Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome.
OBJECTIVE
We aimed to investigate the possible association between SCN2A mutations and early-onset epileptic encephalopathies (EOEEs).


METHODS
We recruited a total of 328 patients with EOEE, including 67 patients with Ohtahara syndrome (OS) and 150 with West syndrome. SCN2A mutations were examined using high resolution melt analysis or whole exome sequencing.


RESULTS
We found 14 novel SCN2A missense mutations in 15 patients: 9 of 67 OS cases (13.4%), 1 of 150 West syndrome cases (0.67%), and 5 of 111 with unclassified EOEEs (4.5%). Twelve of the 14 mutations were confirmed as de novo, and all mutations were absent in 212 control exomes. A de novo mosaic mutation (c.3976G>C) with a mutant allele frequency of 18% was detected in one patient. One mutation (c.634A>G) was found in transcript variant 3, which is a neonatal isoform. All 9 mutations in patients with OS were located in linker regions between 2 transmembrane segments. In 7 of the 9 patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia. All 15 of the patients with novel SCN2A missense mutations had intractable seizures; 3 of them were seizure-free at the last medical examination. All patients showed severe developmental delay.


CONCLUSIONS
Our study confirmed that SCN2A mutations are an important genetic cause of OS. Given the wide clinical spectrum associated with SCN2A mutations, genetic testing for SCN2A should be considered for children with different epileptic conditions.
From the Department of Human Genetics (K. Nakamura, K. Nishiyama, H.K., M.N., Y.T., N. Miyake, N. Matsumoto, H.S.), Yokohama City University Graduate School of Medicine, Yokohama; Department of Pediatrics (K. Nakamura, M.K., K. Hayasaka), Yamagata University Faculty of Medicine, Yamagata; Division of Neurology (H.O., S.Y., M. Okuda, T.W.), Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama; Department of Child Neurology (E.N.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Pediatric Neurology (K. Haginoya), Takuto Rehabilitation Center for Children, Sendai; Department of Pediatrics (J.T.), Epilepsy Center, Nishi-Niigata Chuo National Hospital, Niigata; Department of Pediatrics (S.S.), Osaka Medical College Hospital, Osaka; National Epilepsy Center (K.I.), Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka; Department of Pediatrics (S.T.), Yokohama City University Medical Center, Yokohama; Department of Pediatrics (H.I.), Tokyo Metropolitan Bokuto Hospital, Tokyo, Japan; Metabolic Neurogenetic Clinic (D.L., T.L.-S.), Wolfson Medical Center, Holon, Israel; Department of Human Genetics (D.E.C.-B., C.E.V.), National Institute of Pediatrics, Mexico City, Mexico; Division of Child Neurology (M. Ohfu), Okinawa Nanbu Medical Center and Children's Medical Center, Okinawa, Japan; Institute of Medical Genetics (K.W.), University Medical Center Ljubljana; Department of Child, Adolescent and Developmental Neurology (B.G.S.), University Children's Hospital, Ljubljana, Slovenia; Department of Neurology (S.H.), Nagano Children's Hospital, Nagano, Japan; Department of Obstetrics and Gynecology (D.C.), The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, University of Toronto; and Division of Clinical and Metabolic Genetics (D.C., D.M.R.), The Hospital for Sick Children, University of Toronto, Canada.
Kazuyuki
K
Nakamura
Mitsuhiro
M
Kato
Hitoshi
H
Osaka
Sumimasa
S
Yamashita
Eiji
E
Nakagawa
Kazuhiro
K
Haginoya
Jun
J
Tohyama
Mitsuko
M
Okuda
Takahito
T
Wada
Shuichi
S
Shimakawa
Katsumi
K
Imai
Saoko
S
Takeshita
Hisako
H
Ishiwata
Dorit
D
Lev
Tally
T
Lerman-Sagie
David E
DE
Cervantes-Barragán
Camilo E
CE
Villarroel
Masaharu
M
Ohfu
Karin
K
Writzl
Barbara
B
Gnidovec Strazisar
Shinichi
S
Hirabayashi
David
D
Chitayat
Diane
D
Myles Reid
Kiyomi
K
Nishiyama
Hirofumi
H
Kodera
Mitsuko
M
Nakashima
Yoshinori
Y
Tsurusaki
Noriko
N
Miyake
Kiyoshi
K
Hayasaka
Naomichi
N
Matsumoto
Hirotomo
H
Saitsu
D001921:Brain / Q000473:pathology* / Q000503:physiopathology*; D004569:Electroencephalography; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics*; D013036:Spasms, Infantile / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
D062551:NAV1.2 Voltage-Gated Sodium Channel; C568251:SCN2A protein, human