CHD2基因变异相关癫痫临床特点分析

doi:10.12372/jcp.2023.22e0007

摘要/Abstract

摘要： 目的分析CHD2基因变异相关癫痫患儿的临床特点。方法通过对7例CHD2基因变异相关癫痫患儿的长期随访观察，分析总结其临床特点及治疗方案效果评价。结果 7例患儿癫痫发作中位起病年龄为3岁2个月。5例患儿病程中出现2种及以上的发作类型，以全面强直阵挛发作为主。7例患儿有程度不等的运动、智力及语言发育落后，1例有孤独症倾向。5例患儿发作间期脑电图监测到异常放电，4例有临床发作。头颅MRI均无特异性改变。4例患儿需加用2种以上抗癫痫药物，治疗后发作次数减少；1例患儿对抗癫痫药物不敏感，最后启动生酮饮食治疗，目前无发作。末次随访年龄为2~7岁，其中3例发作控制半年以上，丙戊酸和左乙拉西坦是治疗CHD2基因变异相关癫痫的有效药物。结论 CHD2基因变异相关癫痫患儿起病年龄较早，发作类型多样，多为难治性癫痫，预后较差，应尽早治疗干预。

关键词: CHD2基因, 癫痫, 阵挛发作, 发育落后

Abstract: Objective To analyze the clinical features of epilepsy in children with CHD2 gene variation. Methods The clinical characteristics and treatment efficacy of 7 children with epilepsy related to CHD2 gene variation were analyzed and summarized. Results The median onset age of seizure in 7 children was 3 years and 2 months old. There were two or more seizure types during the course of the disease in 5 children, and the main seizure was generalized tonic-clonic seizure. Seven children had varying degrees of motor, intellectual and language retardation, and one had a tendency to autism. Abnormal discharge was detected by interictal electroencephalogram in 5 children, and clinical episodes were observed in 4 children. There were no specific changes in skull MRI. More than 2 antiepileptic drugs were needed in 4 children, and the number of seizures decreased after treatment. One patient was not sensitive to antiepileptic drugs and was finally treated with ketogenic diet. At present, the child did not have seizures. The age of the last follow-up was 2 to 7 years old, and seizures were controlled for more than half a year in 3 children. Valproate and levetiracetam are effective drugs for the treatment of CHD2 variation-related epilepsy.Conclusions Children with epilepsy related to CHD2 gene variation have early onset age and various seizure types. Most of the children have refractory epilepsy and poor prognosis, so early intervention should be given.

Key words: CHD2 gene, epilepsy, clonic seizure, developmental retardation

冯帆, 陈芳, 孙素真, 李鑫, 刘学芳, 赵彤. CHD2基因变异相关癫痫临床特点分析[J]. 临床儿科杂志, 2023, 41(1): 48-53.

FENG Fan, CHEN Fang, SUN Suzhen, LI Xin, LIU Xuefang, ZHAO Tong. Analysis of the clinical characteristics of epilepsy associated with CHD2 gene variation[J]. Journal of Clinical Pediatrics, 2023, 41(1): 48-53.

