Novel variant in CHRNA4 with benign childhood epilepsy with centrotemporal spikes and contribution to precise medicine.
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ABSTRACT: Background
Benign childhood epilepsy with centrotemporal spikes (BECTS) or benign rolandic epilepsy is the most common epileptic syndrome in school-age children. Genetics is an important factor in BECTS pathogenesis, and <10 genes were associated with BECTS. This study aimed to identify novel genetic causes of BECTS.Methods
We conducted whole-exome sequencing on a patient with BECTS and validated the findings by Sanger sequencing in a pedigree with three patients.Results
CHRNA4 c.1007G>A was identified in three patients with BECTS in a pedigree. Carbamazepine, which should be carefully used in BECTS, was observed to be effective in the treatment of our atypical BECTS proband based on the molecular diagnosis of CHRNA4.Conclusion
This is the first study on CHRNA4 variant in BECTS, which widened the genetic spectrum of BECTS and contributed to precise medicine in BECTS.
SUBMITTER: Neng X
PROVIDER: S-EPMC7336761 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
Publications
Novel variant in CHRNA4 with benign childhood epilepsy with centrotemporal spikes and contribution to precise medicine.
Neng Xiao X Xiao Mao M Yuanlu Chen C Qinyan Li L Li Shu S Zhanyi Song S
Molecular genetics & genomic medicine 20200428 7
<h4>Background</h4>Benign childhood epilepsy with centrotemporal spikes (BECTS) or benign rolandic epilepsy is the most common epileptic syndrome in school-age children. Genetics is an important factor in BECTS pathogenesis, and <10 genes were associated with BECTS. This study aimed to identify novel genetic causes of BECTS.<h4>Methods</h4>We conducted whole-exome sequencing on a patient with BECTS and validated the findings by Sanger sequencing in a pedigree with three patients.<h4>Results</h4> ...[more]
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Project description:Epilepsy is a neurological disorder characterized by abnormal electrical discharges in a group of brain cells. Benign childhood epilepsy, which affect children under the age of 12 years, has been reported to contribute to the cognitive impairment of these children, even in the absence of structural abnormalities. Functional connectivity models have been applied to provide a deeper understanding of the processes that control and regulate interictal activity of benign childhood epilepsy. These studies have shown regions of increased connectivity and activity, particularly at the epileptic zone, which is usually the central region around the sensorimotor cortex, and in the immediate regions surrounding the zone and reduced activity in distant regions, such as the frontal lobe and temporal regions. The present study was designed to identify the neural drivers involved in the initiation and propagation of epileptic activity and the causal relationships between brain regions with increased and decreased connectivity and functional activity. We used three different models to identify neural drivers and casual connectivity with dynamic causal modelling (DCM) of EEG data. All models showed that the central region, the source of the epileptic activity, is the major driver of the brain network during interictal discharges. Other regions include the temporoparietal junction and temporal pole. The central region also had influence on the frontal and contralateral hemisphere, which might explain the cognitive deficits observed in these patients.
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Project description:Background and Purpose: To date, there is no specific treatment guideline for the benign childhood epilepsy with centrotemporal spikes (BECTS). Several countries recommend levetiracetam, carbamazepine, sodium valproate, oxcarbazepine, and lamotrigine as first-line drugs. Nevertheless, some of these drugs are associated with cognitive decline. Available studies that investigated the efficacy of levetiracetam and sodium valproate on BECTS involved small sample sizes. This study aimed to evaluate the efficacy of levetiracetam and sodium valproate on cognition, and to investigate the prognostic factors for BECTS as whole. Methods: Clinical data and treatment status of all patients with BECTS at Xiangya Hospital, Central South University followed from 2008 to 2013 were analyzed retrospectively. Since electrical status epilepticus in sleep (ESES) has been confirmed to play a role in cognitive deterioration, in order to evaluate the response to drugs and their cognitive effects, we created two groups of patients according to the levels of spike wave index (SWI): group 1; 0-50% SWI and group 2; >50% SWI at the last follow up. Results: A total of 195 cases were enrolled: 49.7% received monotherapies, 24.1% duotherapies and 27.2% polytherapies. Medications included; levetiracetam plus other drug (s) (75.9%), levetiracetam alone (32.8%), sodium valproate plus other drug (s) (31.3%), and sodium valproate alone (5.1%). After 2 years of treatment and follow up, 71% of the cases had a good seizure outcome, 15.9% had an improvement of SWI, and 91.7% had a normal DQ/IQ. Sodium valproate combined with levetiracetam, and sodium valproate alone correlated with good improvement of SWI, whereas, focal spikes were linked with poor improvement. For both groups (group 1 and group 2): monotherapy, levetiracetam alone, and a normal DQ/IQ at seizure onset correlated with good cognitive outcomes, in contrast, polytherapy, sodium valproate plus other drug (s), levetiracetam plus sodium valproate, an initial SWI of ≥85%, and multifocal spikes were linked to cognitive deterioration. Conclusions: Monotherapy, particularly levetiracetam seems to be a good first-line therapy which can help in normalizing the electroencephalograph and preventing cognitive decline. Polytherapy, mostly the administration of sodium valproate seems to relate with poor cognition, therefore, it is recommended to avoid it.
