Early Infantile Epileptic Encephalopathy (EIEE) presents shortly after birth with frequent, severe seizures and progressive disturbance of cerebral function. This study was to investigate a cohort of Chinese children with unexplained EIEE, infants with previous genetic diagnoses, causative brain malformations, or inborn errors of metabolism were excluded. We used targeted next-generation sequencing to identify potential pathogenic variants of 308 genes in 68 Han Chinese patients with unexplained EIEE. A filter process was performed to prioritize rare variants of potential functional significance. In all cases where parental testing was accessible, Sanger sequencing confirmed the variants and determined the parental origin. In 15% of patients (n = 10/68), we identified nine de novo pathogenic variants, and one assumed de novo pathogenic variant in the following genes: CDKL5 (n = 2), STXBP1 (n = 2), SCN1A (n = 3), KCNQ2 (n = 2), SCN8A (n = 1), four of the variants are novel variants. In 4% patients (n = 3/68), we identified three likely pathogenic variants; two assumed de novo and one X-linked in the following genes: SCN1A (n = 2) and ARX (n = 1), two of these variants are novel. Variants were assumed de novo when parental testing was not available. Our findings were first reported in Han Chinese patients with unexplained EIEE, enriching the EIEE mutation spectrum bank.

Introduction: The concurrence of intellectual disability/global developmental delay and epilepsy (ID/GDD-EP) is very common in the pediatric population. The etiologies for both conditions are complex and largely unknown. The predictors of significant copy number variations (CNVs) are known for the cases with ID/GDD, but unknown for those with exclusive ID/GDD-EP. Importantly, the known predictors are largely from the same ethnic group; hence, they lack replication.Purpose: We aimed to determine and investigate the diagnostic yield of CNV tests, new causative CNVs, and the independent predictors of significant CNVs in Chinese children with unexplained ID/GDD-EP.Materials and methods: A total of 100 pediatric patients with unexplained ID/GDD-EP and 1,000 healthy controls were recruited. The American College of Medical Genetics guideline was used to classify the CNVs. Additionally, clinical information was collected and compared between those with significant and non-significant CNVs.Results: Twenty-eight percent of the patients had significant CNVs, 16% had variants of unknown significance, and 56% had non-significant CNVs. In total, 31 CNVs were identified in 28% (28/100) of cases: 25 pathogenic and 6 likely pathogenic. Eighteen known syndromes were diagnosed in 17 cases. Thirteen rare CNVs (8 novel and 5 reported in literature) were identified, of which three spanned dosage-sensitive genes: 19q13.2 deletion (ATP1A3), Xp11.4-p11.3 deletion (CASK), and 6q25.3-q25.3 deletion (ARID1B). By comparing clinical features in patients with significant CNVs against those with non-significant CNVs, a statistically significant association was found between the presence of significant CNVs and speech and language delay for those aged above 2 years and for those with facial malformations, microcephaly, congenital heart disease, fair skin, eye malformations, and mega cisterna magna. Multivariate logistic regression analysis allowed the identification of two independent significant CNV predictors, which are eye malformations and facial malformations.Conclusion: Our study supports the performance of CNV tests in pediatric patients with unexplained ID/GDD-EP, as there is high diagnostic yield, which informs genetic counseling. It adds 13 rare CNVs (8 novel), which can be accountable for both conditions. Moreover, congenital eye and facial malformations are clinical markers that can aid clinicians to understand which patients can benefit from the CNV testing and which will not, thus helping patients to avoid unnecessary and expensive tests.

Objective: Mesial temporal lobe epilepsy (MTLE) is the most common type of refractory epilepsy. It is often associated with hippocampal sclerosis, which is histopathologically characterized by selective neuron loss, mossy fiber sprouting, and synapse reconstruction, and is the primary cause of refractory epilepsy. Its mechanism has not been fully elucidated. Substantial evidence now supports that inflammatory pathways are activated in epilepsy foci. We have confirmed that the interleukin-1β (IL-1β) level is involved in the epileptogenesis of MTLE, and we further investigated how it works in its chronicity in this study. Methods: The MTLE model was induced by pilocarpine, and Western blot and co-immunoprecipitation were used to detect proteins related to the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway in the hippocampi of MTLE rats and MTLE children. Meanwhile, primary hippocampal neurons were cultured and transfected by lentivirus, and the same methods were used to test the related protein expression; fluorescent dye FM4-64 was used to measure synaptic vesicle endocytosis (SVE) of neurons. Results: We revealed that mTOR is continuously activated in the rat MTLE model and children with MTLE, and it correlated with the IL-1β level. We further proved that IL-1β activates neurons via the PI3K/Akt/mTOR signaling pathway, accompanied by the upregulation of MAP2 and the enhancement of SVE in hippocampal neurons. Conclusion: Our findings suggest that IL-1β can activate mTOR, followed by activated neurons, which is critical in the pathogenesis of MTLE chronicity. These findings contribute to the understanding of the pathogenesis of MTLE, and targeting inflammation modulators in MTLE may provide new pathways for therapy of refractory epilepsy.

No abstract

We confirmed that IL-1β stimulated SYN expression and epileptiform discharges, and that blocking the PI3K/Akt/mTOR pathway alleviated these phenomena. Therefore, activation of the PI3K/Akt/mTOR signaling pathway by IL-1β contributes to the pathogenesis of MTLE, and modulating this pathway is a promising strategy of study for therapies to prevent or reverse the cellular and molecular mechanisms of epileptogenesis in MTLE.