Abstracts

Rationale: Malignant Migrating Partial Seizures of Infancy (MMPSI) is one of the most devastating infantile epileptic encephalopathies (EE). The cause is not known. Many of the infantile-onset EE remain without an etiological diagnosis despite patients undergoing complicated protocols including advanced imaging and metabolic testing. Mutations in SCN1A, CDKL5, STXBP1, PCDH19 and POLG1 genes are associated with specific EE. In particular, SCN1A mutations are found in the recently described syndrome of Severe Infantile Multi-Focal Epilepsy (SIMFE). MMPSI could be regarded as an earlier onset, more severe form of SIMFE; this observation led us to ask whether it could be due to mutations in SCN1A as well as other genes associated with a range of EE. Methods: Fifteen unrelated children with MMPSI were recruited internationally. Detailed phenotyping was performed. Patients were screened for mutations in SCN1A, CDKL5, STXBP1, PCDH19 genes, the three common mutations of POLG1 and 7 patients had microarray analysis for copy number variation. Results: One patient had a de novo SCN1A missense mutation R862G which affects the voltage sensor segment of SCN1A; the same amino acid R862 has been found mutated in Dravet syndrome (R862Q;unpublished data). A second patient had a de novo deletion spanning 11.06 Mb within the 2q24-q31.1 region that includes more than 40 genes. The deletion includes SCN1A as well as other sodium channel subunit genes and similar deletions have been previously reported. Screening of CDKL5 (13/15), STXBP1 (13/15), PCDH19 (9/10 females), the three common European mutations of POLG1 (11/15) and the microarray studies (6/7) were otherwise negative. Conclusions: We report the first gene mutation found in a patient with MMPSI and a deletion encompassing the same sodium channel gene. Epilepsies associated with SCN1A mutations range in severity from febrile seizures to severe epileptic encephalopathies including Dravet Syndrome and Severe Infantile Multifocal Epilepsy. MMPSI is the most severe SCN1A associated phenotype described to date. Whilst not a common cause of MMPSI, SCN1A screening should be considered in patients with this devastating epileptic encephalopathy.