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.

Case Report: Novel Homozygous Likely Pathogenic SCN1A Variant With Autosomal Recessive Inheritance and Review of the Literature

Dominant pathogenic variations in the SCN1A gene are associated with several neuro developmental disorders with or without epilepsy, including Dravet syndrome (DS). Conversely, there are few published cases with homozygous or compound heterozygous variations in the SCN1A gene. Here, we describe two siblings from a consanguineous pedigree with epilepsy phenotype compatible with genetic epilepsy with febrile seizures plus (GEFS+) associated with the homozygous likely pathogenic variant (NM_001165963.1): c.4513A > C (p.Lys1505Gln). Clinical and genetic data were compared to those of other 10 previously published patients with epilepsy and variants in compound heterozygosity or homozygosity in the SCN1A gene. Most patients (11/12) had missense variants. Patients in whom the variants were located at the cytoplasmic or the extracellular domains frequently presented a less severe phenotype than those in whom they are located at the pore-forming domains. Five of the patients (41.7%) meet clinical criteria for Dravet syndrome (DS), one of them associated acute encephalopathy. Other five patients (41.7%) had a phenotype of epilepsy with febrile seizures plus familial origin, while the two remaining (17%) presented focal epileptic seizures. SCN1A-related epilepsies present in most cases an autosomal dominant inheritance; however, there is growing evidence that some genetic variants only manifest clinical symptoms when they are present in both alleles, following an autosomal recessive inheritance.

Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice

Mutations in the GABRG2 gene encoding the γ-aminobutyric acid (GABA) A receptor gamma 2 subunit are associated with genetic epilepsy with febrile seizures plus, febrile seizures plus, febrile seizures, and other symptoms of epilepsy. However, the mechanisms underlying Gabrg2-mediated febrile seizures are poorly understood. Here, we used the Cre/loxP system to generate conditional knockout (CKO) mice with deficient Gabrg2 in the hippocampus and neocortex. Heterozygous CKO mice (Gabrg2fl/wtCre+) exhibited temperature-dependent myoclonic jerks, generalised tonic-clonic seizures, increased anxiety-like symptoms, and a predisposition to induce seizures. Cortical electroencephalography showed the hyperexcitability in response to temperature elevation in Gabrg2fl/wtCre+ mice, but not in wild-type mice. Gabrg2fl/wtCre+ mice exhibited spontaneous seizures and susceptibility to temperature-induced seizures. Loss of neurons were observed in cortical layers V–VI and hippocampus of Gabrg2fl/wtCre+ mice. Furthermore, the latency of temperature- or pentylenetetrazol-induced seizures were significantly decreased in Gabrg2fl/wtCre+ mice compared with wild-type mice. In summary, Gabrg2fl/wtCre+ mice with Gabrg2 deletion in the neocortex and hippocampus reproduce many features of febrile seizures and therefore provide a novel model to further understand this syndrome at the cellular and molecular level.

SCN1B Gene: A Close Relative to SCN1A

One of the first reported genes associated with epilepsy was SCN1B, which encodes for β-subunit of voltage-gated sodium channel of excitable cells and it is critical for neuronal function in both central and peripheral nervous system. β-subunits modulate the expression levels and functional properties of sodium channels and though their immunoglobulin domains may mediate interactions between channels and other proteins. Traditionally, SCN1B mutations were associated with generalized epilepsy with febrile seizures plus, a familial epilepsy syndrome characterized by heterogeneous phenotypes including febrile seizures (FS), febrile seizures plus (FS + ), mild generalized epilepsies, and severe epileptic encephalopathies. Throughout the years, SCN1B mutations have been also associated with Dravet syndrome and, more recently, with developmental and epileptic encephalopathies, expanding the spectrum associated with this gene mutations to more severe phenotypes.

Genetic epilepsy with febrile seizures plus – an overview

Genetic epilepsy with febrile seizures plus (GEFS+) is characterized by a group of genetic epilepsies associated predominately with an autosomal dominant pattern, but also with de novo and autosomal-recessive inheritance, these last two found in a small number of cases. It was believed that GEFS+ is associated only with generalized seizures, but now the term “genetic epilepsy” is preferred because it has been demonstrated that GEFS+ is associated with both generalized and focal seizures. The “GEFS+ family” was defined as a family with more than two individuals with GEFS+ phenotypes, including at least one with febrile seizure or febrile seizure plus. The GEFS+ spectrum includes febrile seizures (FS), febrile seizures plus (FS+), myoclonic seizures, myoclonic-atonic seizures, absences seizures, focal or generalized seizures. The genetic mutations responsible for inhibitor-excitatory imbalance in neurons network were found in sodium voltage-gated channel alpha subunit 1 (SCN1A), sodium voltage-gated channel beta subunit 1 (SCN1B), sodium voltage-gated channel alpha subunit 2 (SCN2A), sodium voltage-gated channel alpha subunit 9 (SCN9A), gamma-aminobutyric acid type A receptor subunit gamma 2 (GABRG2), which are the main gene in GEFS+ genotype.

Association of SLC32A1 Missense Variants With Genetic Epilepsy With Febrile Seizures Plus

ObjectiveTo identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2,772 additional patients.MethodsWe performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing (ES) data from 1,165 epilepsy patients from the Epi4K dataset and 1,329 Australian epilepsy patients from the Epi25 dataset was interrogated. Targeted resequencing was performed on 278 patients with FS or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing.ResultsEight previously unreported missense variants were identified in SLC32A1, coding for the vesicular inhibitory amino acid co-transporter VGAT. Two variants co-segregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected individuals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE).ConclusionMissense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter GABA transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype-phenotype spectrum associated with SLC32A1 variants.

No association between SCN9A and monogenic human epilepsy disorders

Many studies have demonstrated the clinical utility and importance of epilepsy gene panel testing to confirm the specific aetiology of disease, enable appropriate therapeutic interventions, and inform accurate family counselling. Previously, SCN9A gene variants, in particular a c.1921A>T p.(Asn641Tyr) substitution, have been identified as a likely autosomal dominant cause of febrile seizures/febrile seizures plus and other monogenic seizure phenotypes indistinguishable from those associated with SCN1A, leading to inclusion of SCN9A on epilepsy gene testing panels. Here we present serendipitous findings of genetic studies that identify the SCN9A c.1921A>T p.(Asn641Tyr) variant at high frequency in the Amish community in the absence of such seizure phenotypes. Together with findings in UK Biobank these data refute an association of SCN9A with epilepsy, which has important clinical diagnostic implications.