不同类型KCNQ2基因突变所致癫痫五例临床分析
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摘要
目的探讨KCNQ2基因突变不同基因型与癫痫患儿临床表型之间的关系。方法分析2017年10月-2018年10月河北省儿童医院神经内科收治的5例KCNQ2基因突变相关性癫痫患儿,并查阅万方、中国知网(CNKI)、PubMed、Uptodate等数据库,结合相关文献进行总结。结果本研究共收集5例KCNQ2基因突变阳性患儿,其中自发突变3例:含错义突变2例,截短突变1例;家系遗传2例;错义突变、无义突变各1例。3例自发突变临床表型均为癫痫性脑病,家系遗传中1例为良性家族性新生儿癫痫。家系1同一位点突变呈现3种不同表型。结论①KCNQ2基因突变不仅可以引起良性家族性新生儿癫痫(BFNE),还可引起多种癫痫性脑病;②自发突变更可能导致癫痫性脑病;③同一家系携带同一基因突变位点成员也可能有不同表型。
Objective To explore the relationship between the mutant genotype and phenotype of KCNQ2 gene.Method From October 2017 to October 2018,5 cases of KCNQ2 gene mutation children admitted to the Department of Neurology of Hebei Children's Hospital were collected and their clinical data were analyzed retrospectively.The data base of Wanfang,CNKI,PubMed,Uptodate and other databases were consulted and summarized in combination with relevant literature.Results Five KCNQ2 gene mutation positive children were collected in this study,including 3 spontaneous mutations,2 missense mutations and 1 truncated mutation.There were 2 cases of pedigree inheritance,1 case of missense mutation and 1 case of nonsense mutation.3 cases were spontaneous mutation phenotypes,all of which were epileptic encephalopathy,and 1 case was benign familial neonatal epilepsy in family heredity.Mutations at the same locus in family 1 showed 3 different phenotypes.Conclusion① KCNQ2 gene mutation can not only cause benign familial neonatal epilepsy(BFNE),but also cause a variety of epileptic encephalopathy;②Spontaneous mutation is more likely to lead to epileptic encephalopathy;③Members of the same family carrying the same gene mutation site may also have different phenotypes.
Objective To explore the relationship between the mutant genotype and phenotype of KCNQ2 gene.Method From October 2017 to October 2018,5 cases of KCNQ2 gene mutation children admitted to the Department of Neurology of Hebei Children's Hospital were collected and their clinical data were analyzed retrospectively.The data base of Wanfang,CNKI,PubMed,Uptodate and other databases were consulted and summarized in combination with relevant literature.Results Five KCNQ2 gene mutation positive children were collected in this study,including 3 spontaneous mutations,2 missense mutations and 1 truncated mutation.There were 2 cases of pedigree inheritance,1 case of missense mutation and 1 case of nonsense mutation.3 cases were spontaneous mutation phenotypes,all of which were epileptic encephalopathy,and 1 case was benign familial neonatal epilepsy in family heredity.Mutations at the same locus in family 1 showed 3 different phenotypes.Conclusion① KCNQ2 gene mutation can not only cause benign familial neonatal epilepsy(BFNE),but also cause a variety of epileptic encephalopathy;②Spontaneous mutation is more likely to lead to epileptic encephalopathy;③Members of the same family carrying the same gene mutation site may also have different phenotypes.
引文
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[13]Kim EC,Zhang J,Pang W,et al.Reduced axonal surface expression and phosphoinositide sensitivity in Kv7 channels disrupts their function to inhibit neuronal excitability in Kcnq2 epileptic encephalopathy[J]Neurobiol Dis,2018,118:76-93.
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[15]Lee IC,Yang JJ,Liang JS,et al.KCNQ2-associated neonatal epilepsy:phenotype might correlate with genotype[J].J Child Neurol,2017,32(8):704-711.
[16]Millichap JJ,Park KL,Tsuchida T,et al.KCNQ2 encephalopathy:features,mutational hot spots,and ezogabine treatment of 11patients[J].Neurol Genet,2016,2(5):e96.
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[18]Buttle SG,Sell E,Dyment D,et al.Pointed rhythmic theta waves:a unique EEG pattern in KCNQ2-related neonatal epileptic encephalopathy[J].Epileptic Disord,2017,19(3):351-356.
[19]Klotz KA,Lemke JR,Korinthenberg R,et al.Vitamin B6-responsive epilepsy due to a novel KCNQ2 mutation[J].Neuropediatrics,2017,48(3):199-204.
[20]Hewson S,Puka K,Mercimek-Mahmutoglu S.Variable expressivity of a likely pathogenic variant in KCNQ2 in a three-generation pedigree presenting with intellectual disability with childhood onset seizures[J].Am J Med Genet A,2017,173(8):2226-2230.
[21]Dedek K,Kunath B,Kananura C,et al.Myokymia and neonatalepilepsy caused by a mutation in the voltage sensor of the KCNQ2K+channel[J].Proc Natl Acad Sci U S A,2001,98(21):12272-12277.
[22]Devaux J,Dhifallah S,De Maria M,et al.A possible link between KCNQ2-and STXBP1-related e.ncephalopathies:STXBP1reduces the inhibitory impact of syntaxin-1A on M current[J].Epilepsia,2017,58(12):2073-2084.
