预防出生缺陷的基本知识.ppt

预防出生缺陷的基本知识,Preventionofbirthdefects,医学遗传学国家重点实验室龙志高ZhigaoLong,StateKeyLaboratoryofMedicalGenetics,Whatisabirthdefect?什么是出生缺陷？,Birthdefectmeansthatthebabyhasoccurredmorphology,functionalmetabolic,mental,behavioralandotheraspectsofabnormalwhenhe/shewasinthewombbeforethebirth.出生缺陷是指孩子出生前，在母亲腹中里就已经发生的形态结构、功能代谢、精神、行为等方面的异常。,Abnormalmorphologyoftenshowscongenitalmalformations，suchaschildrenwithoutbrain,spinabifida,cleftlip,abnormallimbs,est.形态结构异常常表现为先天畸形，例如无脑儿、脊柱裂、兔唇、四肢异常等。,Defectsofphysiologicalfunctionsandmetabolismoftenleadtocongenitalmentalretardation,deafness,dumb.生理功能和代谢方面的出生缺陷常常导致先天性智力低下、聋、哑等。在出生缺陷中以先天性心脏病、唐氏综合征、神经管畸形等最为常见。Amongthebirthdefects,congenitalheartdisease,Downssyndromeandneuraltubedefectsarethemostcommondiseases.,WhatisDownssyndrome？什么是唐氏综合征（先天愚型)?,Downssyndromeisanautosomaldiseasewhichisthemostcommoncauseofneonatalcongenitaldementia.唐氏综合征是新生儿中最常见的导致先天性痴呆的常染色体疾病。,MainclinicalmanifestationsofDownssyndrome唐氏综合征的主要临床表现Severementalretardation严重的智力低下Uniqueface，suchaseyeswideapart,lownose独特的面容，如眼距宽、鼻梁低Infertilemalepatients,femalepatientswithoccasionalfertility男性患者无生育能力，女性患者偶有生育能力50%ofchildrenwithcongenitalheartdisease.50%患儿伴有先天性心脏病,Whatisopenneuraltubedefects?什么是开放性神经管缺损？,Openneuraltubedefectswereinthelargeproportionofbirthdefects,mainlyinchildrenwithoutbrain,dominantspinabifidaandothermalformations.Itisduetotheneuraltubecannotbeclosedduringdevelopment，whichoftenresultsinstillbirth,stillbirth,paralysis,etc.开放性神经管缺损在出生缺陷中占很大比例，主要有无脑儿、显性脊柱裂等缺陷。此病是神经管在发育过程中不能闭合所致，常造成死胎、死产、瘫痪等。,Factorsaffectingneuraltubeclosureincludesvirusinfectioninpregnancy,lackoffolicacidintakeormetabolicabnormalitiesoffolicacid,malnutrition,andgeneticfactors,est.影响神经管闭合的因素有孕期病毒感染、叶酸摄入不足或代谢异常、营养不良及遗传因素等,Causesofbirthdefects出生缺陷的原因,遗传因素（Geneticfactors）25（基因20，染色体3-5）不明原因65（遗传与环境因素）环境因素（Environmentalfactors）10（放射1，感染2-3，代谢1-2，化学2-3）,遗传因素（Geneticfactors）,染色体病最多见，包括染色体数目及结构异常。可由父母一方染色体异常遗传引起，亦可由亲代的生殖细胞染色体畸变引起。Chromosomaldiseaseismostcommon,includingabnormalitiesofchromosomenumberandstructure.Itcanbecausedbothbyaparentchromosomeabnormalitiescausedbygeneticandbyparentalgermcellchromosomeaberrations.,遗传因素（Geneticfactors）,染色体外观正常，但基因发生突变，由单个基因突变引起的疾病叫单基因病。其遗传方式可分为常染色体显性或隐性遗传、性连锁显性或隐性遗传等Thediseasecausedbyasinglegenemutationwascalledsingle-genediseasewhileitschromosomeslooknormal,butthegenehasamutation.Itsmodeofinheritancecanbedividedintoautosomaldominantorrecessiveinheritance,sex-linkeddominantorrecessiveinheritance,etc.,遗传因素（Geneticfactors）,由几对基因决定的遗传性状异常导致的疾病成为多基因遗传病；常有家族史，是许多基因和环境因素共同作用的结果。