsy aged 11-17 years completed a 15-item questionnaire to calculate total scores for NDDI-E-Y (12 items) and NDDI-E (6 items). Gold standard for MDD was Children's Depression Inventory (CDI). Receiver operator characteristic (ROC) analyses for total NDDI-E-Y and NDDI-E scores were compared. Psychometric properties of each item were analyzed for: floor/ceiling effect, item-internal consistency, and ROC curve. RESULTS: Ninety-seven YWE were included; 21.6% had MDD (CDI > 15). Correlation was very high between total NDDI-E-Y and NDDI-E scores, and high between NDDI-E-Y and CDI. Cutoff point for the NDDI-E-Y maximizing both sensitivity and specificity was 23 (original study cutoff 32). The ROC analysis of the NDDI-E-Y showed an area under the curve (AUC) 0.967 (95% confidence intervals [CI] 0.909-0.992); (p < 0.0001). Sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) were 100% [83.9; 100], 82.9% [72.5; 90.6], 61.8 [43.6; 77.8], and 100% [94.3; 100], respectively. The NDDI-E-Y was not superior to NDDI-E according to pairwise comparison of ROC (p = 0.07). Psychometric analysis revealed marked differences between items. After eliminating items with poorer performance, a 6-item version of the NDDI-E-Y showed sensitivity, specificity, PPV, and NPV of 100% [85.5; 100], 85.5% [75.6; 92.5], 65.6 [46.8; 81.4], and 100% [94.5; 100], respectively. This was significantly better than the adult NDDI-E (p = 0.03) though not NDDI-E-Y (p = 0.07). SIGNIFICANCE: Significant difference in cutoff indicates that the NDDI-E-Y cannot yet be recommended for widespread screening of MDD in YWE. Discrepancies in psychometric performance between items suggest that further work is needed to examine both validation of the original 12-item NDDI-E-Y and comparison with a shorter version.

2.
J Neurol ; 266(8): 1907-1918, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31055634

RESUMO

OBJECTIVE: We aimed to assess stereoelectroencephalography (SEEG) seizure-onset and interictal patterns associated with MRI-negative epilepsy and investigate their possible links with histology, extent of the epileptogenic zone (EZ) and surgical outcome. METHODS: We retrospectively analysed a cohort of 59 consecutive MRI-negative surgical candidates, who underwent SEEG recordings followed by cortectomy between 2000 and 2016. RESULTS: Most of the eight distinct seizure-onset patterns could be encountered both in confirmed focal cortical dysplasia (FCD) and in histologically non-specific or normal cases. We found strong correlation (p = 0.008) between seizure-onset pattern and histology for: (1) slow-wave/DC-shift prior to low voltage fast activity (LVFA), associated with normal/non-specific histology, and (2) bursts of polyspikes prior to LVFA, exclusively observed in FCD. Three interictal patterns were identified: periodic slow-wave/gamma burst, sub-continuous rhythmic spiking and irregular spikes. Both "periodic" patterns were more frequent in but not specific to FCD. Surgical outcome depended on the EZ complete removal, regardless electrophysiological features. CONCLUSIONS: Histologically normal and FCD-associated epileptogenic zones share distinct interictal and ictal electrophysiological phenotypes, with common patterns between FCD subtypes and between dysplastic and apparently normal brain. SIGNIFICANCE: Some specific seizure-onset patterns seem to be predictive of the underlying histology and may help to detect an MRI-invisible FCD.

3.
Epilepsia ; 60(5): 845-856, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31026061

RESUMO

OBJECTIVE: To describe the mode of onset of SCN8A-related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers. METHODS: We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy-associated missense variant localization over the protein. RESULTS: We found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic-clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep-related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases. SIGNIFICANCE: SCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy.

4.
Genet Med ; 21(7): 1667-1671, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30783266

RESUMO

The article has been corrected to account for one patient being investigated through genome sequencing rather than exome sequencing as originally published; thus amendments to the Abstract and Methods have been made as well as addition of the relevant authors and acknowledgment.

