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Article(id=1198562265088750583, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558106218230069, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.0561.2024.0418, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1681833600000, receivedDateStr=2023-04-19, revisedDate=null, revisedDateStr=null, acceptedDate=1697731200000, acceptedDateStr=2023-10-20, onlineDate=1763689112207, onlineDateStr=2025-11-21, pubDate=1727452800000, pubDateStr=2024-09-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763689112207, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763689112207, creator=13701087609, updateTime=1763689112207, updator=13701087609, issue=Issue{id=1198558106218230069, tenantId=1146029695717560320, journalId=1189873630562394117, year='2024', volume='49', issue='9', pageStart='977', pageEnd='1098', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1763688120655, creator=13701087609, updateTime=1763689155065, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1198562444915339352, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558106218230069, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198562444915339353, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1198558106218230069, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1011, endPage=1017, ext={EN=ArticleExt(id=1198562265323631609, articleId=1198562265088750583, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=DYNC1H1-related infantile epileptic spasms syndrome: two cases report and literature review, columnId=1190310109000602400, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Clinical Research, runingTitle=null, highlight=null, articleAbstract=

Objective To report the clinical characteristics, diagnosis, and treatment process of two infants with infantile epileptic spasms syndrome (IESS) caused by DYNC1H1 mutation, and to review the relevant literature. Methods A retrospective analysis was conducted on the clinical data of two IESS patients with DYNC1H1 mutations who were treated at the First Medical Center of Chinese PLA General Hospital. Databases such as PubMed, Online Mendelian Inheritance in Man (OMIM), China National Knowledge Infrastructure (CNKI), and Wanfang Data Knowledge Service Platform were searched to obtain relevant literature, aiming to summarize the clinical characteristics of IESS patients with DYNC1H1 mutations, and to explore the relationship between treatment and phenotype-genotype. Results Two IESS patients with DYNC1H1 mutations were identified (case 1: c.874C>T, p.Arg292Trp; case 2: c.5884C>T, p.Arg1962Cys). Both patients presented with the onset of spastic seizures in infancy, which were poorly controlled with various medications. They exhibited severe developmental delay, and cranial magnetic resonance imaging in case 1 revealed pachygyria. A search of multiple databases and manual screening yielded a total of 7 English articles and 2 Chinese articles. Fifteen cases of DYNC1H1-related IESS were identified, of which 12 cases progressed to drug-resistant epilepsy and 12 cases had significant congenital structural abnormalities of the cranium. Nine different mutation sites were distributed in 3 structural domains, including 4 cases in the tail domain, 3 cases in the motor with ATPase subunit domain, and 2 cases in the stalk or microtubule-binding domain. Conclusions DYNC1H1 gene variations can cause IESS, often accompanied by brain developmental abnormalities and developmental delay/intellectual disability. The poor prognosis may be attributed to the combined effects of gene dysfunction and brain developmental abnormalities.

, correspAuthors=Guang Yang, authorNote=null, correspAuthorsNote=
E-mail:
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目的 报道2例DYNC1H1基因异常导致婴儿癫痫性痉挛综合征(IESS)患儿的临床特点、诊治过程并进行文献复习。方法 回顾性分析2例解放军总医院第一医学中心住院治疗的DYNC1H1基因突变相关IESS患儿的临床资料，检索PubMed、在线人类孟德尔遗传数据库(OMIM)、中国知网、万方数据知识服务平台等数据库，结合文献总结DYNC1H1基因突变相关IESS患儿的临床特点，探讨其治疗及表型-基因关系。结果 2例DYNC1H1变异相关的IESS患儿(病例1：c.874C>T，p.Arg292Trp；病例2：c.5884C>T，p.Arg1962Cys)，痉挛发作均起始于婴儿期，多种药物控制效果均不佳。2例患儿均存在严重的发育迟缓，且病例1的头颅磁共振成像提示巨脑回畸形。搜索数据库并手动筛选共获得英文文献7篇，中文文献2篇。共15例DYNC1H1基因突变相关婴儿痉挛症，12例发展为药物难治性癫痫；12例存在显著的头颅先天性结构异常。共9个突变位点分别分布于3个结构域，其中尾端结构域4例，细胞活动相关的ATP酶结构域3例，茎或微管结合结构域2例。结论 DYNC1H1基因异常可引起IESS，并常伴有脑发育异常和发育迟缓/智力障碍。预后不佳的原因可能是基因功能障碍和脑发育异常共同作用的结果。

