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International Journal of Molecular... Apr 2024An important component contributing to the onset of epilepsy is the death of hippocampal neurons. Several studies have shown that Dravet syndrome model mice: KO mice...
An important component contributing to the onset of epilepsy is the death of hippocampal neurons. Several studies have shown that Dravet syndrome model mice: KO mice have a high number of apoptotic neurons following seizures, but the precise mechanism underlying this remains unclear. The aim of this research was to elucidate the potential molecular mechanism of neuronal apoptosis in KO mice by integrating proteomics and transcriptomics, with the ultimate goal of offering better neuroprotection. We found that apoptotic processes were enriched in both proteomic and transcriptomic GO analyses, and KEGG results also indicated that differential proteins and genes play a role in neurotransmission, the cell cycle, apoptosis, and neuroinflammation. Then, we examined the upstream and downstream KGML interactions of the pathways to determine the relationship between the two omics, and we found that the HIF-1 signaling pathway plays a significant role in the onset and apoptosis of epilepsy. Meanwhile, the expression of the apoptosis-related protein VHL decreased in this pathway, and the expression of p21 was upregulated. Therefore, this study suggests that VHL/HIF-1α/p21 might be involved in the apoptosis of hippocampal neurons in KO mice.
Topics: Animals; Epilepsies, Myoclonic; Hippocampus; Apoptosis; Mice; Neurons; Disease Models, Animal; NAV1.1 Voltage-Gated Sodium Channel; Proteomics; Mice, Knockout; Transcriptome; Signal Transduction; Gene Expression Profiling; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 38674042
DOI: 10.3390/ijms25084457 -
Cells Apr 2024It has been known for a long time that epileptic seizures provoke brain neuroinflammation involving the activation of microglial cells. However, the role of these cells...
It has been known for a long time that epileptic seizures provoke brain neuroinflammation involving the activation of microglial cells. However, the role of these cells in this disease context and the consequences of their inflammatory activation on subsequent neuron network activity remain poorly understood so far. To fill this gap of knowledge and gain a better understanding of the role of microglia in the pathophysiology of epilepsy, we used an established zebrafish Dravet syndrome epilepsy model based on Scn1Lab sodium channel loss-of-function, combined with live microglia and neuronal Ca imaging, local field potential (LFP) recording, and genetic microglia ablation. Data showed that microglial cells in -deficient larvae experiencing epileptiform seizures displayed morphological and biochemical changes characteristic of M1-like pro-inflammatory activation; i.e., reduced branching, amoeboid-like morphology, and marked increase in the number of microglia expressing pro-inflammatory cytokine Il1β. More importantly, LFP recording, Ca imaging, and swimming behavior analysis showed that microglia-depleted -KD larvae displayed an increase in epileptiform seizure-like neuron activation when compared to that seen in -KD individuals with microglia. These findings strongly suggest that despite microglia activation and the synthesis of pro-inflammatory cytokines, these cells provide neuroprotective activities to epileptic neuronal networks, making these cells a promising therapeutic target in epilepsy.
Topics: Animals; Zebrafish; Microglia; Epilepsies, Myoclonic; Disease Models, Animal; Neurons; NAV1.1 Voltage-Gated Sodium Channel; Interleukin-1beta; Larva; Calcium; Zebrafish Proteins
PubMed: 38667299
DOI: 10.3390/cells13080684 -
Journal of Medical Case Reports Apr 2024Dravet syndrome is an infantile-onset developmental and epileptic encephalopathy (DEE) characterized by drug resistance, intractable seizures, and developmental...
BACKGROUND
Dravet syndrome is an infantile-onset developmental and epileptic encephalopathy (DEE) characterized by drug resistance, intractable seizures, and developmental comorbidities. This article focuses on manifestations in two Indonesian children with Javanese ethnicity who experienced Dravet syndrome with an SCN1A gene mutation, presenting genetic analysis findings using next-generation sequencing.
