促肾上腺皮质激素对不同黑素皮质素受体2基因型婴儿痉挛症疗效及高度失律缓解的影响研究
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摘要
背景婴儿痉挛症为婴幼儿期常见的灾难性癫痫,对多种抗癫痫药物反应欠佳。促肾上腺皮质激素(ACTH)作为其首选用药,有效率在60%～80%。寻找影响ACTH疗效的因素,并加以利用而提高ACTH有效率,成为当前该领域研究的热点及难点之一。目的探讨ACTH对不同黑素皮质素受体2(MC2R)基因型婴儿痉挛症疗效及高度失律缓解的影响,进而指导临床治疗。方法选取2016年10月—2018年10月在河北省儿童医院住院部行ACTH治疗且符合入组标准的婴儿痉挛症56例,进行体格检查、视频脑电图、基因全外显子检查等。根据MC2R基因启动子区4个单核苷酸多态性(SNP)构成的单体型类型分为TCCT携带组(n=46)即TCCT/TCCT或TCCT/0,TCCT非携带组(n=10)即0/0型。均给予ACTH治疗:1 U/kg×3 d+2 U/kg×25 d(共28 d,最大量不超过25 U)。观察两组患儿治疗有效率及高度失律缓解率。结果治疗28 d后,TCCT携带组有效36例,无效10例,有效率为78.2%;TCCT非携带组有效3例,无效7例,有效率为3/10。TCCT携带组有效率高于TCCT非携带组(χ~2=9.26,P<0.05)。视频脑电图检查结果显示高度失律检出率为43例,占76.8%(43/56),TCCT携带组36例,治疗28 d后,缓解24例,未缓解12例,缓解率为66.7%;TCCT非携带组7例,治疗28 d后,缓解3例,未缓解4例,缓解率为3/7。两组高度失律缓解率比较,差异无统计学意义(χ~2=1.46,P>0.05)。结论在婴儿痉挛症治疗中,ACTH对MC2R基因TCCT携带型的痉挛发作治疗效果显著,而两组高度失律缓解率无明显差异。
Background Infantile spasms(IS) is a common catastrophic epilepsy in infancy and early childhood with poor response to many anti-epileptic drugs.Even if the patients use adrenocorticotropic hormone(ACTH),an agent as the first choice for this disease,only 60%-80% of them have responses.Identifying the factors associated with the response to ACTH in IS patients,and making use of advantages and avoiding disadvantages to improve it,become a hot and difficult research topic.Objective To study the clinical outcome and severe VEEG abnormalities in response to ACTH in infants with IS and different MC2 R genotypes.Methods Fifty-six inpatients with IS who were treated in Children's Hospital of Hebei Province during October2016 to October 2018 were enrolled.Data concerning physical examination,VEEG,and whole exomesequencing were collected.According to the haplotypes constituted by 4 SNPS in the promoter region of MC2 R gene,they were divided into TCCT carrying group(n=46)(TCCT/TCCT or TCCT/0) and TCCT non-carrying group(n=10)(0/0).All of them received 28-day ACTH treatment at a dose of 1 U/kg×3 d+2 U/kg×25 d(the maximum amount not exceeding 25 U).Clinical outcome and severe VEEG abnormalities in response to ACTH in both groups were observed.Results Post-treatment status showed that,treatment response rate was 78.2% in TCCT carrying group(36 were responsive to ACTH and 10 were not),and 3/10 in TCCT non-carrying group(3 were responsive to ACTH and 7 were not),showing significant intergroup difference(χ2=9.26,P<0.05).Of the 43 cases(36 in TCCT carrying group and 7 in TCCT non-carrying group) detected with severe VEEG abnormalities,the rate of having reduced abnormalities was 66.7% in TCCT carrying group(24 achieved improvement while12 did not),and was 3/7 in TCCT non-carrying group(3 achieved improvement while 4 did not),indicating insignificant intergroup difference(χ2=1.46,P>0.05).Conclusion IS patients with MC2 R gene TCCT showed good responses to ACTH.But the rates of reduction in VEEG abnormalities were similar in those with MC2 R gene TCCT and without.
