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Early onset epileptic encephalopathy caused by de novo SCN 8A mutations
Author(s) -
Ohba Chihiro,
Kato Mitsuhiro,
Takahashi Satoru,
LermanSagie Tally,
Lev Dorit,
Terashima Hiroshi,
Kubota Masaya,
Kawawaki Hisashi,
Matsufuji Mayumi,
Kojima Yasuko,
Tateno Akihiko,
GoldbergStern Hadassa,
Straussberg Rachel,
Marom Dafna,
LeshinskySilver Esther,
Nakashima Mitsuko,
Nishiyama Kiyomi,
Tsurusaki Yoshinori,
Miyake Noriko,
Tanaka Fumiaki,
Matsumoto Naomichi,
Saitsu Hirotomo
Publication year - 2014
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12668
Subject(s) - missense mutation , exome sequencing , epilepsy , medicine , west syndrome , mutation , epileptic spasms , pediatrics , genetics , biology , gene , psychiatry
Summary 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 ( EOEE s). Methods A total of 163 patients with EOEE s without mutations in known genes, including 6 with malignant migrating partial seizures in infancy ( MMPSI ), and 60 with unclassified EOEE s, 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 EOEE s (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 EOEE s, 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 .