SCN1A (MIM# 182389) is one of four voltage-gated sodium channel (NaV1.1 a subunit) genes that are widely expressed throughout the central nervous system and play important roles in controlling the excitability of neurons (Plummer and Meisler, 1999). SCN1A is one of the most clinically relevant sodium channel genes because its mutations are known to be associated with a series of common central nervous system disorders, such as epilepsy, autism, and migraines (Weiss et al., 2003; Dichgans et al., 2005; Meisler and Kearney, 2005; Cestele et al., 2008). Each of the four domains (DI–DIV) that comprise the NaV1.1, a1 subunit, consists of six transmembrane segments (S1–S6), and the domains themselves are connected by cytoplasmic loops or linkers (Ishii, 2016).
Voltage-gated sodium channels are essential for the generation and propagation of action potentials in electrically excitable tissues, such as brain, muscle and heart. These channels are hetero-multimeric protein complexes consisting of one and one or two subunits (Catterall, 2000). The pore-forming subunits serve as voltage sensors, whereas the accessory subunits modulate the voltage dependence, kinetics and cellular localization of the subunits. Four α and four β subunits have been identified in the mammalian brain (Ogiwara, 2007)
The phenotypes seen in SCN1A related seizure disorders
SCN1A is associated with several epilepsy syndromes, ranging from relatively mild phenotypes found in families with Genetic Epilepsy Febrile Seizures Plus (GEFS+) to the severe, infant-onset epilepsy, Dravet syndrome (Brunklaus, 2014).
DS is a rare disorder (OMIM: 607208) with an estimated incidence of 1:16,000–1:40,000 births (Ishii, 2016). Approximately three fourths of patients with DS are found to have a variant in the voltage-gated sodium channel gene, SCN1A (Ishii, 2016). Most mutations are novel. Dravet syndrome typically presents itself around 6 months of age, in previously healthy children, with prolonged, febrile and afebrile, generalized clonic or hemiclonic epileptic seizures. Other types include myoclonic, focal and atypical absence seizures which appear between the ages of 1 and 4 years (Dravet, 2005). It is usually not responsive to standard antiepileptic medication, and affected children develop cognitive, behavioral, and motor impairment (Brunklaus, 2014).
The phenotypes seen in SCN1A-related seizure disorders include the following (GeneReview):
- Febrile seizures (FS), which may or may not have features suggestive of an SCN1A-related condition
- Generalized epilepsy with febrile seizures plus (GEFS+)
- Dravet syndrome, also known as severe myoclonic epilepsy in infancy (SMEI) or polymorphic myoclonic epilepsy in infancy (PMEI)
- Severe myoclonic epilepsy, borderline (SMEB)
- Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC), which does not represent an epilepsy defined by ILAE, and is most similar to late-onset Dravet syndrome in the ILAE classification system
- Infantile partial seizures with variable foci, also referred to as migrating partial seizures of infancy, cryptogenic focal epilepsy, or severe infantile multifocal epilepsy (Harkin , 2007)
Note: Terms used in the literature to describe the phenotypes sometimes differ from the standard epilepsy syndrome terminology as defined by the International League Against Epilepsy (ILAE).
Mutation of SCN1A
Over 1,200 variants associated with epilepsy have been reported in SCN1A (Meng, 2015). There are two major classes of variant in SCN1A that are associated with DS: those that result in a premature stop codon which may shorten the protein product (truncating) and those that result in an amino acid substitution (missense). Truncating variants that occur in the first 25 exons of SCN1A (i.e., anywhere but exon 26) are predicted to lead to nonsense- mediated RNA decay and haploinsufficiency (Linde L, 2008). These variants are almost always associated with severe phenotypes, whereas missense variants are associated with a wide spectrum of phenotypes that vary from DS to GEFS+ ( Catterall WA,2012).