SCN1A‐related phenotypes: Epilepsy and beyond

Abstract

SCN1A, encoding the alpha 1 subunit of the sodium channel, is associated with several epilepsy syndromes and a range of other diseases. SCN1A represents the archetypal channelopathy associated with a wide phenotypic spectrum of epilepsies ranging from genetic epilepsy with febrile seizures plus (GEFS+), to developmental and epileptic encephalopathies (DEEs). SCN1A disorders also result in other diseases such as hemiplegic migraine and autism spectrum disorder (ASD). Dravet syndrome (DS) is the prototypic DEE with an early onset of febrile status epilepticus, hemiclonic or generalized tonic‐clonic seizures, and later onset of additional seizure types. Electroencephalography (EEG) and magnetic resonance imaging (MRI) are normal at onset. Development is normal in the first year of life but plateaus rapidly, with most patients ultimately having intellectual disability. Epilepsy is drug‐resistant and necessitates polytherapy. Most pathogenic variants occur de novo in the affected child, but they are inherited from mosaic affected or unaffected parents in rare cases. The molecular finding of haploinsufficiency is consistent with a loss‐of‐function defect in cells and animal models. Although seizures are the most commonly reported symptom in DS, many additional issues critically affect patients’ cognitive and behavioral functioning. Hemiplegic migraine (HM) is a rare form of migraine with aura, characterized by the emergence of hemiparesis as part of the aura phase. All SCN1A mutations reported in sporadic/familial HM3 are missense mutations. Most of the experimental results show that they cause a gain of function of NaV1.1 as opposed to the loss of function of the epileptogenic NaV1.1 mutations. SCN1A and SCN2A pathogenic variants have been identified in genetic studies of cohorts of patients with ASD. In addition, ASD features are often reported in patients with Dravet syndrome and other DEEs.

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

“…Heterozygous loss-of-function variants of SCN1A are identified in approximately 80% of patients with Dravet syndrome, which is characterized by fever-induced status epilepticus, refractory myoclonic and absence seizures, ataxia, intellectual disability and autistic features [ 6 ]. Importantly, the pathogenic SCN1A variants have a wide range of phenotypes, which may be also identified in patients with other types of DEE, such as EIEE or milder forms of epilepsy such as genetic epilepsy with febrile seizures plus (GEFS+) [ 7 ]. On the other hand, SCN2A and SCN8A play essential roles in the excitability of glutamatergic neurons and most DEE-associated variants of both these genes are missense with gain-of-function [ 8 , 9 , 10 ].…”

The Genetic Relationship between Paroxysmal Movement Disorders and Epilepsy

“…2) SCN1A SCN1A, which encodes the α1 subunit of the sodium channel, is associated with a range of human diseases [69]. The most well-recognized epilepsy phenotype associated with SCN1A is the Dravet syndrome but it also results in several other epilepsy syndromes ranging from self-limited and pharmacoresponsive epilepsies, such as genetic epilepsy with febrile seizures plus, Dravet syndrome, myoclonic-atonic epilepsy, and epilepsy of infancy with migrating focal seizures.…”

“…The most well-recognized epilepsy phenotype associated with SCN1A is the Dravet syndrome but it also results in several other epilepsy syndromes ranging from self-limited and pharmacoresponsive epilepsies, such as genetic epilepsy with febrile seizures plus, Dravet syndrome, myoclonic-atonic epilepsy, and epilepsy of infancy with migrating focal seizures. SCN1A disorders also result in other neurological disorders such as hemiplegic migraine, intellectual disability, and autism spectrum disorder [69].…”

“…Familial hemiplegic migraine type 3 is caused by heterozygous pathogenic variants of the SCN1A [70]. In contrast to familial hemiplegic migraine due to CACNA1A and ATP1A2 mutations, in the few patients with familial hemiplegic migraine type 3 carrying SCN1A mutations and presenting with seizures [69], hemiplegic migraine attacks are always independent from seizures and the two phenotypes do not generally overlap temporally [69]. All SCN1A mutations reported in familial hemiplegic migraine type 3 are missense mutations.…”

“…Most experimental results show that they cause a gain-of-function of Nav1.1 [71]. Cellular and animal data point to an increased excitability of gamma-aminobutyric acid (GABAergic) neurons in familial hemiplegic migraine type 3, which is a different mechanism from that seen in epileptogenic Nav1.1 mutations [69].…”