, correspAuthors=杨光, authorNote=null, correspAuthorsNote=
杨光，E-mail：
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张珊，硕士研究生，主治医师，主要从事小儿神经系统疾病方面的研究

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3解放军医学院， 北京 100853
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张珊，硕士研究生，主治医师，主要从事小儿神经系统疾病方面的研究

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张珊，硕士研究生，主治医师，主要从事小儿神经系统疾病方面的研究

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2解放军总医院第一医学中心儿科，北京 100853
3解放军医学院， 北京 100853
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caption=Cranial MRI of two cases of DYNC1H1-related IESS, figureFileSmall=wPMrWWlRoVgwV3Xkoohsuw==, figureFileBig=7koWpXBaMWLsYiOPsvKnrg==, tableContent=null), ArticleFig(id=1198562269014618166, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198562265088750583, language=CN, label=图1, caption=两例DYNC1H1相关IESS患儿的头颅MRI, figureFileSmall=wPMrWWlRoVgwV3Xkoohsuw==, figureFileBig=7koWpXBaMWLsYiOPsvKnrg==, tableContent=null), ArticleFig(id=1198562269157224503, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198562265088750583, language=EN, label=Fig.2, caption=Prediction of functionality and stability of DYNC1H1 mutations, figureFileSmall=pplvuw0L2iy+jHJL90ELxA==, figureFileBig=ILDCI2AFzCbNfjhMIKSPPw==, tableContent=null), ArticleFig(id=1198562269211750456, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198562265088750583, language=CN, label=图2, caption=DYNC1H1突变的功能和稳定性预测

A、B. p.Arg292Trp和p.Arg1962Cys的功能预测，结果显示均增加蛋白疏水性；C. 变异蛋白稳定性预测，两错义突变均明显降低蛋白的稳定性(分别减低1.0与0.56 kcal/mol)

, figureFileSmall=pplvuw0L2iy+jHJL90ELxA==, figureFileBig=ILDCI2AFzCbNfjhMIKSPPw==, tableContent=null), ArticleFig(id=1198562269278859321, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198562265088750583, language=EN, label=Fig.3, caption=Diagnosis, treatment and follow-up of 2 patients with DYNC1H1-related IESS, figureFileSmall=PQ+2WE0mxY1fS6qPUl2J/g==, figureFileBig=pGVwKZu0cuqHwrq1MoBAiw==, tableContent=null), ArticleFig(id=1198562269417271354, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198562265088750583, language=CN, label=图3, caption=两例DYNC1H1相关IESS患儿的诊疗及随访

ACTH. 肾上腺促皮质素；LCM. 拉考沙胺；OXC. 奥卡西平；PER. 吡仑帕奈；TPM. 托吡酯；VNS. 迷走神经刺激术；VGB. 氨己烯酸；VPA. 丙戊酸钠

, figureFileSmall=PQ+2WE0mxY1fS6qPUl2J/g==, figureFileBig=pGVwKZu0cuqHwrq1MoBAiw==, tableContent=null), ArticleFig(id=1198562269480185915, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198562265088750583, language=EN, label=Fig.4, caption=Location of mutations in the protein structure of DYNC1H1-related IESS patients, figureFileSmall=pLSKkbInwpgCePUXIcSX6w==, figureFileBig=Pfve7xdbe44iZHIZB+WsYQ==, tableContent=null), ArticleFig(id=1198562269551489084, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198562265088750583, language=CN, label=图4, caption=DYNC1H1相关IESS患儿的突变在蛋白结构内位置

蓝色示尾端结构域；绿色示连接结构域；红色示细胞活动相关的ATP酶结构域；黄色示茎或微管结合结构域

, figureFileSmall=pLSKkbInwpgCePUXIcSX6w==, figureFileBig=Pfve7xdbe44iZHIZB+WsYQ==, tableContent=null), ArticleFig(id=1198562269631180861, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198562265088750583, language=EN, label=Tab.1, caption=

