SCN2A 突变的临床谱扩展至大田原综合征。
Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome.
机构信息
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.
出版信息
Neurology. 2013 Sep 10;81(11):992-8. doi: 10.1212/WNL.0b013e3182a43e57. Epub 2013 Aug 9.
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.
目的
我们旨在研究 SCN2A 突变与早发性癫痫性脑病（EOEE）之间可能存在的关联。
方法
我们共招募了 328 名 EOEE 患者，其中包括 67 名大田原综合征（OS）患者和 150 名 West 综合征患者。通过高分辨率熔解分析或全外显子组测序检测 SCN2A 突变。
结果
我们在 15 名患者中发现了 14 种新的 SCN2A 错义突变：67 例 OS 病例中有 9 例（13.4%），150 例 West 综合征病例中有 1 例（0.67%），111 例未分类的 EOEE 中有 5 例（4.5%）。14 个突变中有 12 个被确认为新生突变，所有突变均未在 212 个对照外显子中出现。在一名患者中检测到一个新生镶嵌突变（c.3976G>C），其突变等位基因频率为 18%。在转录变体 3 中发现一个突变（c.634A>G），这是一种新生儿同工型。OS 患者中的 9 个突变均位于 2 个跨膜段之间的连接区。在 9 名 OS 患者中，7 名患者的脑电图从抑制-爆发模式转变为高度不规则性。所有 15 名患有新型 SCN2A 错义突变的患者均有难治性癫痫发作；其中 3 名在最后一次体检时无癫痫发作。所有患者均表现出严重的发育迟缓。
结论
我们的研究证实 SCN2A 突变是 OS 的一个重要遗传病因。鉴于 SCN2A 突变与广泛的临床表型相关，对于不同癫痫状态的儿童，应考虑进行 SCN2A 基因检测。
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