Background Infantile spasms(IS) is a common catastrophic epilepsy in infancy and early childhood with poor response to many anti-epileptic drugs.Even if the patients use adrenocorticotropic hormone(ACTH),an agent as the first choice for this disease,only 60%-80% of them have responses.Identifying the factors associated with the response to ACTH in IS patients,and making use of advantages and avoiding disadvantages to improve it,become a hot and difficult research topic.Objective To study the clinical outcome and severe VEEG abnormalities in response to ACTH in infants with IS and different MC2 R genotypes.Methods Fifty-six inpatients with IS who were treated in Children's Hospital of Hebei Province during October2016 to October 2018 were enrolled.Data concerning physical examination,VEEG,and whole exomesequencing were collected.According to the haplotypes constituted by 4 SNPS in the promoter region of MC2 R gene,they were divided into TCCT carrying group(n=46)(TCCT/TCCT or TCCT/0) and TCCT non-carrying group(n=10)(0/0).All of them received 28-day ACTH treatment at a dose of 1 U/kg×3 d+2 U/kg×25 d(the maximum amount not exceeding 25 U).Clinical outcome and severe VEEG abnormalities in response to ACTH in both groups were observed.Results Post-treatment status showed that,treatment response rate was 78.2% in TCCT carrying group(36 were responsive to ACTH and 10 were not),and 3/10 in TCCT non-carrying group(3 were responsive to ACTH and 7 were not),showing significant intergroup difference(χ2=9.26,P<0.05).Of the 43 cases(36 in TCCT carrying group and 7 in TCCT non-carrying group) detected with severe VEEG abnormalities,the rate of having reduced abnormalities was 66.7% in TCCT carrying group(24 achieved improvement while12 did not),and was 3/7 in TCCT non-carrying group(3 achieved improvement while 4 did not),indicating insignificant intergroup difference(χ2=1.46,P>0.05).Conclusion IS patients with MC2 R gene TCCT showed good responses to ACTH.But the rates of reduction in VEEG abnormalities were similar in those with MC2 R gene TCCT and without.
引文
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[2]甘靖,屈艺,罗蓉.婴儿痉挛症治疗进展[J].中华实用儿科临床杂志,2014,29(24):1889-1892.DOI:10.3760/cma.j.issn.1673-4408.2002.06.009.GAN J,QU Y,LUO R.Progress in the treatment of infantile spasms[J].Chinese Journal of Applied Clinical Pediatrics,2 0 1 4,2 9(2 4):1 8 8 9-1 8 9 2.D O I:1 0.3 7 6 0/c m a.j.issn.1673-4408.2002.06.009.
[3]刘雨田,杨光,王静,等.中国汉族婴儿痉挛症儿童MC2R基因多态性的分布[J].中华保健医学杂志,2018,20(3):213-216.DOI:10.3969/.issn.1674-3245.2018.03.011.
[4]中国抗癫痫协会.临床诊疗指南-癫痫病分册[M].北京:人民卫生出版社,2015.
[5]王新强,郭洪磊,袁凯杰,等.72例婴儿痉挛的临床和脑电图分析[J].中国优生与遗传杂志,2014,22(3):127,102.DOI:10.13404/j.cnki.cjbhh.2014.03.059.WANG X Q,GUO H L,YUAN K J,et al.A Study on clinical and EEG characters of 72 patients with infantile spasms[J].Chinese Journal of Birth Health&Heredity,2014,22(3):127,102.DOI:10.13404/j.cnki.cjbhh.2014.03.059.
[6]OKA M,KOBAYASHI K,AKIYAMA T,et al.A study of spikedensity on EEG in West syndrome[J].Brain Dev,2004,26(2):105-112.DOI:10.1016/S0387-7604(03)00101-3.
[7]王红梅,陈春红,王晓慧,等.促肾上腺皮质激素注射剂治疗婴儿痉挛症的临床研究[J].中国临床药理学杂志,2018,34(15):1812-1815.DOI:10.13699/j.cnki.1001-6821.2018.15.022.WANG H M,CHEN C H,WANG X H,et al.Clinical trial of adrenocorticotrophic hormone injection in the treatment of infantile spasms[J].The Chinese Journal of Clinical Pharmacology,2018,34(15):1812-1815.DOI:10.13699/j.cnki.1001-6821.2018.15.022.
[8]GALANOPOULOU A S.Basic mechanisms of catastrophic epilepsyoverview from animal models[J].Brain Dev,2013,35(8):748-756.DOI:10.1016/j.braindev.2012.12.005.
[9]杨光,邹丽萍.婴儿痉挛症发病机制的研究进展[J].中华神经医学杂志,2012,11(10):1073-1075.DOI:10.3760/cma.j.issn.1671-8925.2012.10.027.YANG G,ZOU L P.Recent advance in pathogenesis of infantile spasms[J].Chinese Journal of Neuromedicine,2012,11(10):1073-1075.DOI:10.3760/cma.j.issn.1671-8925.2012.10.027.
[10]李巧.婴儿痉挛症的动物模型研究进展[J].国际儿科学杂志,2018,45(9):705-709.DOI:10.3760/cma.j.issn.1673-4408.2018.09.014.LI Q.Animal models of infantile spasms[J].International Journal of Pediatrics,2018,45(9):705-709.DOI:10.3760/cma.j.issn.1673-4408.2018.09.014.