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Project description:ObjectiveBenign Childhood Epilepsy with Centrotemporal Spikes (BECTS) and Childhood Absence Epilepsy (CAE) are the most common childhood epilepsy syndromes and they share a similar age-dependence. However, the two syndromes clearly differ in seizures and EEG patterns. The aim of this study is to investigate whether children of the same age with BECTS, CAE and typically-developing children have significant differences in grey matter volume that may underlie the different profiles of these syndromes.MethodsTwenty one patients with newly-diagnosed BECTS and 18 newly diagnosed and drug naïve CAE were included and compared to 31 typically-developing children. Voxel-based morphometry was utilized to investigate grey matter volume differences among BECTS, CAE, and controls. We also examined the effect of age on grey matter volume in all three groups. In addition to the whole brain analysis, we chose regions of interest analysis based on previous literature suggesting the involvement of these regions in BECTS or CAE. The group differences of grey matter volume was tested with 2-sample t-test for between two groups' comparisons and ANOVA for three group comparisons.ResultsIn the whole brain group comparisons, the grey matter volume in CAE was significantly decreased in the areas of right inferior frontal and anterior temporal compared to BECTS and controls (F2,67 = 27.53, p < 0.001). In the control group, grey matter volume in bifrontal lobes showed a negative correlation with age (r=-0.54, p < 0.05), whereas no correlation was found in either CAE or BECTS. With ROI analyses, the grey matter volume of posterior thalami was increased in CAE compared to other 2 groups (p < 0.05).SignificanceThis study shows that there are grey matter volume differences between CAE and BECTS. Our findings of grey matter volume differences may suggest that there may be localized, specific differences in brain structure between these two types of epilepsy.
| S-EPMC7494623 | biostudies-literature
Project description:Benign childhood epilepsy with centrotemporal spikes (BECTS) is associated with cognitive and language problems. According to recent studies, disruptions in brain structure and function in children with BECTS are beyond a Rolandic focus, suggesting atypical cortical development. However, previous studies utilizing surface-based metrics (e.g., cortical gyrification) and their structural covariance networks at high resolution in children with BECTS are limited. Twenty-six children with BECTS (15 males/11 females; 10.35 ± 2.91 years) and 26 demographically matched controls (15 males/11 females; 11.35 ± 2.51 years) were included in this study and subjected to high-resolution structural brain MRI scans. The gyrification index was calculated, and structural brain networks were reconstructed based on the covariance of the cortical folding. In the BECTS group, significantly increased gyrification was observed in the bilateral Sylvain fissures and the left pars triangularis, temporal, rostral middle frontal, lateral orbitofrontal, and supramarginal areas (cluster-corrected p < 0.05). Global brain network measures were not significantly different between the groups; however, the nodal alterations were most pronounced in the insular, frontal, temporal, and occipital lobes (FDR corrected, p < 0.05). In children with BECTS, brain hubs increased in number and tended to shift to sensorimotor and temporal areas. Furthermore, we observed significantly positive relationships between the gyrification index and age (vertex p < 0.001, cluster-level correction) as well as duration of epilepsy (vertex p < 0.001, cluster-level correction). Our results suggest that BECTS may be a condition that features abnormal over-folding of the Sylvian fissures and uncoordinated development of structural wiring, disrupted nodal profiles of centrality, and shifted hub distribution, which potentially represents a neuroanatomical hallmark of BECTS in the developing brain.
