We investigated how two distinct mutations in SCN1A differentially affect electrophysiological properties of the patient-derived GABAergic neurons and clinical severities in two Dravet syndrome (DS) patients.
Deletions and duplications/amplifications of the α1-sodium channel subunit (SCN1A) gene occur in about 12% of patients with Dravet syndrome (DS) who are otherwise mutation-negative.
Epilepsies associated with SCN1A mutations range in severity from febrile seizures to severe epileptic encephalopathies including Dravet syndrome and severe infantile multifocal epilepsy.
Mutations in the voltage-gated sodium channel (VGSC) gene SCN1A, encoding the Na<sub>v</sub>1.1 channel, are responsible for a number of epilepsy disorders including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS).
Our aim was the molecular analysis of SCN1A gene in affected Iranian patients with GEFS+ and Dravet syndrome diagnosed clinically to explain genotype-phenotype correlation and exact classification.
We report on the use of the voltage-gated calcium channel blocker (Vg-CCB), verapamil, as an add-on anticonvulsant medication in two girls, 4 and 14 years of age, who were affected by severe myoclonic epilepsy in infancy (SMEI) or Dravet syndrome, a channelopathy caused by abnormalities in the voltage-gated sodium channel neuronal type alpha1 subunit (SCN1A) gene at 2q24.
On the other hand, 11 known single nucleotide polymorphisms were identified in the SCN1A gene and composed a putative disease-associated haplotype in patients with DS phenotype.
Loss-of-function mutations in human SCN1A gene encoding Nav1.1 are associated with a severe epileptic disorder known as severe myoclonic epilepsy in infancy.
Topics discussed at this meeting included (1) comparison between mutations of SCN8A and the SCN1A mutations in Dravet syndrome, (2) biophysical properties of the Nav 1.6 channel, (3) electrophysiologic effects of patient mutations on channel properties, (4) cell and animal models of SCN8A encephalopathy, (5) drug screening strategies, (6) the phenotypic spectrum of SCN8A encephalopathy, and (7) efforts to develop a bioregistry.
Thus, the discovery of KCNQ2 mutations in benign familial neonatal convulsions, SCN1A mutations in severe myoclonic epilepsy of infancy and in generalized epilepsy with febrile seizures plus, and CHRA4 and CHRB2 mutations in autosomal-dominant nocturnal frontal lobe epilepsy, has led to the establishment of epilepsy as a disorder of ion channel function and, furthermore, has led to the introduction of genetic tests that are available clinically to aid in diagnosis and treatment.
Here we describe that a C57BL/6 J knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V) presents a full spectrum of DS manifestations.
The clinical spectrum of epilepsies harboring SCN1A mutations may be consisted of various phenotypes with GEFS+ on the mildest end and SMEI on the severest end of the spectrum.
Point mutations or microdeletions of SCN1A have previously been identified in SMEI patients, but this is the first report of a balanced translocation disrupting the SCN1A gene in an epilepsy patient.