5.
Epilepsia ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30426477

RESUMO

OBJECTIVE: In this study, we seek to analyze the determinants of the intracranial electroencephalography seizure onset pattern (SOP) and the impact of the SOP in predicting postsurgical seizure outcome. METHODS: To this end, we analyzed 820 seizures from 252 consecutive patients explored by stereo-electroencephalography (total of 2148 electrodes), including various forms of focal refractory epilepsies. We used a reproducible method combining visual and time-frequency analyses. RESULTS: We described eight SOPs: low-voltage fast activity (LVFA), preictal spiking followed by LVFA, burst of polyspikes followed by LVFA, slow wave/DC shift followed by LVFA, sharp theta/alpha waves, beta sharp waves, rhythmic spikes/spike-waves, and delta-brush. LVFA occurred in 79% of patients. The seizure onset pattern was significantly associated with (1) underlying etiology (burst of polyspikes followed by LVFA with the presence of a focal cortical dysplasia, LVFA with malformation of cortical development, postvascular and undetermined epilepsies), (2) spatial organization of the epileptogenic zone (EZ; burst of polyspikes followed by LVFA with focal organization, slow wave/DC shift followed by LVFA with network organization), and (3) postsurgical seizure outcome (better outcome when LVFA present). SIGNIFICANCE: This study demonstrates that the main determinants of the SOP are the underlying etiology and the spatial organization of the EZ. Concerning the postsurgical seizure outcome, the main determinant factor is the spatial organization of the EZ, but the SOP plays also a role, conferring better prognosis when LVFA is present.

7.
Genet Med ; 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30356099

RESUMO

PURPOSE: Germline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations. METHODS: We report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing). RESULTS: Two copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes. CONCLUSION: Germline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.

8.
Cereb Cortex ; 2018 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-30295710

RESUMO

Epilepsy is a multifactorial disorder associated with neuronal hyperexcitability that affects more than 1% of the human population. It has long been known that adenosine can reduce seizure generation in animal models of epilepsies. However, in addition to various side effects, the instability of adenosine has precluded its use as an anticonvulsant treatment. Here we report that a stable analogue of diadenosine-tetraphosphate: AppCH2ppA effectively suppresses spontaneous epileptiform activity in vitro and in vivo in a Tuberous Sclerosis Complex (TSC) mouse model (Tsc1+/-), and in postsurgery cortical samples from TSC human patients. These effects are mediated by enhanced adenosine signaling in the cortex post local neuronal adenosine release. The released adenosine induces A1 receptor-dependent activation of potassium channels thereby reducing neuronal excitability, temporal summation, and hypersynchronicity. AppCH2ppA does not cause any disturbances of the main vital autonomous functions of Tsc1+/- mice in vivo. Therefore, we propose this compound to be a potent new candidate for adenosine-related treatment strategies to suppress intractable epilepsies.

10.
Genet Med ; 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30206421

RESUMO

PURPOSE: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. METHODS: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. RESULTS: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. CONCLUSION: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.

11.
J Neurosurg Pediatr ; : 1-9, 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30141751

RESUMO

OBJECTIVE Hemispherotomy is currently the most frequently performed surgical option for refractory epilepsy associated with large perinatal or childhood ischemic events. Such an approach may lead to good seizure control, but it has inherent functional consequences linked to the disconnection of functional cortices. The authors report on 6 consecutive patients who presented with severe epilepsy associated with hemiplegia due to stroke and who benefitted from a new, stereoelectroencephalography-guided partial disconnection technique. METHODS The authors developed a new disconnection technique termed "tailored suprainsular partial hemispherotomy" (TSIPH). Disconnection always included premotor and motor cortex with variable anterior and posterior extent. RESULTS At a mean follow-up of 28 months, there were no deaths and no patient had hydrocephalus. Motor degradation was observed in all patients in the 2 weeks after surgery, but all patients completely recovered. The 6 patients were seizure free (Engel class IA) at the last follow-up. No neuropsychological aggravation was observed. CONCLUSIONS TSIPH appears to be a conservative alternative to classic hemispherotomy, leading to favorable outcome in this series.

