Mutations in the sodium channel genes SCN1A, SCN3A, and SCN9A in children with epilepsy with febrile seizures plus(EFS+)

Ma, Hong-Xia; Guo, Yuxiong; Chen, Zhihong; Wang, Lin-Gan; Tang, Zhe; Zhang, Jingwen; Miao, Qinfei; Zhai, Qixiao

doi:10.1016/j.seizure.2021.04.006

Cited by 15 publications

(10 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, SCN1A mutations have been implicated in various other epilepsy syndromes, often accompanied by significant comorbidities 29 . Numerous epilepsy syndromes in humans stem from mutations in genes encoding voltage-gated sodium channels 30 , with most of these mutations occurring in the SCN1A gene 31 , and following a dominant inheritance pattern in addition to other genes such as SCN5A and SCN9A 32,33 . We observed that the c.2133G>C (p.Leu711Phe) variant in the SCN9A gene was repeated in 3% of our tests.…”

Section: Discussionmentioning

confidence: 99%

Previously defined variants of uncertain significance may play an important role in epilepsy and interactions between certain variants may become pathogenic

Hussein

Weisblum-Neuman

Ben‐Zeev

et al. 2023

Preprint

View full text Add to dashboard Cite

Epilepsy is a chronic neurological disorder characterized by recurrent seizures and associated neurological, cognitive, psychological, and social effects. The prevalence of active epilepsy is estimated to be between 4-10 per 1000 individuals in the general population, with the highest incidence occurring during infancy and childhood. Genetic mutations play a significant role in epilepsy, and over 500 genes have been associated with the condition. Next-Generation Sequencing (NGS) panels are utilized for genetic testing, but a substantial proportion of results remain uncertain and are not considered directly causative of epilepsy. In this study, we reevaluated a subgroup of patients with inconclusive variant findings or multiple Variants of Uncertain Significance (VUSs) in their test results. We identified two unrelated variants c.2133G>C in SCN9A and c.316G>A in QARS1 to be potentially pathogenic variants. Additionally, we identified a frequent genetic combination, the RANBP2&RYR3 being prominent among other possible combinations. The RANBP2 gene consistently co-occurred with RYR3 variants in uncertain results, suggesting potential pathogenicity. We also analyzed unaffected parents' data and observed certain combinations inherited from different parents, raising the possibility of specific gene combinations as risk factors for the disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Previously defined variants of uncertain significance may play an important role in epilepsy and interactions between certain variants may become pathogenic

Hussein

Weisblum-Neuman

Ben‐Zeev

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Recent reports show that SCN9A mutations are mostly associated with febrile seizures and DS ( 29 ). One study showed that SCN9A mutations coexist with SCN1A mutations, that this mutation is a genetic modification factor in SCN1A mutation-related FS+, and that it may worsen the symptoms of mild FS+ ( 30 ). As another study showed that the SCN9A variant caused febrile seizures in families without the SCN1A variant ( 29 , 31 ), it is possible that some SCN9A mutations may portray a modifying role in the presence of more potent mutations, or that it may itself induce mild epileptic seizures ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

Clinical characteristics and genetic analysis of pediatric patients with sodium channel gene mutation-related childhood epilepsy: a review of 94 patients

Fang,

Hu,

Kang

et al. 2023

Front. Neurol.

View full text Add to dashboard Cite

ObjectiveThis study aimed to examine the clinical and gene-mutation characteristics of pediatric patients with sodium channel gene mutation-related childhood epilepsy and to provide a basis for precision treatment and genetic counseling.MethodsThe clinical data from 94 patients with sodium channel gene mutation-related childhood epilepsy who were treated at Hunan Children's Hospital from August 2012 to December 2022 were retrospectively evaluated, and the clinical characteristics, gene variants, treatment, and follow-up status were analyzed and summarized.ResultsOur 94 pediatric patients with sodium channel gene variant-related childhood epilepsy comprised 37 girls and 57 boys. The age of disease onset ranged from 1 day to 3 years. We observed seven different sodium channel gene variants, and 55, 14, 9, 6, 6, 2, and 2 patients had SCNlA, SCN2A, SCN8A, SCN9A, SCN1B, SCN11A, and SCN3A variants, respectively. We noted that 52 were reported variants and 42 were novel variants. Among all gene types, SCN1A, SCN2A, and SCN8A variants were associated with an earlier disease onset age. With the exception of the SCN1B, the other six genes were associated with clustering seizures. Except for variants SCN3A and SCN11A, some patients with other variants had status epilepticus (SE). The main diagnosis of children with SCN1A variants was Dravet syndrome (DS) (72.7%), whereas patients with SCN2A and SCN8A variants were mainly diagnosed with various types of epileptic encephalopathy, accounting for 85.7% (12 of 14) and 88.9% (8 of 9) respectively. A total of five cases of sudden unexpected death in epilepsy (SUDEP) occurred in patients with SCN1A, SCN2A, and SCN8A variants. The proportion of benign epilepsy in patients with SCN9A, SCN11A, and SCN1B variants was relatively high, and the epilepsy control rate was higher than the rate of other variant types.ConclusionSodium channel gene variants involve different epileptic syndromes, and the treatment responses also vary. We herein reported 42 novel variants, and we are also the first ever to report two patients with SCN11A variants, thereby increasing the gene spectrum and phenotypic profile of sodium channel dysfunction. We provide a basis for precision treatment and prognostic assessment.

show abstract

“…15 A few pathogenic SCN3A variants have been reported in familial focal epilepsy with variable foci, as well as in patients with early onset DEEs. 16 SCN1B encodes sodium channel β subunit (Na V β1), which is enriched in the neuronal axon initiation segment and node of Ranvier. 17 variants are associated with severe DEEs resembling DS and GEFS + .…”

Section: Abnormal Ion Channel Functionmentioning

confidence: 99%

Advances in Epilepsy: Mechanisms, Clinical Trials, and Drug Therapies

Zhang

Wang

et al. 2023

J. Med. Chem.

View full text Add to dashboard Cite

Epilepsy is a common disease of the nervous system characterized by transient brain dysfunction caused by an abnormal electrical discharge from the brain neurons. The pathogenesis of epilepsy is complex and remains elusive. Nowadays, drug therapy is the mainstay method for the treatment of epilepsy. More than 30 antiseizure drugs (ASDs) were approved for clinical use. Unfortunately, about 30% of patients still display pharmacoresistance against ASDs. The long-term use of ASDs may cause adverse effects, raise tolerability concerns, bring unexpected drug interactions, generate withdrawal symptoms, and increase the economic burden. Thus, the research uncovering more effective ASDs that are safe is still a difficult and urgent task. In this Perspective, we describe the pathogenesis, clinical trials, and drug therapy progress of epilepsy, focusing on summarizing the current situation of small-molecule drug candidates progressing in epilepsy therapy, which provides future directions for the development of more promising ASDs.

show abstract

Mutations in the sodium channel genes SCN1A, SCN3A, and SCN9A in children with epilepsy with febrile seizures plus(EFS+)

Cited by 15 publications

References 40 publications

Previously defined variants of uncertain significance may play an important role in epilepsy and interactions between certain variants may become pathogenic

Previously defined variants of uncertain significance may play an important role in epilepsy and interactions between certain variants may become pathogenic

Clinical characteristics and genetic analysis of pediatric patients with sodium channel gene mutation-related childhood epilepsy: a review of 94 patients

Advances in Epilepsy: Mechanisms, Clinical Trials, and Drug Therapies

Contact Info

Product

Resources

About