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