12.
Brain ; 141(10): 2966-2980, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30107499

RESUMO

Drug-refractory focal epilepsies are network diseases associated with functional connectivity alterations both during ictal and interictal periods. A large majority of studies on the interictal/resting state have focused on functional MRI-based functional connectivity. Few studies have used electrophysiology, despite its high temporal capacities. In particular, stereotactic-EEG is highly suitable to study functional connectivity because it permits direct intracranial electrophysiological recordings with relative large-scale sampling. Most previous studies in stereotactic-EEG have been directed towards temporal lobe epilepsy, which does not represent the whole spectrum of drug-refractory epilepsies. The present study aims at filling this gap, investigating interictal functional connectivity alterations behind cortical epileptic organization and its association with post-surgical prognosis. To this purpose, we studied a large cohort of 59 patients with malformation of cortical development explored by stereotactic-EEG with a wide spatial sampling (76 distinct brain areas were recorded, median of 13.2 per patient). We computed functional connectivity using non-linear correlation. We focused on three zones defined by stereotactic-EEG ictal activity: the epileptogenic zone, the propagation zone and the non-involved zone. First, we compared within-zone and between-zones functional connectivity. Second, we analysed the directionality of functional connectivity between these zones. Third, we measured the associations between functional connectivity measures and clinical variables, especially post-surgical prognosis. Our study confirms that functional connectivity differs according to the zone under investigation. We found: (i) a gradual decrease of the within-zone functional connectivity with higher values for epileptogenic zone and propagation zone, and lower for non-involved zones; (ii) preferential coupling between structures of the epileptogenic zone; (iii) preferential coupling between epileptogenic zone and propagation zone; and (iv) poorer post-surgical outcome in patients with higher functional connectivity of non-involved zone (within- non-involved zone, between non-involved zone and propagation zone functional connectivity). Our work suggests that, even during the interictal state, functional connectivity is reinforced within epileptic cortices (epileptogenic zone and propagation zone) with a gradual organization. Moreover, larger functional connectivity alterations, suggesting more diffuse disease, are associated with poorer post-surgical prognosis. This is consistent with computational studies suggesting that connectivity is crucial in order to model the spatiotemporal dynamics of seizures.10.1093/brain/awy214_video1awy214media15833456182001.

13.
Genet Med ; 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-29997391

RESUMO

PURPOSE: To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes. METHODS: Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes. RESULTS: We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant. CONCLUSION: Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).

14.
Brain Dev ; 40(9): 768-774, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29861155

RESUMO

OBJECTIVE: Heterozygous mutations in the ATP1A3 gene are responsible for various neurological disorders, ranging from early-onset alternating hemiplegia of childhood to adult-onset dystonia-parkinsonism. Next generation sequencing allowed the description of other phenotypes, including early-onset epileptic encephalopathy in two patients. We report on three more patients carrying ATP1A3 mutations with a close phenotype and discuss the relationship of this phenotype to alternating hemiplegia of childhood. METHODS: The patients' DNA underwent next generation sequencing. A retrospective analysis of clinical case records is reported. RESULTS: Each of the three patients had an unreported heterozygous de novo sequence variant in ATP1A3. These patients shared a similar phenotype characterized by early-onset attacks of movement disorders, some of which proved to be epileptic, and severe developmental delay. (Hemi)plegic attacks had not been considered before genetic testing. SIGNIFICANCE: Together with the two previously reported cases, our patients confirm that ATP1A3 mutations are associated with a phenotype combining features of early-onset encephalopathy, epilepsy and dystonic fits, as in the most severe forms of alternating hemiplegia of childhood, but in which (hemi)plegic attacks are absent or only suspected retrospectively.


Assuntos
Epilepsia/genética , Transtornos dos Movimentos/genética , Mutação , Convulsões/genética , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Feminino , Hemiplegia/genética , Hemiplegia/fisiopatologia , Humanos , Masculino , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/fisiopatologia , Convulsões/diagnóstico , Convulsões/fisiopatologia
15.
Epilepsia ; 59(6): 1188-1197, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29727013

RESUMO

OBJECTIVE: The present analysis examined the exposure-response relationship by means of the predose everolimus concentration (Cmin ) and the seizure response in patients with tuberous sclerosis complex-associated seizures in the EXIST-3 study. Recommendations have been made for the target Cmin range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target Cmin . METHODS: A model-based approach was used to predict patients' daily Cmin . Time-normalized Cmin (TN-Cmin ) was calculated as the average predicted Cmin in a time interval. TN-Cmin was used to link exposure to efficacy and safety end points via model-based approaches. A conditional logistic regression stratified by age subgroup was used to estimate the probability of response in relation to exposure. A multiplicative linear regression model was used to estimate the exposure-response relationship for seizure frequency (SF). An extended Cox regression model was used to link exposure to the time to first adverse event. RESULTS: There was a strong, consistent, and highly significant relationship between everolimus exposure and efficacy, measured by TN-Cmin and SF, regardless of patient's age and concomitant use of cytochrome P450 3A4 (CYP3A4) inhibitors/inducers. Results of an extended Cox regression analyses indicated that twofold increases in TN-Cmin were not associated with statistically significant increases in the risk of stomatitis or infections. SIGNIFICANCE: The recommended TDM is to target everolimus Cmin within a range of 5-7 ng/mL initially and 5-15 ng/mL in the event of an inadequate clinical response, and safety is consistent with previous reports. Starting doses depend on age and the concomitant use of CYP3A4/P-glycoprotein inducers/inhibitors.