Pathogenicity prediction and American College of Medical Genetics and Genomics rating of DYNC1H1 mutations

, figureFileSmall=null, figureFileBig=null, tableContent=
突变PolyPhen-2预测Mutation Taster预测CADD 分数SIFT预测ACMG评级
c.874C>T, p.Arg292Trp0.986(可能有害)致病28.80.01(有害)致病(PS2+PS3+PS4+PP2+PP3+PM2)
c.5884C>T, p.Arg1962Cys1(可能有害)致病29.60(有害)致病(PS2+PP2+PP3+PM2+PM5)
), ArticleFig(id=1198562269694095422, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198562265088750583, language=CN, label=表1, caption=

DYNC1H1突变的致病性预测和美国医学遗传学与基因组学学会(ACMG)评级

, figureFileSmall=null, figureFileBig=null, tableContent=
突变PolyPhen-2预测Mutation Taster预测CADD 分数SIFT预测ACMG评级
c.874C>T, p.Arg292Trp0.986(可能有害)致病28.80.01(有害)致病(PS2+PS3+PS4+PP2+PP3+PM2)
c.5884C>T, p.Arg1962Cys1(可能有害)致病29.60(有害)致病(PS2+PP2+PP3+PM2+PM5)
), ArticleFig(id=1198562269761204287, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198562265088750583, language=EN, label=Tab.2, caption=

Clinical phenotypes and genotypes of DYNC1H1-associated IESS patients

, figureFileSmall=null, figureFileBig=null, tableContent=
序号性别年龄

痉挛发

作年龄

碱基变化氨基酸变化

突变

类型

来源结构域头颅核磁

发育迟缓/

智力障碍

癫痫预后
1男1岁4个月3个月c.10973G>Ap.Gly3658Glu错义De novo细胞活动相关的ATP酶结构域巨脑回/无脑回是药物难治性癫痫
2男未报道未报道c.10174A>Gp.Met3392Val错义De novo茎或微管结合结构域未报道是未报道
3未报道未报道婴儿期c.3278T>Cp.Phe1093Ser错义De novo尾端结构域未报道是药物难治性癫痫
4男4岁6个月c.5884C>Tp.Arg1962Cys错义De novo细胞活动相关的ATP酶结构域巨脑回是药物难治性癫痫
5未报道未报道未报道c.1682A>Gp.Glu561Gly错义De novo尾端结构域巨脑回是药物难治性癫痫
6女10个月7个月c.10213A>Cp.Met3405Leu错义De novo茎或微管结合结构域脑发育不良是药物难治性癫痫
7女10个月7个月c.10213A>Cp.Met3405Leu错义De novo茎或微管结合结构域脑发育不良是药物难治性癫痫
8女3岁2个月5个月c.874C>Tp.Arg292Trp错义De novo尾端结构域巨脑回/无脑回是药物难治性癫痫
9女5岁10个月c.3351C>Gp.Asn1117Lys错义De novo尾端结构域白质发育不良是控制
10女2岁9个月5个月c.5884C>Tp.Arg1962Cys错义De novo细胞活动相关的ATP酶结构域巨脑回，白质减少是控制
11女3岁7个月c.10213A>Cp.Met3405Leu错义De novo茎或微管结合结构域巨脑回，胼胝体发育不良是药物难治性癫痫
12女3岁7个月c.10213A>Cp.Met3405Leu错义De novo茎或微管结合结构域巨脑回，胼胝体发育不良是药物难治性癫痫
13女1岁2个月4个月c.5885G>Ap.Arg1962His错义De novo细胞活动相关的ATP酶结构域巨脑回是药物难治性癫痫
例1*女4岁3个月c.874C>Tp.Arg292Trp错义De novo尾端结构域巨脑回是药物难治性癫痫
例2*女9个月3个月c.5884C>Tp.Arg1962Cys错义De novo细胞活动相关的ATP酶结构域正常是药物难治性癫痫
), ArticleFig(id=1198562269845090368, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1198562265088750583, language=CN, label=表2, caption=