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参考文献 31

[1]	Wilson MM, Henshall DC, Byrne SM, et al. CHD2-related CNS pathologies[J]. Int J Mol Sci, 2021, 22(2): 588. doi: 10.3390/ijms22020588
[2]	Cardoso AR, Lopes-Marques M, Oliveira M, et al. Genetic variability of the functional domains of chromodomains helicase DNA-Binding (CHD) proteins[J]. Genes (Basel), 2021, 12(11): 1827. doi: 10.3390/genes12111827
[3]	Lamar KJ, Carvill GL. Chromatin remodeling proteins in epilepsy: lessons from CHD2-Associated epilepsy[J]. Front Mol Neurosci, 2018, 11: 208. doi: 10.3389/fnmol.2018.00208
[4]	Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy[J]. Epilepsia, 2014, 55 (4): 475-482. doi: 10.1111/epi.12550 pmid: 24730690
[5]	EuroEPINOMICS-RES Consortium. Electronic address: euroepinomics-RES@ua.ac.be; Epilepsy Phenome/Genome Project;et al, De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies[J]. Am J Hum Genet, 2017, 100(1): 179. doi: S0002-9297(16)30538-9 pmid: 28061363
[6]	Carvill GL, Heavin SB, Yendle SC, et al. Targeted Resequencing in Epileptic Encephalopathies identifies do novo mutations in CHD2 and SYNGAP1[J]. Nat Genat, 2013, 45(7): 825-830.
[7]	Chénier S, Yoon G, Argiropoulos B, et al. CHD 2 haplo- insufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems[J]. J Neurodev Disord, 2014, 6(1): 9. doi: 10.1186/1866-1955-6-9
[8]	Courage C, Houge G, Gallati S, et al. 15q26.1 Microdeletion encompassing only CHD2 and RGMA in two adults with moderate intellectual disability, epilepsy and truncal obesity[J]. Eur J Med Genet, 2014, 57(9): 520-523. doi: 10.1016/j.ejmg.2014.06.003 pmid: 24932903
[9]	Lund C, Brodtkorb E, Øye A M, et al. CHD2 mutations in Lennox-Gastaut syndrome[J]. Epilepsy Behav, 2014, 33: 18-21. doi: 10.1016/j.yebeh.2014.02.005 pmid: 24614520
[10]	Thomas RH, Zhang LM, Carvill GL, et al. CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures[J]. Neurology, 2015, 84(9): 951-958. doi: 10.1212/WNL.0000000000001305 pmid: 25672921
[11]	Trivisano M, Striano P, Sartorelli J, et al. CHD2 mutations are a rare cause of generalized epilepsy with myoclonic-atonic seizures[J]. Epilepsy Behav, 2015, 51: 53-56. doi: 10.1016/j.yebeh.2015.06.029 pmid: 26262932
[12]	Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology[J]. Epilepsia, 2017, 58(4): 512-521. doi: 10.1111/epi.13709 pmid: 28276062
[13]	Zimmern V, Korff C. Status epilepticus in children[J]. Clin Neurophysiol, 2020, 37(5): 429-433.
[14]	Carvill GL, Mefford HC. CHD2-Related Neuro-developmental Disorders[M]//Adam MP, Everman DB, Mirzaa GM, et al. GeneReviews®[Internet]. Seattle (WA): University of Washington: 1993-2022.
[15]	Thomas RH, Zhang LM, Carvill GL, et al. CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures[J]. Neurology, 2015, 84(9): 951-958. doi: 10.1212/WNL.0000000000001305 pmid: 25672921
[16]	Firth HV, Richards SM, Bevan AP, et al. DECIPHER: database of chromosomal imbalance and phenotype in humans using ensembl resources[J]. Am J Hum Genet, 2009, 84(4): 524-33. doi: 10.1016/j.ajhg.2009.03.010 pmid: 19344873
[17]	Galizia EC, Myers CT, Leu C, et al. CHD2 variants are a risk factor for photosensitivity in epilepsy[J]. Brain, 2015, 138(Pt 5): 1198-1207. doi: 10.1093/brain/awv052 pmid: 25783594
