Epileptic Phenotypes Associated With SNAREs and Related Synaptic Vesicle Exocytosis Machinery

SNAREs (soluble N-ethylmaleimide sensitive factor attachment protein receptor) are an heterogeneous family of proteins that, together with their key regulators, are implicated in synaptic vesicle exocytosis and synaptic transmission. SNAREs represent the core component of this protein complex. Although the specific mechanisms of the SNARE machinery is still not completely uncovered, studies in recent years have provided a clearer understanding of the interactions regulating the essential fusion machinery for neurotransmitter release. Mutations in genes encoding SNARE proteins or SNARE complex associated proteins have been associated with a variable spectrum of neurological conditions that have been recently defined as “SNAREopathies.” These include neurodevelopmental disorder, autism spectrum disorder (ASD), movement disorders, seizures and epileptiform abnormalities. The SNARE phenotypic spectrum associated with seizures ranges from simple febrile seizures and infantile spasms, to severe early-onset epileptic encephalopathies. Our study aims to review and delineate the epileptic phenotypes associated with dysregulation of synaptic vesicle exocytosis and transmission, focusing on the main proteins of the SNARE core complex (STX1B, VAMP2, SNAP25), tethering complex (STXBP1), and related downstream regulators.

Molecular Mechanisms of Epileptic Encephalopathy Caused by KCNMA1 Loss-of-Function Mutations

The gene kcnma1 encodes the α-subunit of high-conductance calcium- and voltage-dependent K+ (BK) potassium channel. With the development of generation gene sequencing technology, many KCNMA1 mutants have been identified and are more closely related to generalized epilepsy and paroxysmal dyskinesia. Here, we performed a genetic screen of 26 patients with febrile seizures and identified a novel mutation of KCNMA1 (E155Q). Electrophysiological characterization of different KCNMA1 mutants in HEK 293T cells, the previously-reported R458T and E884K variants (not yet determined), as well as the newly-found E155Q variant, revealed that the current density amplitude of all the above variants was significantly smaller than that of the wild-type (WT) channel. All the above variants caused a positive shift of the I-V curve and played a role through the loss-of-function (LOF) mechanism. Moreover, the β4 subunit slowed down the activation of the E155Q mutant. Then, we used kcnma1 knockout (BK KO) mice as the overall animal model of LOF mutants. It was found that BK KO mice had spontaneous epilepsy, motor impairment, autophagic dysfunction, abnormal electroencephalogram (EEG) signals, as well as possible anxiety and cognitive impairment. In addition, we performed transcriptomic analysis on the hippocampus and cortex of BK KO and WT mice. We identified many differentially expressed genes (DEGs). Eight dysregulated genes [i.e., (Gfap and Grm3 associated with astrocyte activation) (Alpl and Nlrp10 associated with neuroinflammation) (Efna5 and Reln associated with epilepsy) (Cdkn1a and Nr4a1 associated with autophagy)] were validated by RT-PCR, which showed a high concordance with transcriptomic analysis. Calcium imaging results suggested that BK might regulate the autophagy pathway from TRPML1. In conclusion, our study indicated that newly-found point E155Q resulted in a novel loss-of-function variant and the dysregulation of gene expression, especially astrocyte activation, neuroinflammation and autophagy, might be the molecular mechanism of BK-LOF meditated epilepsy.

A Review of Febrile Seizures: Recent Advances in Understanding of Febrile Seizure Pathophysiology and Commonly Implicated Viral Triggers

Febrile seizures are one of the commonest presentations in young children, with a 2–5% incidence in Western countries. Though they are generally benign, with rare long-term sequelae, there is much to be learned about their pathophysiology and risk factors. Febrile seizures are propagated by a variety of genetic and environmental factors, including viruses and vaccines. These factors must be taken into consideration by a clinician aiming to assess, diagnose and treat a child presenting with fevers and seizures, as well as to explain the sequelae of the febrile seizures to the concerned parents of the child. Our article provides an overview of this common childhood condition, outlining both the underlying mechanisms and the appropriate clinical approach to a child presenting with febrile seizures.

Evaluation of Influenza Patients Admitted in 2019–2020 Flu Season

Objective Influenza viruses are among the most common respiratory pathogens for all age groups, and may cause seasonal outbreaks. The aim of our study was to describe the clinical characteristics of influenza cases in the 2019–2020 flu season and to study the risk factors for hospital admission and complications. Methods This was a retrospective study in 251 children (group 1: nonhospitalized; group 2: hospitalized) with influenza in the 2019–2020 flu season. Data on demographic features, influenza type, complaints, complications, and hospitalization length were collected and recorded. Results Influenza A was detected in 199 (79.3%) patients, and influenza B was detected in 52 (20.7%); 43.4% of patients were girls and 56.6% were boys. The mean age of the patients was 3.91 ± 3.3 years (16 days to 18 years). A total of 52 (20.7%) patients were hospitalized. The age of the patients in group 2 was lower than that in group 1 (3.1 vs. 4.2 years, p = 0.03). Group 2 patients were more likely to have creatine kinase (CK) elevation, febrile seizures, and physical examination abnormalities. Group 2 patients were also more likely to have influenza A. Patients with febrile seizures, chronic diseases, abnormal physical examination findings, developed complications, and additional drug use apart from oseltamivir in the treatment were also more likely to require hospitalization. Conclusion Infants and children with chronic diseases, history of febrile seizures, complications, and the use of drugs other than antiviral drugs should be carefully evaluated in case they need hospitalization. Increasing vaccination rates, initiation of antiviral treatment for selected patients, and close monitoring of patients in risk groups can decrease morbidity and mortality. Myalgias are a common complaint in patients with acute influenza infection. Previous studies suggest CK measurement be part of the work-up for the hospitalized patient with acute influenza infection.