DYNC1H1相关IESS患儿的临床表型和基因型

, figureFileSmall=null, figureFileBig=null, tableContent=
序号性别年龄

痉挛发

作年龄

碱基变化氨基酸变化

突变

类型

来源结构域头颅核磁

发育迟缓/

智力障碍

癫痫预后
1男1岁4个月3个月c.10973G>Ap.Gly3658Glu错义De novo细胞活动相关的ATP酶结构域巨脑回/无脑回是药物难治性癫痫
2男未报道未报道c.10174A>Gp.Met3392Val错义De novo茎或微管结合结构域未报道是未报道
3未报道未报道婴儿期c.3278T>Cp.Phe1093Ser错义De novo尾端结构域未报道是药物难治性癫痫
4男4岁6个月c.5884C>Tp.Arg1962Cys错义De novo细胞活动相关的ATP酶结构域巨脑回是药物难治性癫痫
5未报道未报道未报道c.1682A>Gp.Glu561Gly错义De novo尾端结构域巨脑回是药物难治性癫痫
6女10个月7个月c.10213A>Cp.Met3405Leu错义De novo茎或微管结合结构域脑发育不良是药物难治性癫痫
7女10个月7个月c.10213A>Cp.Met3405Leu错义De novo茎或微管结合结构域脑发育不良是药物难治性癫痫
8女3岁2个月5个月c.874C>Tp.Arg292Trp错义De novo尾端结构域巨脑回/无脑回是药物难治性癫痫
9女5岁10个月c.3351C>Gp.Asn1117Lys错义De novo尾端结构域白质发育不良是控制
10女2岁9个月5个月c.5884C>Tp.Arg1962Cys错义De novo细胞活动相关的ATP酶结构域巨脑回，白质减少是控制
11女3岁7个月c.10213A>Cp.Met3405Leu错义De novo茎或微管结合结构域巨脑回，胼胝体发育不良是药物难治性癫痫
12女3岁7个月c.10213A>Cp.Met3405Leu错义De novo茎或微管结合结构域巨脑回，胼胝体发育不良是药物难治性癫痫
13女1岁2个月4个月c.5885G>Ap.Arg1962His错义De novo细胞活动相关的ATP酶结构域巨脑回是药物难治性癫痫
例1*女4岁3个月c.874C>Tp.Arg292Trp错义De novo尾端结构域巨脑回是药物难治性癫痫
例2*女9个月3个月c.5884C>Tp.Arg1962Cys错义De novo细胞活动相关的ATP酶结构域正常是药物难治性癫痫
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DYNC1H1导致婴儿癫痫性痉挛综合征2例并文献复习
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张珊 1, 2, 3, 4 , 张璟 1, 2, 3 , 杨光 1, 2, 3, 5, *
解放军医学杂志 | 临床研究 2024,49(9): 1011-1017
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解放军医学杂志 | 临床研究 2024, 49(9): 1011-1017
DYNC1H1导致婴儿癫痫性痉挛综合征2例并文献复习
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张珊1, 2, 3, 4, 张璟1, 2, 3, 杨光1, 2, 3, 5, *
作者信息
  • 1解放军总医院儿科医学部，北京 100853
  • 2解放军总医院第一医学中心儿科，北京 100853
  • 3解放军医学院， 北京 100853
  • 4解放军总医院京南医疗区复兴路门诊部，北京 100842
  • 5南方医科大学第二临床医学院，广东广州 510280

    • 张珊，硕士研究生，主治医师，主要从事小儿神经系统疾病方面的研究

通讯作者:

