Abstract
Mutations of the voltage-gated sodium channel SCN8A have been identified in approximately 1% of nearly 1,500 children with early-infantile epileptic encephalopathies (EIEE) who have been tested by DNA sequencing. EIEE caused by mutation of SCN8A is designated EIEE13 (OMIM #614558). Affected children have seizure onset before 18 months of age as well as developmental and cognitive disabilities, movement disorders, and a high incidence of sudden death (SUDEP). EIEE13 is caused by de novo missense mutations of evolutionarily conserved residues in the Nav1.6 channel protein. One-third of the mutations are recurrent, and many occur at CpG dinucleotides. In this review, we discuss the effect of pathogenic mutations on the structure of the channel protein, the rate of recurrent mutation, and changes in channel function underlying this devastating disorder.
Highlights
Neuronal voltage-gated sodium channels contain one large, pore-forming α subunit and two smaller β subunits [1]
The sodium channel α subunit genes SCN1A, SCN2A, and SCN8A are broadly expressed in brain neurons, where they play a critical role in the regulation of neuronal excitability
Mutations in each of these closely related genes can result in early-infantile epileptic encephalopathy (EIEE), characterized by early-onset seizures that are refractory to treatment and accompanied by cognitive and behavioral disabilities [2, 3]
Summary
Neuronal voltage-gated sodium channels contain one large, pore-forming α subunit and two smaller β subunits [1]. The recent introduction of exome sequencing in patients with early-onset epileptic encephalopathy resulted in identification of de novo mutation of SCN8A as an important cause of this nonfamilial disorder. Sodium channel blockers usually exacerbate seizures in patients with Dravet syndrome, which is caused by a deficiency of SCN1A activity. CpG dinucleotides are mutation hotspots that can undergo enzymatic methylation of cytosine followed by spontaneous deamination of the methylated C to form thymine (Figure 2) Both of these arginine codons contain CpG sequences on coding and non-coding strands, and CpG deamination at these sites can account for most of the observed amino acid substitutions (Figure 2). Clinical information is available for five patients with the p.Arg1617Gln mutation
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