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Project description:ObjectiveTo describe the natural history of electroencephalography (EEG) changes in patients with benign epilepsy with centrotemporal spikes (BECTS) over 1 year.MethodsCentrotemporal spikes were visually evaluated based on 24-h ambulatory EEG studies to determine the total, left, right, and bilateral centrotemporal spikes patients were awake and asleep. These spike rates were then used to compare the entire night of sleep to the first 2 h of sleep, the repeatability of spike frequency over two recordings (done within days to weeks), and longitudinal changes in spike rate over 6 and 12 months.ResultsNineteen children with newly diagnosed and untreated BECTS were included in this analysis. An excellent correlation was found between the centrotemporal spike rate during the entire duration of sleep and the first 2 h of sleep (intraclass correlation [ICC] 0.87, 95% confidence interval [CI] 0.67-0.95). In addition, an excellent correlation was found between two recordings completed an average of 23 days apart while patients were asleep (ICC 0.92, 95% CI 0.80-0.97) and good correlation while patients were awake (ICC 0.70, 95% CI 0.39-0.87). The average change in spike rate between recordings at baseline and at 6 months was a decrease of 64.7% (range -100% to +51.5%, p = 0.01) and the average change in rate between recordings at baseline and at 12 months was a decrease of 57.7% (range -100% to +29.1%, p = 0.01). In addition, within 6 months, most children had decreased centrotemporal rates, with 30% of children being spike-free. This absence of spikes did not continue in all children, since the majority (60%) had some spikes at 1 year following diagnosis.SignificanceCentrotemporal spike rates during sleep are stable when compared over days to weeks; however, when comparing spike rates over months there is a larger degree of variability.
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Project description:BackgroundThe study aimed to explore cortical morphology in benign childhood epilepsy with centrotemporal spikes (BECTS) and the relationship between cortical characteristics and age of onset and intelligence quotient (IQ).MethodsCortical morphometry with surface-based morphometry (SBM) was used to compare changes in cortical thickness, gyrification, sulcal depth, and fractal dimension of the cerebral cortex between 25 BECTS patients and 20 healthy controls (HCs) with two-sample t-tests [P<0.05, family-wise error (FWE) corrected]. Relationships between abnormal cortical morphological changes and age of onset and IQ, which included verbal intelligence quotient (VIQ), performance intelligence quotient (PIQ), and full-scale intelligence quotient (FIQ) were investigated with Spearman correlation analysis (P<0.05, uncorrected).ResultsThe BECTS patients showed extensive cortical thinning predominantly in bilateral frontal, temporal regions, and limbic system. Cortical gyrification increased in the left hemisphere and partial right hemisphere, and the decreased cortical gyrification was only in the left hemisphere. The increased sulcal depth was the left fusiform gyrus. There are no statistically significant differences in the fractal dimension. Correlation analysis revealed the negative correlation between age of onset and cortical thickness in the right precentral gyrus. It also revealed the negative correlation between the age of onset and cortical gyrification in the left inferior parietal gyrus. Also, there was negative correlation between VIQ and cortical gyrification in the left supramarginal gyrus of BECTS patients.ConclusionsThis study reveals aberrant cortical thickness, cortical gyrification, and sulcal depth of BECTS in areas related to cognitive functions including language, attention and memory, and the correlation between some brain regions and VIQ and age of onset, providing a potential marker of early neurodevelopmental disturbance and cognitive dysfunction in BECTS.
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Project description:BACKGROUND AND PURPOSE:Benign childhood epilepsy with centrotemporal spikes (BECTS) does not always have a benign cognitive outcome. We investigated the relationship between cognitive performance and altered functional connectivity (FC) in the resting-state brain networks of BECTS patients. METHODS:We studied 42 subjects, comprising 19 BECTS patients and 23 healthy controls. Cognitive performance was assessed using the Korean version of the Wechsler Intelligence Scale for Children-III, in addition to verbal and visuospatial memory tests and executive function tests. Resting-state functional magnetic resonance imaging was acquired in addition to high-resolution structural data. We selected Rolandic and language-related areas as regions of interest (ROIs) and analyzed the seed-based FC to voxels throughout the brain. We evaluated the correlations between the neuropsychological test scores and seed-based FC values using the same ROIs. RESULTS:The verbal intelligence quotient (VIQ) and full-scale intelligence quotient (FSIQ) were lower in BECTS patients than in healthy controls (p<0.001). The prevalence of subjects with a higher performance IQ than VIQ was significantly higher in BECTS patients than in healthy controls (73.7% vs. 26.1%, respectively; p=0.002). Both the Rolandic and language-related ROIs exhibited more enhanced FC to voxels in the left inferior temporal gyrus in BECTS patients than in healthy controls. A particularly interestingly finding was that the enhanced FC was correlated with lower cognitive performance as measured by the VIQ and the FSIQ in both patients and control subjects. CONCLUSIONS:Our findings suggest that the FC alterations in resting-state brain networks related to the seizure onset zone and language processing areas could be related to adaptive plasticity for coping with cognitive dysfunction.