杨光，E-mail：
DYNC1H1-related infantile epileptic spasms syndrome: two cases report and literature review
Shan Zhang1, 2, 3, 4, Jing Zhang1, 2, 3, Guang Yang1, 2, 3, 5, *
Affiliations
  • 1Senior Department of Pediatrics, Center of Chinese PLA General Hospital, Beijing 100853, China
  • 2Department of Pediatric, the First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
  • 3Medical School of Chinese PLA, Beijing 100853, China
  • 4Outpatient Department of Fuxing Road, Southern Medical Branch of Chinese PLA General Hospital, Beijing 100842, China
  • 5The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong 510280, China
出版时间: 2024-09-28 doi: 10.11855/j.issn.0577-7402.0561.2024.0418
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摘要
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目的 报道2例DYNC1H1基因异常导致婴儿癫痫性痉挛综合征(IESS)患儿的临床特点、诊治过程并进行文献复习。方法 回顾性分析2例解放军总医院第一医学中心住院治疗的DYNC1H1基因突变相关IESS患儿的临床资料，检索PubMed、在线人类孟德尔遗传数据库(OMIM)、中国知网、万方数据知识服务平台等数据库，结合文献总结DYNC1H1基因突变相关IESS患儿的临床特点，探讨其治疗及表型-基因关系。结果 2例DYNC1H1变异相关的IESS患儿(病例1：c.874C>T，p.Arg292Trp；病例2：c.5884C>T，p.Arg1962Cys)，痉挛发作均起始于婴儿期，多种药物控制效果均不佳。2例患儿均存在严重的发育迟缓，且病例1的头颅磁共振成像提示巨脑回畸形。搜索数据库并手动筛选共获得英文文献7篇，中文文献2篇。共15例DYNC1H1基因突变相关婴儿痉挛症，12例发展为药物难治性癫痫；12例存在显著的头颅先天性结构异常。共9个突变位点分别分布于3个结构域，其中尾端结构域4例，细胞活动相关的ATP酶结构域3例，茎或微管结合结构域2例。结论 DYNC1H1基因异常可引起IESS，并常伴有脑发育异常和发育迟缓/智力障碍。预后不佳的原因可能是基因功能障碍和脑发育异常共同作用的结果。

婴儿癫痫性痉挛综合征  /  DYNC1H1基因  /  皮质发育畸形

Objective To report the clinical characteristics, diagnosis, and treatment process of two infants with infantile epileptic spasms syndrome (IESS) caused by DYNC1H1 mutation, and to review the relevant literature. Methods A retrospective analysis was conducted on the clinical data of two IESS patients with DYNC1H1 mutations who were treated at the First Medical Center of Chinese PLA General Hospital. Databases such as PubMed, Online Mendelian Inheritance in Man (OMIM), China National Knowledge Infrastructure (CNKI), and Wanfang Data Knowledge Service Platform were searched to obtain relevant literature, aiming to summarize the clinical characteristics of IESS patients with DYNC1H1 mutations, and to explore the relationship between treatment and phenotype-genotype. Results Two IESS patients with DYNC1H1 mutations were identified (case 1: c.874C>T, p.Arg292Trp; case 2: c.5884C>T, p.Arg1962Cys). Both patients presented with the onset of spastic seizures in infancy, which were poorly controlled with various medications. They exhibited severe developmental delay, and cranial magnetic resonance imaging in case 1 revealed pachygyria. A search of multiple databases and manual screening yielded a total of 7 English articles and 2 Chinese articles. Fifteen cases of DYNC1H1-related IESS were identified, of which 12 cases progressed to drug-resistant epilepsy and 12 cases had significant congenital structural abnormalities of the cranium. Nine different mutation sites were distributed in 3 structural domains, including 4 cases in the tail domain, 3 cases in the motor with ATPase subunit domain, and 2 cases in the stalk or microtubule-binding domain. Conclusions DYNC1H1 gene variations can cause IESS, often accompanied by brain developmental abnormalities and developmental delay/intellectual disability. The poor prognosis may be attributed to the combined effects of gene dysfunction and brain developmental abnormalities.

