Large international consortia examining the genomic architecture of the epilepsiesfocus on large diagnostic subgroupings such as“all focal epilepsy”and“all genetic gen-eralized epilepsy”. In addition, phenotypic data are generally entered into these largediscovery databases in a unidirectional manner at one point in time only.

Brevetoxins (PbTx) and brevenal are marine ladder-frame polyethers. PbTx binds to and activates voltage-gated sodium (Nav) channels in native tissues, whereas brevenal antagonizes these actions. However, the effects of PbTx and brevenal on recombinant Nav channel function have not been systematically analyzed.

Autism spectrum disorder (ASD) is a major neurodevelopmental disorder affecting 1 in 36 children in the United States. While neurons have been the focus to understand ASD, an altered neuro-immune response in the brain may be closely associated with ASD, and a neuro-immune interaction could play a role in the disease progression.

Proline-rich transmembrane protein 2 (PRRT2) is the single causative gene for pleiotropic paroxysmal syndromes, including epilepsy, kinesigenic dyskinesia, episodic ataxia, and migraine. PRRT2 is a neuron-specific type-2 membrane protein with a COOH-terminal intramembrane domain and a long proline-rich NH2-terminal cytoplasmic region. A large array of experimental data indicates that PRRT2 is a neuron stability gene that negatively controls intrinsic excitability by regulating surface membrane localization and biophysical properties of voltage-dependent Na+ channels Nav1.2 and Nav1.6, but not Nav1.1.

This study was aimed to analyze the commonalities and distinctions of voltage- gated sodium channels, Nav1.2, Nav1.6, in neurodevelopmental disorders. An observational study was performed including two patients with neurodevelopmental disorders. The demographic, electroclinical, genetic, and neuropsychological characteristics were analyzed and compared with each other and then with the subjects carrying the same genetic variants reported in the literature.

Pathogenic variants in SCN2A are associated with a range of neurodevelopmental disorders (NDD). SCN2A-related NDD show wide phenotypic heterogeneity, suggesting that modifying factors must be considered in order to properly elucidate the mechanisms of pathogenic variants. Recently, we characterized neurological phenotypes in a mouse model of the variant SCN2Ap.K1422E. We demonstrated that heterozygous Scn2aK1422E female mice showed a distinct, reproducible distribution of flurothyl-induced seizure thresholds.

Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel NaV1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that NaV1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism.

Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. As a consequence, therapeutic decision-making is challenging without molecular testing of each variant.

The pore-forming subunits (α subunits) of voltage-gated sodium channels (VGSC) are encoded in humans by a family of nine highly conserved genes. Among them, SCN1A, SCN2A, SCN3A, and SCN8A are primarily expressed in the central nervous system.

In 72 patients with SCN2A variants, the seizure onset age ranged from the first day of life to 2 years and 6 months. The epilepsy phenotypes included febrile seizures (plus) (n = 2), benign (familial) infantile epilepsy (n = 9), benign familial neonatal-infantile epilepsy (n = 3), benign neonatal epilepsy (n = 1), West syndrome (n = 16), ...

The genetic developmental and epileptic encephalopathies (DEEs) comprise a large group of severe epilepsy syndromes, with a wide phenotypic spectrum. Currently, the rates of convulsive status epilepticus (CSE), nonconvulsive status epilepticus (NCSE), and sudden unexplained death in epilepsy (SUDEP) in these diseases are not well understood.

The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes.

Perampanel, an antiseizure drug with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist properties, may have a targeted effect in genetic epilepsies with overwhelming glutamate receptor activation. Epilepsies with loss of γ-aminobutyric acid inhibition (e.g., SCN1A), overactive excitatory neurons (e.g., SCN2A, SCN8A), and variants in glutamate receptors (e.g., GRIN2A) hold special interest.

Many previous genetic studies in autism spectrum disorder (ASD), a neurodevelopmental condition characterized by social communication difficulties and repetitive behaviors1, focused on de novo variants (DNVs) identified from parentoffspring trios2–8.

Epilepsy is one of the most common neurological diseases. Epileptic individuals are faced with seizures, which are largely caused by enhanced neuronal excitability and/or decreased neuronal inhibitory activity. SCN2A encodes a neuronal voltage-gated sodium channel, NaV 1.2 that is ...

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy.

Pathogenic variants in the voltage-gated sodium channel gene family lead to early onset epilepsies, neurodevelopmental disorders, skeletal muscle channelopathies, peripheral neuropathies and cardiac arrhythmias. Disease-associated variants have diverse functional effects ranging from complete loss-of-function to marked gain-of-function.

Episodic ataxia (EA), characterized by recurrent attacks of cerebellar dysfunc tion, is the manifestation of a group of rare autosomal dominant inherited disorders. EA1 and EA2 are most frequently encountered, caused by mutations in KCNA1 and CACNA1A.

Pathogenic variants in neuronal voltage-gated sodium (NaV) channel genes including SCN2A, which encodes NaV1.2, are frequently discovered in neurodevelopmental disorders with and without epilepsy.

Mutations in the SCN2A gene encoding the voltage-gated sodium channel Nav1.2 are one of the most frequent monogenic causes of neurodevelopmental disorders, with a number of distinct phenotypes reported.

The majority of autism spectrum disorder (ASD) risk genes are associated with ASD due to haploinsufficiency, where only one gene copy is functional.

Autism spectrum disorder (ASD) affects ~2% of the population in the US, and monogenic forms of ASD often result in the most severe manifestation of the disorder.