CASE PRESENTATION
We present a case series involving two Indonesian children with Javanese ethnicity whom had their first febrile seizure at the age of 3 months, triggered after immunization. Both patients had global developmental delay and intractable seizures. We observed distinct genetic findings in both our cases. The first patient revealed heterozygous deletion mutation in three genes (TTC21B, SCN1A, and SCN9A). In our second patient, previously unreported mutation was discovered at canonical splice site upstream of exon 24 of the SCN1A gene. Our patient's outcomes improved after therapeutic evaluation based on mutation findings When comparing clinical manifestations in our first and second patients, we found that the more severe the genetic mutation discovered, the more severe the patient's clinical manifestations.
CONCLUSION
These findings emphasize the importance of comprehensive genetic testing beyond SCN1A, providing valuable insights for personalized management and tailored therapeutic interventions in patients with Dravet syndrome. Our study underscores the potential of next-generation sequencing in advancing genotype-phenotype correlations and enhancing diagnostic precision for effective disease management.
Topics: Humans; Epilepsies, Myoclonic; NAV1.1 Voltage-Gated Sodium Channel; Male; Female; Infant; NAV1.7 Voltage-Gated Sodium Channel; Indonesia; Anticonvulsants; Mutation; Genetic Testing; High-Throughput Nucleotide Sequencing; Child, Preschool
PubMed: 38649973
DOI: 10.1186/s13256-024-04514-2 -
Acta Neurologica Belgica Apr 2024There are rising evidences that subcortical structures, including the basal ganglia, are affected in patients with epilepsy. These structures are thought to influence...
INTRODUCTION
There are rising evidences that subcortical structures, including the basal ganglia, are affected in patients with epilepsy. These structures are thought to influence the modulation and phenotypic expression of epileptic seizures. Our study aimed to evaluate the presence of structural abnormalities in subcortical structures in patients with juvenile myoclonic epilepsy (JME).
METHODS
This cross-sectional study included 51 patients who were diagnosed with JME and who were monitored on an outpatient basis at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade from January 1985 to October 2017. All patients underwent transcranial parenchymal sonography (TCS) from October 2015 to October 2017. Relation of clinical parameters (seizure control andcognitive functioning,) with TCS results was assessed.
RESULTS
Hyperechogenicity of the substantia nigra (SN) was detected in 37.2% of JME subjects and it was significantly more common in patients with JME than in the control group. The marked echogenicity of the red nucleus (RN) was detected in 17.6% of cases, while 11.8% of subjects had hyperechogenic RN. The presence of hyperechogenic RN (both right and left) was significantly more frequent in the group of patients with JME compared to the control group. The third ventricle diameter was larger in patients with JME than in controls.
CONCLUSION
Structural changes of certain subcortical structures, primarily SN and RN, detected in JME patients indicate additional non-lesional abnormalities of the basal ganglia and midbrain structures in these patients.
PubMed: 38644442
DOI: 10.1007/s13760-024-02561-6 -
Epilepsy & Behavior : E&B Jun 2024Dravet syndrome is a rare developmental epilepsy syndrome associated with severe, treatment-resistant seizures. Since seizures and seizure clusters are linked to... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Dravet syndrome is a rare developmental epilepsy syndrome associated with severe, treatment-resistant seizures. Since seizures and seizure clusters are linked to morbidity, reduced quality of life, and premature mortality, a greater understanding of these outcomes could improve trial designs. This analysis explored seizure types, seizure clusters, and factors affecting seizure cluster variability in Dravet syndrome patients.
METHODS
Pooled post-hoc analyses were performed on data from placebo-treated patients in GWPCARE 1B and GWPCARE 2 randomized controlled phase III trials comparing cannabidiol and placebo in Dravet syndrome patients aged 2-18 years. Multivariate stepwise analysis of covariance of log-transformed convulsive seizure cluster frequency was performed, body weight and body mass index z-scores were calculated, and incidence of adverse events was assessed. Data were summarized in three age groups.
RESULTS
We analyzed 124 placebo-treated patients across both studies (2-5 years: n = 35; 6-12 years: n = 52; 13-18 years: n = 37). Generalized tonic-clonic seizures followed by myoclonic seizures were the most frequent seizure types. Mean and median convulsive seizure cluster frequency overall decreased between baseline and maintenance period but did not change significantly during the latter; variation in convulsive seizure cluster frequency was observed across age groups. Multivariate analysis suggested correlations between convulsive seizure cluster frequency and age (positive), and body mass index (BMI) (negative).