infantile epileptic spasms syndrome  /  gene, DYNC1H1  /  malformations of cortical development
张珊, 张璟, 杨光. DYNC1H1导致婴儿癫痫性痉挛综合征2例并文献复习. 解放军医学杂志, 2024 , 49 (9) : 1011 -1017 . DOI: 10.11855/j.issn.0577-7402.0561.2024.0418
Shan Zhang, Jing Zhang, Guang Yang. DYNC1H1-related infantile epileptic spasms syndrome: two cases report and literature review[J]. Medical Journal of Chinese People’s Liberation Army, 2024 , 49 (9) : 1011 -1017 . DOI: 10.11855/j.issn.0577-7402.0561.2024.0418
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DYNC1H1编码细胞质肌动蛋白复合物的一个大的关键亚基(>530 kD)，在轴突运输功能中发挥重要作用[1]。DYNC1H1基因突变与多种临床表现相关，具体可分为两大类，包括皮质发育畸形(MCD)、智力发育障碍和发育性癫痫性脑病等中枢神经系统表现，以及主要累及下肢的脊髓性肌萎缩(SMA-LED)、腓骨肌萎缩症(又称Charcot-Marie Tooth综合征)等神经肌肉疾病[2]。婴儿癫痫性痉挛综合征(infantile epileptic spasms syndrome，IESS)是一种特殊类型的癫痫综合征，以癫痫性痉挛发作为主要临床特征，发病年龄为1~24月龄，发病率为30/10万活产婴儿[3]。病因学是IESS患儿预后最重要的影响因素，尤其是遗传或结构异常者，可能导致耐药性癫痫、发育迟缓或智力障碍等[4]。本研究报道2例DYNC1H1突变相关的IESS患儿，并进行文献复习，旨在探讨DYNC1H1突变导致IESS的特点及预后。
1 病例资料
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1.1 病史
例1，2岁女童。主述“间断抽搐1年余”就诊于解放军总医院第一医学中心小儿内科。患儿5月龄时首次出现癫痫性痉挛发作，表现为点头抱团样成串发作，10余次/串，10~20串/d，就诊于当地医院，脑电图检查示高度失律，而头颅磁共振(MRI)检查未见明显异常，诊断为IESS。给予促肾上腺皮质激素(ACTH)治疗，痉挛未控制。随后分别于7月龄及10月龄时加用氨己烯酸和托吡酯进行抗癫痫治疗，痉挛发作仍然无法控制。1岁2个月时行头颅MRI检查，发现双侧顶枕及后颞区脑回增厚、粗大，巨脑回畸形(图1)。给予加用生酮饮食，效果欠佳，仍有痉挛发作。患儿系G1P1，足月顺产，出生体重为3100 g，其母孕期及围产期无明显异常。4个月可翻身及抬头，9个月可独坐，现不会独走。父母体健，家族史无异常。
例2，8月龄，女童。因“间断抽搐5个月”就诊于解放军总医院第一医学中心小儿内科。患儿 3月龄时，无明显诱因出现点头，四肢上举，4或5次/d，家长未予重视，发作渐频繁，发展为10余串/d，20~30次/串。就诊于当地医院，脑电图检查示高度失律，头颅MRI检查未见明显异常(图1)。诊断为IESS，4月及6月龄时分别给予口服丙戊酸钠及托吡酯抗癫痫治疗，痉挛未控制，遂至我院就诊。患儿系G3P3，足月顺产，出生体重为3200 g，其母孕期及围产期无明显异常。4个月时可翻身及抬头，现不会独坐，追声追视差。父母及哥哥体健，家族史无异常。
1.2 入院查体
例1身长81 cm，体重10 kg。无特殊面容，皮肤及黏膜无明显异常；心、肺、腹部无异常；四肢肌力、肌张力减低，生理反射减弱，病理反射未引出。例2身长65 cm，体重6 kg。无特殊面容，皮肤及黏膜无明显异常；追声追视差，心、肺、腹部无异常；四肢肌力、肌张力正常，生理反射正常，病理反射未引出。
1.3 辅助检查
2例患儿入院后检查血常规、肝肾功能、血氨、乳酸、血尿代谢均正常，脑电图检查均示痉挛发作(图1)。
1.4 遗传学检测
Trio全外显子检测结果显示，例1的DYNC1H1基因新发错义突变(c.874C>T，p.Arg292Trp)，父母均为野生型，根据美国医学遗传学与基因组学学会(ACMG)指南评为致病(PS2+PS3+PS4+PP2+PP3+PM2)。例2的DYNC1H1基因新发错义突变(c.5884C>T，p.Arg1962Cys)，父母均为野生型，根据ACMG指南评为致病(PS2+PP2+PP3+PM2+PM5)(表1)。使用软件对错义突变造成的蛋白结构变化进行预测，显示两个错义突变均可能严重影响蛋白功能及结构(图2)。
1.5 诊断、治疗及随访
