Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures

Abstract

A group of infant onset epilepsies manifest very frequent generalized tonic-clonic seizures (GTC) intractable to medical therapy, which may or may not be accompanied by minor seizures such as myoclonic seizures, absences and partial seizures. They include severe myoclonic epilepsy in infancy (SMEI) and intractable childhood epilepsy with GTC (ICEGTC). They are commonly associated with fever-sensitivity, family history of seizure disorders and developmental decline after seizure onset. Mutations of the neuronal voltage-gated sodium channel alpha subunit type 1 gene (SCN1A) were recently reported in SMEI patients. To clarify the genotypic differences in this group of epilepsies, we searched for SCN1A abnormalities in 25 patients with SMEI and 10 with ICEGTC, together with the family members of 15 patients. Frameshift mutations in SCN1A were observed in four patients, nonsense mutations in five patients, missense mutations in 21 patients, other mutations in two patients and no mutation in five patients. SMEI patients showed nonsense mutations, frameshifts, or missense mutations, while ICEGTC patients showed only missense mutations. Study of both parents of 11 patients revealed that the mutations in these patients were de novo. However, two mothers had the same missense mutations as their ICEGTC children, and they had generalized epilepsy with febrile seizures plus. Here we suggest that SMEI and ICEGTC represent a continuum with minor phenotypic and genotypic differences.

Sodium channel genes and the evolution of diversity in communication signals of electric fishes: Convergent molecular evolution

“…It will also be intriguing to see whether any of these other genes show comparable alterations in expression or sequence especially in those species with extremely rapid EOD pulses. Na ϩ channel genes are highly constrained, as evidenced by the large number of amino acid replacements that change the properties of the Na ϩ current and lead to neurological, cardiac, and muscular diseases (15)(16)(17)(18)(19)(20). A critical step in the evolution of electric organs is the disabling of excitation-contraction so that the organ does not twitch when it discharges.…”

“…We focused on Na ϩ channel genes because the EOD in at least one species of gymnotiform is shaped by the properties of the EO Na ϩ current (10) and because of the wealth of information on channel structure͞function from site-directed mutagenesis and point mutations underlying clinical syndromes (15)(16)(17)(18)(19)(20).…”

Molecular Targets for Antiepileptic Drug Development

“…43,44 Intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTCS), also due to mutations in SCN1A, is similar clinically to SMEI except that there is reduced severity of psychomotor impairment and no myoclonus. 45 Mutations in SCN2A have recently been associated with benign familial neonatal-infantile seizures (BFNIS) 46 ; the functional effects of these mutations are not known.…”

“…Connexins (Cx) 26,29,30,32,36,37,40,43,45,46, and 47 are expressed in the brain, with marked variation according to developmental stage and cell type. 402 In astrocytes, where a key function for gap junctions is calcium wave signaling, Cx43 is the major connexin.…”

Moving gating charges through the gating pore in a Kv channel voltage sensor

“…Similarly, in the related VSD of human voltage-gated sodium channels, the inherited gating pore mutations I739V in Nav1.7, I141V in Nav1.4, F1250L in Nav1.5, and V1611F and V1612I in Nav1.1 (respectively homologous to residues I237, I241, F290, A319, and I320 in Shaker) are linked to Dravet syndrome (I739V, V1611F, and V1612I), paramyotonia congenita (I141V), and long QT syndrome (F1250L) (32)(33)(34)(35)(36)(37) (Fig. 1B).…”