Novel SCN1A Mutation in a Proband With Malignant Migrating Partial Seizures of Infancy

Abstract

Objective To characterize a novelSCN1Amutation in a proband with malignant migrating partial seizures of infancy. Design Genomic DNA was isolated from blood and submitted for commercial testing. The identified missense mutation was confirmed in brain DNA obtained at autopsy. Genomic DNA from the brain of the proband was analyzed by comparative genome hybridization, and the coding exons ofSCN9Awere amplified. Quantitation studies of the mutant transcript were performed. Setting Children’s National Medical Center and Yale University School of Medicine. Proband A full-term female infant who experienced seizure onset at age 10 weeks, with progression of hemiclonic, apneic, and multifocal migrating partial seizures leading to recurrent status epilepticus and death at age 9 months. Main Outcome Measures Electroencephalographic and magnetic resonance imaging results, quantitative RNA expression, and secondary mutation test results. Results The heterozygous missense mutation c.C5006C>A was identified by sequencing genomic DNA from blood and was confirmed in brain DNA. The resulting amino acid substitution p.A1669E alters an evolutionarily conserved residue in an intracellular linker of domain 4 of theSCN1Asodium channel protein Na_v1.1. The mutant transcript is found to be expressed at levels comparable to the wild-type allele in brain RNA. No variation in copy number was detected in the chromosome region 2q24 containingSCN1Aor elsewhere in the genome. No mutations were detected in the linked sodium channel geneSCN9A, which has been reported to act as a modifier ofSCN1Amutations. Conclusion This report expands the spectrum ofSCN1Aepileptic channelopathies to include malignant migrating partial seizures of infancy.