2例患儿的发作形式均为癫痫性痉挛，均在婴儿期发病，脑电图可见高度失律，IESS诊断明确。根据全外显子检测结果，两例患儿均为DYNC1H1突变相关的IESS。例1入院后给予迷走神经刺激术植入治疗，院外逐渐调整参数至最大耐受值，痉挛发作频率稍减少；2岁3个月时加用吡仑帕奈；2岁4个月时患儿痉挛发作消失，转变为局灶性发作，具体表现形式为左侧肢体强直抖动，伴意识丧失，持续1~2 min后缓解；2岁7个月及2岁10个月时依次加用丙戊酸钠及奥卡西平予以抗癫痫治疗，疗效欠佳，仍有发作。例2入院后给予ACTH 25 U静脉输注治疗14 d，治疗结束时患儿仍有痉挛发作。截至患儿4岁末次随访时，例1仍有局灶性发作，形式同前，2或3次/d，精神运动发育明显落后，无法独走，无语言发育，无法听懂及执行指令。截至患儿22月龄末次随访时，例2仍有痉挛发作，精神运动发育明显滞后，可扶站，无意识发音，可与人眼神交流(图3)。
2 文献检索及复习
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以中文“婴儿癫痫性痉挛综合征”“DYNC1H1”，英文“infantile epileptic spasms syndrome”“IESS”“DYNC1H1””及“infantile spasm”为关键词，检索PubMed、在线人类孟德尔遗传数据库(OMIM)、中国知网及万方数据知识服务平台等数据库，检索截至2022年10月。经获取全文并手动筛选后，共获得英文文献7篇，中文文献2篇[5-13]，包括本研究病例共纳入15例DYNC1H1基因突变相关的IESS患儿，其中女10例，男3例，2例未确定性别。15例患儿均存在严重发育迟缓或智力障碍。13例报告了MRI检测结果，除1例报告未见明显异常外，其余12例存在明显的先天性结构异常(6例为巨脑回/无脑回，2例为巨脑回/无脑回合并胼胝体发育不良，1例巨脑回/无脑回合并白质减少，3例为脑发育不良)。在报告癫痫预后的14例患儿中，12例发展为耐药性癫痫，2例患儿痉挛得到有效控制。14例患儿报告了痉挛首次发作的年龄，均为1岁内发病(表2)。
在15例患儿中，共报道了9个变异，均为de novo杂合错义突变，位于3个结构域内，其中尾端结构域4例，细胞活动相关的ATP酶结构域3例，茎或微管结合结构域2例(表2、图4)。
3 讨论
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本研究报告的两个变异在既往研究中已有报道。Su等[13]报道了1例表现为IESS和脑发育异常的女孩，存在DYNC1H1的p. Arg292Trp突变，即使采用多种药物联合治疗，仍发展为耐药性癫痫，并有严重发育迟缓和智力障碍。本研究中的例1具有与上述研究相同的突变位点和临床症状。Palmer等[8]报道了1例表现为IESS的男孩，具有DYNC1H1的p.Arg1962Cys变异，脑电图显示异常背景和多灶性癫痫样活动。该患儿表现为严重的发育迟缓和智力障碍，且存在巨脑回畸形。缑梦帆等[10]报道了1例携带与例2相同的p.Arg1962Cys变异的女孩，表现为IESS、皮质发育畸形、严重发育迟缓和智力障碍。例2虽具有上述相同变异，但头颅MRI未见明显异常。
DYNC1H1蛋白分为4个结构域：尾端结构域(tail domain，氨基酸残基1-1373和4222-4646)、连接结构域(linker domain，氨基酸残基1374-1867)、细胞活动相关的ATP酶结构域(motor with AAA domain，氨基酸残基1868-3168和3553-4221)和茎或微管结合结构域(stalk or microtubule-binding domain，氨基酸残基3169-3552)。与神经肌肉症状相关的变异集中在尾端结构域，而与常染色体显性智力障碍13型和皮层发育畸形等中枢神经系统表现相关的变异则集中在细胞活动相关的ATP酶结构域[2]。然而，文献复习发现，DYNC1H1相关IESS的变异并不具备结构域的特异性，其突变位点分散在多个不同的结构域中。
既往研究发现，DYNC1H1基因还可导致皮质发育畸形[14]。Hoang等[15]发现，DYNC1H1突变强烈抑制了固定在表面的动力蛋白对微管的滑动，损害了进步性动力蛋白运动的激活，减少了Bicaudal-D2复合物促进动力蛋白-动力蛋白-n端卷曲螺旋结构域的过程，并最终损伤动力蛋白复合物的表达和运动，可能造成皮质发育畸形。MCD是癫痫尤其是早期药物难治性癫痫的重要病因[16]。巨脑回/无脑回畸形是MCD的一个亚型，其特征是皮质增厚和脑回异常。既往研究表明，DYNC1H1是巨脑回/无脑回畸形的致病基因之一[17]。本研究发现，12例具有MCD的DYNC1H1相关的IESS患儿中，9例为巨脑回/无脑回畸形；14例报道预后的患儿中12例发展为耐药性癫痫，与既往的研究结论[14]一致，即DYNC1H1相关的发育性癫痫性脑病患儿癫痫发作较难控制，多数伴随有MCD。