INTERPRETATION
Post-hoc analyses suggested that potential relationships could exist between BMI, age and convulsive seizure cluster variation. Results suggested that seizure cluster frequency may be a valuable outcome in future trials. Further research is needed to confirm our findings.
Topics: Humans; Adolescent; Child; Epilepsies, Myoclonic; Female; Male; Seizures; Child, Preschool; Cannabidiol; Anticonvulsants; Cluster Analysis; Double-Blind Method
PubMed: 38643658
DOI: 10.1016/j.yebeh.2024.109774 -
Brain Communications 2024[This corrects the article DOI: 10.1093/braincomms/fcae054.].
[This corrects the article DOI: 10.1093/braincomms/fcae054.].
PubMed: 38638151
DOI: 10.1093/braincomms/fcae125 -
Epilepsy Research May 2024Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a rare autosomal recessive disorder due to a deficiency of α-aminoadipic semialdehyde dehydrogenase. This study aimed to...
Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a rare autosomal recessive disorder due to a deficiency of α-aminoadipic semialdehyde dehydrogenase. This study aimed to systematically explore genotypic and phenotypic features and prognostic factors of neonatal-onset PDE. A literature search covering PubMed, Elsevier, and Web of Science was conducted from January 2006 to August 2023. We identified 56 eligible studies involving 169 patients and 334 alleles. The c.1279 G>C variant was the most common variant of neonatal-onset PDE (25.7 %). All patients were treated with pyridoxine; forty patients received dietary intervention therapy. 63.9 % of the patients were completely seizure-free; however, 68.6 % of the patients had neurodevelopmental delays. Additionally, homozygous c.1279 G>C variants were significantly associated with ventriculomegaly, abnormal white matter signal, and cysts (P<0.05). In contrast, homozygous c.1364 T>C was associated with clonic seizure (P=0.031). Pyridoxine used immediately at seizure onset was an independent protective factor for developmental delay (P=0.035; odds ratio [OR]: 3.14). Besides, pyridoxine used early in the neonatal period was a protective factor for language delay (P=0.044; OR: 4.59). In contrast, neonatal respiratory distress (P=0.001; OR: 127.44) and abnormal brain magnetic resonance imaging (P=0.049; OR: 3.64) were risk factors. Prenatal movement abnormality (P=0.041; OR: 20.56) and abnormal white matter signal (P=0.012; OR: 24.30) were risk factors for motor delay. Myoclonic seizure (P=0.023; OR: 7.13) and status epilepticus (P=0.000; OR: 9.93) were risk factors for breakthrough seizures. In conclusion, our study indicated that pyridoxine should be started immediately when unexplained neonatal seizures occur and not later than the neonatal period to prevent poor neurodevelopmental outcomes.
Topics: Humans; Infant, Newborn; Aldehyde Dehydrogenase; Epilepsy; Genotype; Phenotype; Prognosis; Pyridoxine; Seizures
PubMed: 38636407
DOI: 10.1016/j.eplepsyres.2024.107363 -
Epilepsy & Behavior : E&B Jun 2024To evaluate the clinical predictors of positive genetic investigation in developmental and epileptic encephalopathies, beyond the influence of Dravet Syndrome.
OBJECTIVE
To evaluate the clinical predictors of positive genetic investigation in developmental and epileptic encephalopathies, beyond the influence of Dravet Syndrome.
METHODS
The study included 98 patients diagnosed with developmental and epileptic encephalopathies. The patients underwent Sanger sequencing of SCN1A, Chromosomal Microarray Analysis, and Whole Exome Sequencing. The association of clinical variables with a positive genetic test was investigated using univariate and multivariate analysis.