Out of 176 received responses, the most common genetic diagnoses reported were SCN2A (n=42/173, 24%), SLC6A1 (n=28/173, 16%), SCN1A (n=22/173, 13%), and KCNQ2 (n=21/173, 12%).

A new class of therapies based on transfer RNA could treat forms of cystic fibrosis, muscular dystrophy, genetic epilepsies, and more

Aim: To determine whether functional impairments and autonomic symptoms are correlated in young people with developmental and epileptic encephalopathies (DEEs).

Genetic variants in SCN2A, encoding the NaV1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to infantile epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to developmental delay and/or autism spectrum disorder with or without comorbid seizures.

Within the central nervous system (CNS), voltage-gated Na+ (NaV) channels such as the SCN2A-encoded NaV1.2 initiate action potentials (APs) and are thus fundamental to defining neuronal excitability. In addition to NaV1.2, which is found in excitatory neurons and a small set of inhibitory interneurons (1), the major NaV channels are SCN1A-encoded NaV1.1 (expressed mainly in inhibitory neurons), SCN3A-encoded NaV1.3 (expressed in embryonic neurons), and SCN8A-encoded NaV1.6 (found in excitatory and inhibitory neurons).

Over the last decade, more than 100 genetic etiologies have been identified for neurodevelopmental disorders, which include the developmental and epileptic encephalopathies (DEE). The DEE are a group of childhood epilepsies associated with multiple neurological and non-neurological comorbidities that frequently start in the first years of life and are associated with drug-resistant epilepsy

Autism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein NaV1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons.

SCN2A encodes the voltage-gated sodium channel Nav1.2, which is primarily expressed in the cortex and several subcortical structures. Its role in neurodevelopmental disorders was first appreciated in the context of benign familial neonatal and infantile seizures; however, it is now recognized to play key roles in more severe neurodevelopmental disorders including autism and severe encephalopathies associated with epilepsy.

Dysfunction of the autonomic nervous system (ANS) is an increasingly recognized health problem in the pediatric population. Patients with ANS dysfunction may present with a number of seemingly unrelated symptoms, including lightheadedness on standing, syncope, labile blood pressure, problems with sweating or thermoregulation, gastrointestinal dysmotility, bladder urgency or incontinence, and sleep abnormalities.

Mutations in the SCN2A gene encoding a voltage-gated sodium channel Nav1.2 are associated with epilepsies, intellectual disability, and autism. SCN2A gain-of-function mutations cause early-onset severe epilepsies, while loss-of-function mutations cause autism with milder and/or later-onset epilepsies. Here we show that both heterozygous Scn2a-knockout and knock-in mice harboring a patient-derived nonsense mutation exhibit ethosuximide-sensitive absence-like seizures associated with spike-and-wave discharges at adult stages.

The splicing of pre-mRNAs into mature transcripts is remarkable for its precision, but the mechanisms by which the cellular machinery achieves such specificity are incompletely understood. Here, we describe a deep neural network that accurately predicts splice junctions from an arbitrary pre-mRNA transcript sequence, enabling precise prediction of noncoding genetic variants that cause cryptic splicing.

Efforts to identify the causes of autism spectrum disorders have highlighted the importance of both genetics and environment, but the lack of human models for many of these disorders limits researchers’ attempts to understand the mechanisms of disease and to develop new treatments. Induced pluripotent stem cells offer the opportunity to study specific genetic and environmental risk factors, but the heterogeneity of donor genetics may obscure important findings.

The efficacy of valproic acid (VPA) varies widely in clinical treatment of epileptic patients. Our study is aimed at exploring a potential association between polymorphisms of SCN1A, SCN2A, and UGT2B7 genetic factors and VPA responses. Methods. In this observational study, a total of 114 epileptic patients only treated with VPA for at least 1 year were included to explore the genetic polymorphisms of drug responses (mean follow-up time: 3:68 ± 1:78 years).

On August 2–3, 2019, the FamilieSCN2A Foundation held their biennial SCN2A Professional and Family meeting, in Seattle, Washington. The gathering brought together 37 families of individuals with mutations in the SCN2A gene, 60 investigators, eight clinicians and five industry groups that conduct research and/or clinical work on conditions related to this genetic change. A number of SFARI scientists and staff also attended the event.

Clinical exome sequencing is frequently used to identify gene-disrupting variants in individuals with neurodevelopmental disorders. While splice-disrupting variants are known to contribute to these disorders, clinical interpretation of cryptic splice variants outside of the canonical splice site has been challenging. Here, we discuss papers that improve such detection.

We identified a novel de novo SCN2A variant (M1879T) associated with infantile-onset epilepsy that responded dramatically to sodium channel blocker antiepileptic drugs. We analyzed the functional and pharmacological consequences of this variant to establish pathogenicity, and to correlate genotype with phenotype and clinical drug response.

Epileptic encephalopathies are severe forms of infantile-onset epilepsy often complicated by severe neurodevelopmental impairments. Some forms of early-onset epileptic encephalopathy (EOEE) have been associated with variants in SCN2A, which encodes the brain voltage-gated sodium channel NaV1.2.

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, andintellectual disability.SCN2Aencodes the neuronal sodium channel NaV1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms.

SCN2A in benign seizures, autism and epileptic encephalopathy

SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain

SCN2a: This is what you need to know A 2016 UPDATE

BRAIN a journal of neurology published 2017: SCN2A: phenotypes and treatment