[18]	Suls A, Jaehn JA, Kecskés A, et al. De novo loss-of-functionmutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome[J]. Am J Hum Genet, 2013, 93 (5):967-975. doi: 10.1016/j.ajhg.2013.09.017
[19]	Chen J, Zhang J, Liu A, et al. CHD2-related epilepsy: novel mutations and new phenotypes[J]. Dev Med Child Neurol, 2020, 62(5): 647-653. doi: 10.1111/dmcn.14367 pmid: 31677157
[20]	Lebrun N, Parent P, Gendras J, et al. Autism spectrum disorder recurrence, resulting of germline mosaicism for a CHD2 gene missense variant[J]. Clin Genet, 2017, 92(6): 669-670. doi: 10.1111/cge.13073 pmid: 28960266
[21]	Veredice C, Bianco F, Contaldo I, et al. Early onset myoclonic epilepsy and 15q26 microdeletion: observation of the first case[J]. Epilepsia, 2009, 50(7): 1810-1815. doi: 10.1111/j.1528-1167.2009.02078.x pmid: 19486360
[22]	Trivisano M, Striano P, Sartorelli J, et al. CHD2 mutations are a rare cause of generalized epilepsy with myoclonic-atonic seizures[J]. Epilepsy Behav, 2015, 51: 53-56. doi: 10.1016/j.yebeh.2015.06.029 pmid: 26262932
[23]	Singh N, Ritaccio A. Juvenile myoclonic epilepsy mimic associated with CHD2 gene mutation[J]. Epilepsy Behav Rep, 2020, 13: 100355.
[24]	Carvill GL, Heavin SB, Yendle SC, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1[J]. Nat Genet, 2013, 45(7): 825-830. doi: 10.1038/ng.2646 pmid: 23708187
[25]	Cardoso AR, Lopes-Marques M, Oliveira M, et al. Genetic variability of the functional domains of chromodomains helicase DNA-binding (CHD) proteins[J]. Genes (Basel), 2021, 12(11): 1827. doi: 10.3390/genes12111827
[26]	Galizia EC, Myers CT, Leu C, et al. CHD2 variants are a risk factor for photosensitivity in epilepsy[J]. Brain, 2015, 138(Pt 5): 1198-1207. doi: 10.1093/brain/awv052
[27]	Pinto AM, Bianciardi L, Mencarelli MA, et al. Exome sequencing analysis in a pair of monozygotic twins re-evaluates the genetics behind their intellectual disability and reveals a CHD2 mutation[J]. Brain Dev, 2016, 38(6): 590-596. doi: 10.1016/j.braindev.2015.12.006
[28]	Lebrun N, Parent P, Gendras J, et al. Autism spectrum disorder recurrence, resulting of germline mosaicism for a CHD2 gene missense variant[J]. Clin Genet, 2017, 92(6): 669-670. doi: 10.1111/cge.13073 pmid: 28960266
[29]	Verhoeven WM, Egger JI, Knegt AC, et al. Absence epilepsy and the CHD2 gene: an adolescent male with moderate intellectual disability, short-lasting psychoses, and an interstitial deletion in 15q26.1-q26.2[J]. Neuropsychiatr Dis Treat, 2016, 12: 1135-1139.
[30]	旷小军, 张晓, 宁泽淑, 等. 颈部肌阵挛伴失神发作2例报告并文献复习[J]. 临床儿科杂志, 2021, 39(5):366-369.
[31]	Kessler SK, McGinnis E. A practical guide to treatment of childhood absence epilepsy[J]. Paediatr Drugs, 2019, 21(1): 15-24. doi: 10.1007/s40272-019-00325-x pmid: 30734897

项目	例1	例2	例3	例4	例5	例6	例7
性别	女	男	女	女	男	女	女
起病年龄	3岁4月	2岁8月	3岁3月	5岁8月	3岁2月	2岁4月	8月
发作类型	GTCS、MAS、SE、Fs	GTCS	GTCS、Fs、SE	GTCS	MS、Fs	GTCS、Fs、SE	MS、ES
诱发因素	发热	-	-	发热	发热	发热	-
发育落后	+	+	+	+	+	+	+
孤独症表现	-	+	-	-	-	-	-
治疗	LEV、VPA、TPM、PB、KD	LEV	LEV、VPA	LEV、VPA、LTG	LEV、TPM	LEV、VPA、TPM	LEV、CLZ、OXC、ACTH
核苷酸改变（氨基酸改变）	c.2416dup （p.R806Kfs*20）	c.2671C>T （p.P891S）	c.2584T>C （p.C862R）	c.1628_1653del (p.S543Ffs*2)	c.481G>T (P.E161X)	c.4286dup （p.S1429Rfs*3）	c.390C>T （p.S130S）
变异来源	新生变异	新生变异	新生变异	母源	新生变异	新生变异	新生变异
是否新变异位点	是	是	是	是	是	是	否