RESULTS
Genetic diagnosis was identified in 47 (48 %) patients with developmental and epileptic encephalopathies. Beyond Dravet Syndrome influence, first seizure in the context of fever (p < 0.01), seizures precipitated by temperature (p = 0.04), cognitive regression (p = 0.04), hypotonia (p < 0.01), and focal seizures (p = 0.03) increased the chances of a positive genetic investigation. In contrast, atonic seizures (p = 0.01) and generalized discharges on electroencephalogram (p = 0.02) decreased the chances. Dravet Syndrome was positively associated with a genetic developmental and epileptic encephalopathies etiology (p < 0.01), whereas epilepsy with myoclonic-atonic seizures (p = 0.01), developmental and epileptic encephalopathies with spike-wave activation in sleep (p = 0.04), and Lennox-Gastaut syndrome (p = 0.03) were negatively associated. In multivariate analysis, the first seizure in the context of fever (p < 0.01) and hypotonia (p = 0.02) were positively, and atonic seizures (p = 0.01) were negatively and independently associated with a genetic etiology.
CONCLUSION
The predictive variables of genetic investigation in developmental and epileptic encephalopathies are first seizure in the context of fever and hypotonia, whereas atonic seizures decrease the chances of finding a genetic cause for developmental and epileptic encephalopathies. Regarding epileptic syndromes, Dravet Syndrome is highly associated with a positive genetic test, whereas epilepsy with myoclonic-atonic seizures, developmental and epileptic encephalopathies with spike-wave activation in sleep, and Lennox-Gastaut syndrome are rarely associated with a positive genetic investigation.
Topics: Humans; Male; Female; Child; Child, Preschool; Epilepsies, Myoclonic; NAV1.1 Voltage-Gated Sodium Channel; Infant; Adolescent; Electroencephalography; Genetic Testing; Adult; Epilepsy; Young Adult; Exome Sequencing; Lennox Gastaut Syndrome
PubMed: 38636144
DOI: 10.1016/j.yebeh.2024.109762 -
Annals of Neurology Jun 2024The objective was to analyze seizure semiology in pediatric frontal lobe epilepsy patients, considering age, to localize the seizure onset zone for surgical resection in...
OBJECTIVE
The objective was to analyze seizure semiology in pediatric frontal lobe epilepsy patients, considering age, to localize the seizure onset zone for surgical resection in focal epilepsy.
METHODS
Fifty patients were identified retrospectively, who achieved seizure freedom after frontal lobe resective surgery at Great Ormond Street Hospital. Video-electroencephalography recordings of preoperative ictal seizure semiology were analyzed, stratifying the data based on resection region (mesial or lateral frontal lobe) and age at surgery (≤4 vs >4).
RESULTS
Pediatric frontal lobe epilepsy is characterized by frequent, short, complex seizures, similar to adult cohorts. Children with mesial onset had higher occurrence of head deviation (either direction: 55.6% vs 17.4%; p = 0.02) and contralateral head deviation (22.2% vs 0.0%; p = 0.03), ictal body-turning (55.6% vs 13.0%; p = 0.006; ipsilateral: 55.6% vs 4.3%; p = 0.0003), and complex motor signs (88.9% vs 56.5%; p = 0.037). Both age groups (≤4 and >4 years) showed hyperkinetic features (21.1% vs 32.1%), contrary to previous reports. The very young group showed more myoclonic (36.8% vs 3.6%; p = 0.005) and hypomotor features (31.6% vs 0.0%; p = 0.003), and fewer behavioral features (36.8% vs 71.4%; p = 0.03) and reduced responsiveness (31.6% vs 78.6%; p = 0.002).
INTERPRETATION
This study presents the most extensive semiological analysis of children with confirmed frontal lobe epilepsy. It identifies semiological features that aid in differentiating between mesial and lateral onset. Despite age-dependent differences, typical frontal lobe features, including hyperkinetic seizures, are observed even in very young children. A better understanding of pediatric seizure semiology may enhance the accuracy of onset identification, and enable earlier presurgical evaluation, improving postsurgical outcomes. ANN NEUROL 2024;95:1138-1148.
Topics: Humans; Child; Male; Female; Epilepsy, Frontal Lobe; Child, Preschool; Electroencephalography; Retrospective Studies; Adolescent; Seizures; Infant; Frontal Lobe; Video Recording
PubMed: 38624073
DOI: 10.1002/ana.26922