[23]Manville RW,Neverisky DL,Abbott GW.SMIT1 modifies KCNQ channel function and pharmacology by physical interaction with the pore[J].Biophys J,2017,113(3):613-626.
[24]Uchida T,Lossin C,Ihara Y,et al.Abnormalγ-aminobutyric acid neurotransmission in a Kcnq2 model of early onset epilepsy[J].Epilepsia,2017,58(8):1430-1439.
[2]郎悦,王小峰,尹剑,等.离子通道与癫痫遗传学研究进展[J].中华神经科杂志,2018,51(8):642-648.
[3]Butler KM,da Silva C,Alexander JJ,et al.Diagnostic yield from 339epilepsy patients screened on a clinical gene panel[J].Pediatric Neurology,2017,77:61-66.
[4]屈晓旋,谢涵,姜玉武.KCNQ2基因相关癫痫:一种谱系疾病[J].中国医师杂志,2017,19(8):1134-1138.
[5]Kessi M,Peng J,Yang L,et al.Genetic etiologies of the electrical status epilepticus during slow wave sleep:systematic review[J].BMC Genetics,2018,19(1):40.
[6]Lee IC,Yang JJ,Li SY.A KCNQ2 E515D mutation associated with benign familial neonatal seizures and continuous spike and wavesduring slow-wave sleep syndrome in Taiwan[J].J Formos Med Assoc,2017,116(9):711-719.
[7]Ambrosino P,Freri E,Castellotti B,et al.Kv7.3 Compound heterozygous variants in early onset encephalopathy reveal additive contribution of C-Terminal residues to PIP
[8]Shellhaas RA,Wusthoff CJ,Tsuchida TN,et al.Profile of neonatal epilepsies:Characteristics of a prospective US cohort[J].Neurology,2017,89(9):893-899.
[9]Kim EC,Zhang J,Pang W,et al.Reduced axonal surface expression and phosphninositide sensitivity in K
[10]李宝广,杨花芳,郑华城,等.16例PRRT2基因突变家系研究[J].中国优生与遗传杂志,2019,27(2):152-156.
[11]曾琦,张月华,杨小玲,等.良性家族性新生儿-婴儿癫痫致病基因谱研究[J].中华儿科杂志,2018,56(4):267-273.
[12]Niday Z,Hawkins VE,Soh H,et al.Epilepsy-Associated KCNQ2channels regulate multiple intrinsic properties of layer 2/3pyramidal neurons[J].J Neurosci,2017,37(3):576-586.
[13]Kim EC,Zhang J,Pang W,et al.Reduced axonal surface expression and phosphoinositide sensitivity in Kv7 channels disrupts their function to inhibit neuronal excitability in Kcnq2 epileptic encephalopathy[J]Neurobiol Dis,2018,118:76-93.
[14]Niday Z,Tzingounis AV.Potassium channel gain of function in epilepsy:an unresolved paradox[J].Neuroscientist,2018,24(4):368-380.
[15]Lee IC,Yang JJ,Liang JS,et al.KCNQ2-associated neonatal epilepsy:phenotype might correlate with genotype[J].J Child Neurol,2017,32(8):704-711.
[16]Millichap JJ,Park KL,Tsuchida T,et al.KCNQ2 encephalopathy:features,mutational hot spots,and ezogabine treatment of 11patients[J].Neurol Genet,2016,2(5):e96.
[17]Kuersten M,Tacke M,Gerstl L,et al.Antiepileptic therapy approaches in KCNQ2 related epilepsy:A systematic review[J].Eur J Med Genet,2019,pii:S1769-7212(18)30663-3.
[18]Buttle SG,Sell E,Dyment D,et al.Pointed rhythmic theta waves:a unique EEG pattern in KCNQ2-related neonatal epileptic encephalopathy[J].Epileptic Disord,2017,19(3):351-356.
[19]Klotz KA,Lemke JR,Korinthenberg R,et al.Vitamin B6-responsive epilepsy due to a novel KCNQ2 mutation[J].Neuropediatrics,2017,48(3):199-204.
[20]Hewson S,Puka K,Mercimek-Mahmutoglu S.Variable expressivity of a likely pathogenic variant in KCNQ2 in a three-generation pedigree presenting with intellectual disability with childhood onset seizures[J].Am J Med Genet A,2017,173(8):2226-2230.
[21]Dedek K,Kunath B,Kananura C,et al.Myokymia and neonatalepilepsy caused by a mutation in the voltage sensor of the KCNQ2K+channel[J].Proc Natl Acad Sci U S A,2001,98(21):12272-12277.
[22]Devaux J,Dhifallah S,De Maria M,et al.A possible link between KCNQ2-and STXBP1-related e.ncephalopathies:STXBP1reduces the inhibitory impact of syntaxin-1A on M current[J].Epilepsia,2017,58(12):2073-2084.
[23]Manville RW,Neverisky DL,Abbott GW.SMIT1 modifies KCNQ channel function and pharmacology by physical interaction with the pore[J].Biophys J,2017,113(3):613-626.
[24]Uchida T,Lossin C,Ihara Y,et al.Abnormalγ-aminobutyric acid neurotransmission in a Kcnq2 model of early onset epilepsy[J].Epilepsia,2017,58(8):1430-1439.