[LS3] Luncheon Seminar 3: Epilepsy

[LS3-1C-2] Childhood Epilepsy and Brain Somatic Mutations

^○Jun TOHYAMA^{1, 2} (1.Department of Pediatrics, Nishi-Niigata Chuo National Hospital, Japan, 2.Bioscience Medical Research Center, Niigata University Medical and Dental Hospital, Japan)

Recent genetic studies have elucidated causative roles for genetic abnormalities in epilepsy. In addition, somatic mutation has been shown to be one of the underlying causes for childhood epilepsy. For example, germline and somatic mutations in genes involved in PI3K-AKT3-mTOR pathway cause a spectrum of megalencephaly related disorders. Recently, we identified the low-prevalence somatic MTOR mutations in the developing brain are a major genetic cause of focal cortical dysplasia (FCD) type IIb. Somatic MTOR mutations in FCD type IIb are likely to cause hyperactivation of the mTOR-signaling pathway, implying that the mTOR inhibitors would be able to alleviate intractable epilepsy in FCD type IIb. Hypothalamic hamartoma (HH) is observed in syndromic disorders such as Pallister-Hall syndrome (PHS) and oral-facial-digital syndrome (OFD), and germline nonsense mutations in GLI3 and OFD1 are known to cause PHS and OFD type I, respectively. We also identified hamartoma-specific somatic mutations in GLI3 and OFD1 in patients with HH, suggesting that impaired sonic hedgehog signalling is one of the pathomechanisms of HH. Our data indicate that human disorders associated with childhood epilepsy can be caused by lesion-specific somatic mutations.