Abstracts

Rationale: A novel SCN1A mutation was discovered in a patient who clinically fulfilled the criteria for malignant migrating partial seizures of infancy. The full-term, female patient had seizure onset at two months, with progression of hemiclonic, apneic, and generalized tonic-clonic seizures leading to recurrent status epilepticus and fatality at nine months of age. The ictal EEG showed migratory seizure foci and evolved until ictal and interictal EEGs became indistinguishable. We further characterize this novel SCN1A mutation. Methods: Extensive metabolic, radiologic, and electrodiagnostic studies were undertaken. Genomic DNA was isolated from blood and submitted for commercial testing. The missense mutation was identified and confirmed in brain DNA obtained at autopsy. Genomic DNA from patient brain was analyzed by comparative genome hybridization and the coding exons of SCN9A were amplified. Quantitation studies of the mutant transcript were performed. Results: The heterozygous missense mutation c.C5006A was identified by sequencing genomic DNA from blood and was confirmed in brain DNA upon autopsy. The resulting amino acid substitution p.A1669E alters an evolutionarily conserved residue in an intracellular linker of domain 4 of the channel protein. The mutant transcript is found to be expressed at levels comparable to the wildtype allele in brain RNA. No variation in copy number was detected in the chromosome region 2q24 containing SCN1A or elsewhere in the genome. No mutations were detected in the linked sodium channel gene SCN9A, which has been reported to act as a modifier of SCN1A mutations. Conclusions: More than 600 mutations of SCN1A have been reported, most of them in patients with the sporadic syndrome severe myoclonic epilepsy of infancy (SMEI), also known as Dravet syndrome. Mutations have also been reported in patients with the related variant syndrome, SME-Borderland (SMEB), and in the milder, inherited epilepsy syndrome known as GEFS , or generalized epilepsy with febrile seizures plus other seizure types. This report expands the spectrum of SCN1A epileptic encephalopathies to include malignant migrating partial seizures of infancy.