PROFILE OF HISTORY OF FEBRILE SEIZURE IN PATIENTS WITH EPILEPSY

Background: Febrile seizure is convulsions with fever (temperature ³38°C) with no central nervous system infection that commonly found in children (6-60 months). Febrile seizures do not always mean the child has epilepsy. However, febrile seizures can be a possible long-term risk factor for epilepsy. Objective: The objective of this study is to know the profile of febrile seizure in patients with epilepsy. Methods: A retrospective descriptive study on 23 patients with epilepsy in the EEG Department of Neurology, Dr. Soetomo General Hospital, Surabaya, Indonesia in the period 2018-2019 based on inclusion and exclusion criteria. The total number of epilepsy patients is 849 patients, 216 of whom had a history of febrile seizure. Among 216 epilepsy patients who had a history of febrile seizures, 23 of them were qualified as the sample. The sampling technique used was total population sampling. The instrument of this research is the patients’ medical record. Data analysis is carried out descriptively. Results: The characteristics of the history of febrile seizures that found in patients with epilepsy are more patients are male, have the age of onset on less than 2 years old, have the body temperature more than 38.3°C, have the seizure duration less than 15 minutes, have focal seizures, have recurrent seizures in 24 hours, have a history of more than one febrile seizure, have accompanying neurological disorders, and have no family history of epilepsy. Conclusion: Febrile seizure is still becoming a concern because there is a possibility that it may develop into epilepsy. Even though, not all children who experience febrile seizure will generate epilepsy.

Incidence of iron deficiency anemia among the children with febrile seizures.

Objective: To determine frequency of iron deficiency anemia among the children having febrile seizures. Study Design: Descriptive Cross Sectional study. Setting: Pediatric Unit Allama Iqbal Memorial Teaching Hospital Sialkot. Period: September 2020 to February 2021. Material & Methods: Total 70 children were studied with age six months to 10 years with either gender presenting with febrile seizures. All data of the patients was documented including demographic data like age, gender, residential area, educational status, socioeconomic status and clinical findings at the time of presentation like fever, fits and duration of symptoms etc. Blood hemoglobin and ferritin level were tested of each patient to evaluate iron deficiency anemia. Results: There were 65.7% male and 34.3% female cases in this study. Age range of the patients was 6 months to 10 years with mean age of 4.36 ± 2.71 years. Most of the children (60%) were below three years of age. Mostly children belonged to low and middle socioeconomic status with the frequency of 42.8% and 45.7% respectively. Iron deficiency anemia was found in 38.6% cases. Majority of the mothers were illiterate (65%). There were 44.3% cases from rural areas and 55.7% from urban area. Conclusion: Iron deficiency anemia is a common problem among children with febrile seizures, younger than 03 years and belonging to rural areas. Illiterate mothers, is an important risk factor of iron deficiency anemia in their children.

SCN1A Mutation—Beyond Dravet Syndrome: A Systematic Review and Narrative Synthesis

Background:SCN1A is one of the most common epilepsy genes. About 80% of SCN1A gene mutations cause Dravet syndrome (DS), which is a severe and catastrophic epileptic encephalopathy. More than 1,800 mutations have been identified in SCN1A. Although it is known that SCN1A is the main cause of DS and genetic epilepsy with febrile seizures plus (GEFS+), there is a dearth of information on the other related diseases caused by mutations of SCN1A.Objective: The aim of this study is to systematically review the literature associated with SCN1A and other non-DS-related disorders.Methods: We searched PubMed and SCOPUS for all the published cases related to gene mutations of SCN1A until October 20, 2021. The results reported by each study were summarized narratively.Results: The PubMed and SCOPUS search yielded 2,889 items. A total of 453 studies published between 2005 and 2020 met the final inclusion criteria. Overall, 303 studies on DS, 93 on GEFS+, three on Doose syndrome, nine on the epilepsy of infancy with migrating focal seizures (EIMFS), six on the West syndrome, two on the Lennox–Gastaut syndrome (LGS), one on the Rett syndrome, seven on the nonsyndromic epileptic encephalopathy (NEE), 19 on hemiplegia migraine, six on autism spectrum disorder (ASD), two on nonepileptic SCN1A-related sudden deaths, and two on the arthrogryposis multiplex congenital were included.Conclusion: Aside from DS, SCN1A also causes other epileptic encephalopathies, such as GEFS+, Doose syndrome, EIMFS, West syndrome, LGS, Rett syndrome, and NEE. In addition to epilepsy, hemiplegic migraine, ASD, sudden death, and arthrogryposis multiplex congenital can also be caused by mutations of SCN1A.