既往研究报道IESS发病年龄为1~24月龄，但发病高峰期为3~12月龄[3]。本研究报道的2例患儿与既往研究中详细描述了痉挛发作年龄的患儿的发病时间均在1岁以内。既往研究证实，存在结构或遗传病因的IESS患儿预后较差[4]。除2例患儿外，其余13例DYNC1H1相关IESS患儿的癫痫痉挛均未得到控制，并发展为耐药性癫痫。DYNC1H1相关IESS的治疗应答远低于既往研究报道的IESS的平均应答率[4]。MCD是癫痫，尤其是早期药物难治性癫痫的重要病因[16]。在本研究中，14例报道预后的患儿中12例发展为耐药性癫痫，与以往的结论一致。因此，DYNC1H1相关的IESS患儿预后不佳的原因，可能不仅仅与基因突变本身相关，还可能与DYNC1H1突变造成的MCD有关。
综上所述，DYNC1H1基因变异可引起IESS，并常伴有脑发育异常和发育迟缓/智力障碍。癫痫性痉挛常在1岁以内发病，且难以控制，其预后不良可能是基因功能障碍和脑发育异常共同作用的结果。本研究存在一定的局限性，仅针对DYNC1H1基因突变导致的IESS患儿进行了研究，未包括其他类型癫痫，未来的研究可针对除DYNC1H1基因外相关的其他基因突变造成的癫痫患者进行全面研究，以探索基因型与表型之间的关联。
基金
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  • 北京市自然科学基金面上项目(7222187)
  • 中国抗癫痫协会癫痫科研基金-UCB基金(CU-B-2021-11)
  • 军队计划生育专项科研课题(军后综22JSZ20)()
文献
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参考文献 引证文献
排序方式：
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[2]
Amabile S, Jeffries L, McGrath JM, et al. DYNC1H1-related disorders: a description of four new unrelated patients and a comprehensive review of previously reported variants[J]. Am J Med Genet A, 2020, 182(9): 2049-2057.
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Su T, Yan Y, Hu Q, et al. De novo DYNC1H1 mutation causes infantile developmental and epileptic encephalopathy with brain malformations[J]. Mol Genet Genomic Med, 2022, 10(3): e1874.
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Hoang HT, Schlager MA, Carter AP, et al. DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein-dynactin-cargo adaptor complexes[J]. Proc Natl Acad Sci U S A, 2017, 114(9): E1597-E1606.
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2024年第49卷第9期
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doi: 10.11855/j.issn.0577-7402.0561.2024.0418
  • 接收时间：2023-04-19
  • 首发时间：2025-11-21
  • 出版时间：2024-09-28
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  • 收稿日期：2023-04-19
  • 录用日期：2023-10-20
基金
General Project of Beijing Natural Science Foundation(7222187)
北京市自然科学基金面上项目(7222187)
Epilepsy Research Foundation of Chinese Association Against Epilepsy(CU-B-2021-11)
中国抗癫痫协会癫痫科研基金-UCB基金(CU-B-2021-11)
Special Scientific Research Project of Military Family Planning(22JSZ20)()
军队计划生育专项科研课题(军后综22JSZ20)()
作者信息
    1解放军总医院儿科医学部，北京 100853
    2解放军总医院第一医学中心儿科，北京 100853
    3解放军医学院， 北京 100853
    4解放军总医院京南医疗区复兴路门诊部，北京 100842
    5南方医科大学第二临床医学院，广东广州 510280

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