16.
Hum Mutat ; 39(7): 934-938, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29663568

RESUMO

Early myoclonic epilepsy (EME) or Aicardi syndrome is one of the most severe epileptic syndromes affecting neonates. We performed whole exome sequencing in a sporadic case affected by EME and his parents. In the proband, we identified a homozygous missense variant in the ubiquitin-like modifier activating enzyme 5 (UBA5) gene, encoding a protein involved in post-translational modifications. Functional analysis of the UBA5 variant protein reveals that it is almost completely unable to perform its trans-thiolation activity. Although recessive variants in UBA5 have recently been associated with epileptic encephalopathy, variants in this gene have never been reported to cause EME. Our results further demonstrate the importance of post-translational modifications such as the addition of an ubiquitin-fold modifier 1 (UFM1) to target proteins (ufmylation) for normal neuronal networks activity, and reveal that the dysfunction of the ubiquitous UBA5 protein is a cause of EME.

17.
Epilepsy Behav ; 81: 86-93, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29526579

RESUMO

Management of patients after initial epilepsy surgical failure is challenging. In this study, we report our experience in using the stereoelectroencephalography (SEEG) method in the reevaluation of patients after initial epilepsy surgical failure. We selected 28 patients examined through SEEG in our department for drug-resistant focal epilepsy following initial epilepsy surgical failure. For each patient, the residual seizure onset zone (rSOZ) as defined by SEEG was classified as either contiguous if the seizure onset zone (SOZ) was focal and close to the surgical cavity (same lobe) or noncontiguous in cases where the SOZ included site(s) distant from the surgical cavity. The rSOZ was defined according to visual analysis of SEEG traces completed by an estimation of the epileptogenicity index (EI). A second surgical procedure was performed in 12 patients (45%). A favorable outcome (Engel class I or II) was obtained in 9/12 patients (6 in Engel class I, 50%). The proportion of patients that had reoperation was higher in the contiguous group (80%) than in the noncontiguous group (22%) (p=0.02). A rSOZ localized in close relation to the initial surgical resection zone (contiguous group) was found in 10 patients (35%). Among them, 8 have since undergone reoperation, and a good outcome (Engel class I) was achieved in 5/8 (63%). A rSOZ involving a distant region from the first surgery was observed in 18 patients (65%) (noncontiguous group). Among them, only 4 have undergone reoperation, leading to a failure in 2 (Engel class III or IV) and a good outcome in 2 (IA). Ten patients had a first standard temporal lobectomy, and in 50% of these cases, the insula was involved in the rSOZ. Stereoelectroencephalography offers a unique way to evaluate the rSOZ at the individual level and thus guide further surgical decision-making. The best results are observed in patients having a focal rSOZ close to the site of the surgical resection in the first surgery.

19.
Semin Cell Dev Biol ; 76: 120-129, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28899717

RESUMO

Early development of somatotopic cortical maps occurs during the fetal period in humans and during the postnatal period in rodents. During this period, the sensorimotor cortex expresses transient patterns of correlated neuronal activity including delta waves, gamma- and spindle-burst oscillations. These early activity patterns are largely driven by the thalamus and triggered, in a topographic manner, by sensory feedback resulting from spontaneous movements. Early cortical activities are instrumental for competitive interactions between sensory inputs for the cortical territories, they prevent cortical neurons from apoptosis and their alteration may lead to disturbances in cortical network development in a number of neurodevelopmental diseases.


Assuntos
Neurônios/fisiologia , Córtex Somatossensorial/embriologia , Humanos , Córtex Somatossensorial/fisiologia
20.
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
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