Dravet Syndrome (DS) is a developmental epileptic encephalopathy characterized by drug-resistant seizures and other clinical features, including intellectual disability and behavioral, sleep, and gait problems. The pathogenesis is strongly connected to voltage-gated sodium channel dysfunction. The current consensus of seizure management in DS consists of a combination of conventional and recently approved drugs such as stiripentol, cannabidiol, and fenfluramine. Despite promising results in randomized clinical trials and extension studies, the prognosis of the developmental outcomes of patients with DS remains unfavorable. The article summarizes recent changes in the therapeutic approach to DS and discusses ongoing clinical research directions. Serotonergic agents under investigation show promising results and may replace less DS-specific medicines. The use of antisense nucleotides and gene therapy is focused not only on symptom relief but primarily addresses the underlying cause of the syndrome. Novel compounds, after expected safe and successful implementation in clinical practice, will open a new era for patients with DS. The main goal of causative treatment is to modify the natural course of the disease and provide the best neurodevelopmental outcome with minimum neurological deficit.

Introduction, Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder caused by mutations inactivating TSC1 or TSC2 genes and characterized by the presence of tumors involving many organs, including the brain, heart, kidneys, and skin. Subependymal giant cell astrocytoma (SEGA) is a slow-growing brain tumor almost exclusively associated with TSC. State of the Art: Despite the fact that SEGAs are benign, they require well-considered decisions regarding the timing and modality of pharmacological or surgical treatment. In TSC children and adolescents, SEGA is the major cause of mortality and morbidity. Clinical Implications: Until recently, surgical resection has been the standard therapy for SEGAs but the discovery of the role of the mTOR pathway and the introduction of mTOR inhibitors to clinical practice changed the therapeutic landscape of these tumors. In the current paper, we discuss the pros and cons of mTOR inhibitors and surgical approaches in SEGA treatment. Future Directions: In 2021, the International Tuberous Sclerosis Complex Consensus Group proposed a new integrative strategy for SEGA management. In the following review, we discuss the proposed recommendations and report the results of the literature search for the latest treatment directions.

Objective: This study presents the clinical phenotypes and genetic analysis of seven patients with benign familial infantile epilepsy (BFIE) diagnosed by whole-exome sequencing.Methods: The clinical data of seven children with BFIE diagnosed at the Department of Neurology, Children’s Hospital Affiliated to Zhengzhou University between December 2017 and April 2022 were retrospectively analyzed. Whole-exome sequencing was used to identify the genetic causes, and the variants were verified by Sanger sequencing in other family members.Results: The seven patients with BFIE included two males and five females ranging in age between 3 and 7 months old. The main clinical phenotype of the seven affected children was the presence of focal or generalized tonic–clonic seizures, which was well controlled by anti-seizure medication. Cases 1 and 5 exhibited predominantly generalized tonic–clonic seizures accompanied by focal seizures while cases 2, 3, and 7 displayed generalized tonic–clonic seizures, and cases 4 and 6 had focal seizures. The grandmother and father of cases 2, 6, and 7 had histories of seizures. However, there was no family history of seizures in the remaining cases. Case 1 carried a de novo frameshift variant c.397delG (p.E133Nfs*43) in the proline-rich transmembrane protein 2 (PRRT2) gene while case 2 had a nonsense variant c.46G > T (p.Glu16*) inherited from the father, and cases 3–7 carried a heterozygous frameshift variant c.649dup (p.R217Pfs*8) in the same gene. In cases 3 and 4, the frameshift variant was de novo, while in cases 5–7, the variant was paternally inherited. The c.397delG (p.E133Nfs*43) variant is previously unreported.Conclusion: This study demonstrated the effectiveness of whole-exome sequencing in the diagnosis of BFIE. Moreover, our findings revealed a novel pathogenic variant c.397delG (p.E133Nfs*43) in the PRRT2 gene that causes BFIE, expanding the mutation spectrum of PRRT2.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including deficits in social interaction, repetitive and stereotyped behaviors, along with higher levels of anxiety and cognitive impairments. Previous studies demonstrate pronounced reduced density of calretinin (CR)-expressing GABAergic interneurons in both ASD patients and animal models. The object of the current study was to determine the role of CR in ASD-relevant behavioral aberrations. Herein, the mRNA and protein levels of CR in the prefrontal cortex (PFC) of mouse model of ASD based on prenatal exposure to valproic acid (VPA) were determined by qRT-PCR and Western blot analysis, respectively. Moreover, the behavioral abnormalities in naive mice with CR deficiency mediated by recombinant adeno-associated virus (rAAV) were evaluated in a comprehensive testing battery including social interaction, marble burying, self-grooming, open-field, elevated plus maze and novel object recognition tests. Furthermore, the action potential changes caused by CR deficiency were examined in neurons within the PFC in naive mouse. The results show that the mRNA and protein levels of PFC CR of VPA-induced mouse ASD model were reduced. Concomitantly, mice with CR knockdown displayed ASD-like behavioral aberrations, such as social impairments, elevated stereotypes, anxiety and memory defects. Intriguingly, patch-clamp recordings revealed that CR knockdown provoked decreased neuronal excitability by increasing action potential discharge frequencies together with decreased action potential threshold and rheobase. Our findings support a notion that CR knockdown might contribute to ASD-like phenotypes, with the pathogenesis most likely stemming from increased neuronal excitability.

Objective: To summarize the clinical characteristics of a cohort of nine Chinese children with GNAO1 encephalopathy and analyze their genotypes. Methods: A retrospective study was conducted on nine children diagnosed with GNAO1 encephalopathy at the Neurology Department of two children’s hospitals between January 2019 and December 2022. Their clinical manifestations, genetic test results, cranial imaging, electroencephalography and treatment were summarized. Their prognosis was followed up. Results: All nine patients presented with moderate-to-severe psychomotor developmental delay and dystonia. Six patients exhibited neonatal or infantile-onset epilepsy, manifesting as generalized tonic-clonic seizure, myoclonic seizure, epileptic spasms, and were diagnosed with developmental and epileptic encephalopathy 17 (DEE 17). Two patients presented with choreoathetosis in infancy without epileptic seizure and were diagnosed with the neurodevelopmental disorder with involuntary movements (NEDIM). One patient presented with choreoathetosis at two years of age and developed focal seizures at six years of age, representing an intermediate phenotype. During a follow-up period of 0.8–3.5 years, one child died due to infection. The remaining eight continued to exhibit psychomotor retardation. Pathogenic or likely pathogenic de novo heterozygous missense variants in GNAO1 were identified in all nine cases. Among these, the variants c.17G > T (p.Ser6Ile), c.119G > C (p.Gly40Ala), and c.748 C > T (p.Leu250Phe) are novel. Conclusion: In conclusion, we analyzed the clinical characteristics and genetic variants of a cohort of nine Chinese children with GNAO1 variants and identified three novel GNAO1 variants. Our study expanded the spectrum of genotypes and phenotypes in GNOA1-associated encephalopathy.