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Project description:ObjectiveBenign childhood epilepsy with centrotemporal spikes (BECTS) affects brain network hierarchy and cognitive function; however, itremainsunclearhowhierarchical changeaffectscognition in patients with BECTS. A major aim of this study was to examine changes in the macro-network function hierarchy in BECTS and its potential contribution to cognitive function.MethodsOverall, the study included 50 children with BECTS and 69 healthy controls. Connectome gradient analysis was used to determine the brain network hierarchy of each group. By comparing gradient scores at each voxel level and network between groups, we assessed changes in whole-brain voxel-level and network hierarchy. Functional connectivity was used to detect the functional reorganization of epilepsy caused by these abnormal brain regions based on these aberrant gradients. Lastly, we explored the relationships between the change gradient and functional connectivity values and clinical variables and further predicted the cognitive function associated with BECTS gradient changes.ResultsIn children with BECTS, the gradient was extended at different network and voxel levels. The gradient scores frontoparietal network was increased in the principal gradient of patients with BECTS. The left precentral gyrus (PCG) and right angular gyrus gradient scores were significantly increased in the principal gradient of children with BECTS. Moreover, in regions of the brain with abnormal principal gradients, functional connectivity was disrupted. The left PCG gradient score of children with BECTS was correlated with the verbal intelligence quotient (VIQ), and the disruption of functional connectivity in brain regions with abnormal principal gradients was closely related to cognitive function. VIQ was significantly predicted by the principal gradient map of patients.SignificanceThe results indicate connectome gradient disruption in children with BECTS and its relationship to cognitive function, thereby increasing our understanding of the functional connectome hierarchy and providing potential biomarkers for cognitive function of children with BECTS.
| S-EPMC11201345 | biostudies-literature
Project description:ObjectiveBenign epilepsy with centrotemporal spikes (BECTS), the most common focal childhood epilepsy, is associated with subtle abnormalities in cognition and possible developmental alterations in brain structure when compared to healthy participants, as indicated by previous cross-sectional studies. To examine the natural history of BECTS, we investigated cognition, cortical thickness, and subcortical volumes in children with new/recent onset BECTS and healthy controls (HC).MethodsParticipants were 8-15 years of age, including 24 children with new-onset BECTS and 41 age- and gender-matched HC. At baseline and 2 years later, all participants completed a cognitive assessment, and a subset (13 BECTS, 24 HC) underwent T1 volumetric magnetic resonance imaging (MRI) scans focusing on cortical thickness and subcortical volumes.ResultsBaseline cognitive abnormalities associated with BECTS (object naming, verbal learning, arithmetic computation, and psychomotor speed/dexterity) persisted over 2 years, with the rate of cognitive development paralleling that of HC. Baseline neuroimaging revealed thinner cortex in BECTS compared to controls in frontal, temporal, and occipital regions. Longitudinally, HC showed widespread cortical thinning in both hemispheres, whereas BECTS participants showed sparse regions of both cortical thinning and thickening. Analyses of subcortical volumes showed larger left and right putamens persisting over 2 years in BECTS compared to HC.SignificanceCognitive and structural brain abnormalities associated with BECTS are present at onset and persist (cognition) and/or evolve (brain structure) over time. Atypical maturation of cortical thickness antecedent to BECTS onset results in early identified abnormalities that continue to develop abnormally over time. However, compared to anatomic development, cognition appears more resistant to further change over time.
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Project description:There are 2 intrinsic networks in the human brain: the task positive network (TPN) and task negative network (alternately termed the default mode network, DMN) in which inverse correlations have been observed during resting state and event-related functional magnetic resonance imaging (fMRI). The antagonism between the 2 networks might indicate a dynamic interaction in the brain that is associated with development.To evaluate the alterations in the relations of the 2 networks in children with benign childhood epilepsy with centrotemporal spikes (BECTS), resting state fMRI was performed in 17 patients with BECTS and 17 healthy controls. The functional and effective connectivities of 29 nodes in the TPN and DMN were analyzed. Positive functional connectivity (FC) within the networks and negative FC between the 2 networks were observed in both groups.The patients exhibited increased FC within both networks, particularly in the frontoparietal nodes such as the left superior frontal cortex, and enhanced antagonism between the 2 networks, suggesting abnormal functional integration of the nodes of the 2 networks in the patients. Granger causality analysis revealed a significant difference in the degree of outflow to inflow in the left superior frontal cortex and the left ventral occipital lobe.The alterations observed in the combined functional and effective connectivity analyses might indicate an association of an abnormal ability to integrate information between the DMN and TPN and the epileptic neuropathology of BECTS and provide preliminary evidence supporting the occurrence of abnormal development in children with BECTS.
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