Early onset epileptic encephalopathy caused by de novo SCN8A mutations

Chihiro Ohba, Mitsuhiro Kato, Satoru Takahashi, Tally Lerman-Sagie, Dorit Lev, Hiroshi Terashima, Masaya Kubota, Hisashi Kawawaki, Mayumi Matsufuji, Yasuko Kojima, Akihiko Tateno, Hadassa Goldberg-Stern, Rachel Straussberg, Dafna Marom, Esther Leshinsky-Silver, Mitsuko Nakashima, Kiyomi Nishiyama, Yoshinori Tsurusaki, Noriko Miyake, Fumiaki TanakaNaomichi Matsumoto, Hirotomo Saitsu

Research output: Contribution to journalArticlepeer-review

115 Scopus citations


Objective De novo SCN8A mutations have been reported in patients with epileptic encephalopathy. Herein we report seven patients with de novo heterozygous SCN8A mutations, which were found in our comprehensive genetic analysis (target capture or whole-exome sequencing) for early onset epileptic encephalopathies (EOEEs). Methods A total of 163 patients with EOEEs without mutations in known genes, including 6 with malignant migrating partial seizures in infancy (MMPSI), and 60 with unclassified EOEEs, were analyzed by target capture (28 samples) or whole-exome sequencing (135 samples). Results We identified de novo SCN8A mutations in 7 patients: 6 of 60 unclassified EOEEs (10.0%), and one of 6 MMPSI cases (16.7%). The mutations were scattered through the entire gene: four mutations were located in linker regions, two in the fourth transmembrane segments, and one in the C-terminal domain. The type of the initial seizures was variable including generalized tonic-clonic, atypical absence, partial, apneic attack, febrile convulsion, and loss of tone and consciousness. Onset of seizures was during the neonatal period in two patients, and between 3 and 7 months of age in five patients. Brain magnetic resonance imaging (MRI) showed cerebellar and cerebral atrophy in one and six patients, respectively. All patients with SCN8A missense mutations showed initially uncontrollable seizures by any drugs, but eventually one was seizure-free and three were controlled at the last examination. All patients showed developmental delay or regression in infancy, resulting in severe intellectual disability. Significance Our data reveal that SCN8A mutations can cause variable phenotypes, most of which can be diagnosed as unclassified EOEEs, and rarely as MMPSI. Together with previous reports, our study further indicates that genetic testing of SCN8A should be considered in children with unclassified severe epilepsy. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Original languageEnglish
Pages (from-to)994-1000
Number of pages7
Issue number7
StatePublished - Jul 2014
Externally publishedYes


FundersFunder number
Japan Science and Technology Agency
Japan Society for the Promotion of Science
Japan Society for the Promotion of Science24591500, 25293085, 25293235, 24249019


    • De novo mutation
    • Early onset epileptic encephalopathies
    • SCN8A


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