[11]BARAM T Z.Pathophysiology of massive infantile spasms:perspective on the putative role of the brain adrenal axis[J].Ann Neurol,1993,33(3):231-236.DOI:10.1002/ana.410330302.
[12]PENG J,LONG B,YUAN J,et al.A quantitative analysis of the distribution of CRH neurons in whole mouse brain[J].Front Neuroanat,2017,11:63.DOI:10.3389/fnana.2017.00063.
[13]INDA C,ARMANDO N G,DOS SANTOS CLARO P A,et al.Endocrinology and the brain:corticotropin-releasing hormone signaling[J].Endocr Connect,2017,6(6):R99-120.DOI:10.1530/EC-17-0111.
[14]GUNN B G,COX C D,CHEN Y,et al.The endogenous stress hormone CRH modulates excitatory transmission and network physiology in hippocampus[J].Cereb Cortex,2017,27(8):4182-4198.DOI:10.1093/cercor/bhx103.
[15]GARCIA I,BHULLAR P K,TEPE B,et al.Local corticotropin releasing hormone(CRH)signals to its receptor CRHR1 during postnatal development of the mouse olfactory bulb[J].Brain Struct Funct,2016,221(1):1-20.DOI:10.1007/s00429-014-0888-4.
[16]RAFTOGIANNI A,ROTH L C,GARCíA-GONZáLEZ D,et al.Deciphering the contributions of CRH receptors in the brain and pituitary to stress-induced inhibition of the reproductive axis[J].Front Mol Neurosci,2018,11:305.DOI:10.3389/fnmol.2018.00305.
[17]TORRES-REVERóN A,RIVERA-LOPEZ L L,FLORES I,et al.Antagonizing the corticotropin releasing hormone receptor 1with antalarmin reduces the progression of endometriosis[J].PLoS One,2018,13(11):e0197698.DOI:10.1371/journal.pone.0197698.
[18]YANG G,ZOU L P,WANG J,et al.Association analysis of polymorphisms of the CRHR1 gene with infantile spasms[J].Mol Med Rep,2015,12(2):2539-2546.DOI:10.3892/mmr.2015.3751.
[19]BARAM T Z,SCHULTZ L.Corticotropin-releasing hormone is a rapid and potent convulsant in the infant rat[J].Brain Res Dev Brain Res,1991,61(1):97-101.
[20]HOLLRIGEL G S,CHEN K,BARAM T Z,et al.The proconvulsant actions of corticotropin-releasing hormone in the hippocampus of infant rats[J].Neuroscience,1998,84(1):71-79.
[21]BARAM T Z,HATALSKI C G.Neuropeptide-mediated excitability:a key triggering mechanism for seizure generation in the developing brain[J].Trends Neurosci,1998,21(11):471-476.
[22]SHI X Y,JU J,ZOU L P,et al.Increased precipitation of spasms in an animal model of infantile spasms by prenatal stress exposure[J].Life Sci,2016,152:171-177.DOI:10.1016/j.lfs.2016.03.047.
[23]王蕾,高宝勤,邹丽萍,等.痉挛症大鼠海马CRH mRNA表达及ACTH的神经保护机制研究[J].中华神经医学杂志,2017,16(4):325-328.DOI:10.3760/cma.j.issn.1671-8925.2017.04.001.WANG L,GAO B Q,ZOU L P,et al.Hippocampal corticotropin releasing hormone mRNA expression and neuroprotective mechanism of adrenocorticotropic hormore in immature rats after N-methylD-aspartate induced spasm seizures[J].Chinese Journal of Neuromedicine,2017,16(4):325-328.DOI:10.3760/cma.j.issn.1671-8925.2017.04.001.
[24]WANG W,MURPHY B,DOW K E,et al.Systemic adrenocorticotropic hormone administration down-regulates the expression of corticotropin-releasing hormone(CRH)and CRH-binding protein in infant rat hippocampus[J].Pediatr Res,2004,55(4):604-610.DOI:10.1203/01.PDR.0000112105.33521.DC.
[25]SCANTLEBURY M H,CHUN K C,MA S C,et al.Adrenocorticotropic hormone protects learning and memory function in epileptic Kcna1-null mice[J].Neurosci Lett,2017,645:14-18.DOI:10.1016/j.neulet.2017.02.069.
[26]HERNAN A E,ALEXANDER A,LENCK-SANTINI P P,et al.Attention deficit associated with early life interictal spikes in a rat model is improved with ACTH[J].PLoS One,2014,9(2):e89812.DOI:10.1371/journal.pone.0089812.
[27]ARAGUASR M,SANZN,V I?A S J,et al.MC1 Rpolymorphism associated with plumage color variations in Coturnix chinensis[J].Anim Genet,2018,49(5):475-477.DOI:10.1111/age.12679.
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