Diseasecausedbyabnormalitiesofafewgenesdeterminingthegenetictraitswascalledamulti-geneticdisease;Familyhistoryoftenoccurred.Itistheresultoftheinteractionofmanygenesandenvironmentalfactors.,环境因素(Environmentalfactors)和遗传及共同作用,宫内(womb)：营养因素、微生物感染、不良嗜好、心理因素等；Nutritionalfactors,microbialinfections,badhabits,psychologicalfactors宫外(outofuterus)：职业因素、物理因素、环境类雌激素、次生环境（城市建筑、工业污染等）等；Occupationalfactors,physicalfactors,environmentalestrogen,secondaryenvironment(urbanarchitecture,industrialpollution,etc.),致畸率与暴露的时间有关Teratogenicrateandtheexposuretime,致畸率与暴露的时间有关Teratogenicrateandtheexposuretime,怀孕第几周最容易引起胎儿畸形？Whenmostlikelytocausefetalmalformations？,Inthefifthtotenweeksofgestation,fetusvulnerabletotheimpactcausedbyTheexternalenvironmentortheinfluenceofdrugs.ThisperiodiscalledtheTeratogenicsensitiveperiod一般在怀孕后第5-10周（从末次月经算起）受到外界环境或药物因素影响最容易引起胎儿畸形.因为这个时期是受精卵形成的细胞正在向胎儿分化的时期，特别容易引起畸形，所以又称为“致畸敏感期”。,Howtopreventbirthdefects？如何预防出生缺陷？,How?,Tertiarypreventionofbirthdefectssystem出生缺陷的三级预防体系,PrimarypreventionTopreventtheoccurrenceofbirthdefectsinchildren第1道防线防止出生缺陷儿的发生,1、婚前检查（Premaritalmedicalexamination）2、遗传咨询（Geneticcounseling）3、孕前保健（Preconceptioncare）,1、婚前检查（Premaritalmedicalexamination）,识别严重的遗传性疾病，根据遗传规律，推算下一代发病的风险，提出可以结婚，但限制生育、禁止生育。指定的传染病，在传染期内应暂缓结婚；有关的精神病在发病期内，暂缓结婚；攻击性精神病禁止结婚；Seriousgeneticdiseasecanbemarried,buttolimitfertility,banreproductive.Thespecifiedinfectiousdiseases,shouldpostponetheirmarriageintheinfectiousperiod.Relatedpsychosisshouldpostponetheirmarriageintheonsetoftheperiod;attackpsychosisprohibitmarriage.,2、遗传咨询（Geneticcounseling）,由医学遗传的专业人员或医师，对咨询者提出的家庭中遗传性疾病的发病原因、遗传方式、诊断、预后、复发风险率、防治等问题予以解答，并提出婚育医学提议。ProfessionalsorphysiciansoftheMedicalGeneticansweredcausesofhereditarydiseasesinthefamilyconsultant,themodeofinheritance,diagnosis,prognosis,recurrenceriskratio,preventionandotherissues,andproposedmarriageandchildbearingmedicalproposal.,有下列情况之一的夫妻应进行遗传咨询Coupleswithoneofthefollowingshouldbecarriedoutgeneticcounseling,遗传病或先天畸形的家族史或生育史;Geneticdiseaseorcongenitalmalformationsoffamilyhistoryorhistoryoffertility;子女有不明原因智力低下；Childrenhaveunexplainedmentalretardation不明原因的流产、死胎、死产或新生儿死亡；Unexplainedmiscarriage,stillbirth,stillbirthorneonataldeath孕期接触不良因素或患有某些慢性病;Pregnancyexposuretoadversefactorsorsufferingfromcertainchronicdiseases;常规检查或常见遗传病筛查发现异常;Routineinspectionorcommongeneticdiseasescreeningabnormal;多年不育、高龄或其他情况Yearsofinfertility,oldageorothercircumstances.,3、孕前保健（Preconceptioncare）,孕前4至6个月进行孕前检查Pre-pregnancycheckinthe4-6monthsbeforepregnancy.怀孕前后3个月补充叶酸可以有效预防神经管畸形的发生Folicacidsupplementationinthe3monthsbeforeandafterpregnancytopreventneuraltubedefectseffectively.食盐加碘可预防地方性克汀病Iodizationofsaltcanpreventendemiccretinism.孕前3个月接种风疹疫苗Rubellavaccineinthe3monthsbeforepregnancy.远离毒品、戒烟、戒酒Stayawayfromdrugs,smokingandalcohol.女性应避免接触有害物质Womenshouldavoidexposuretoharmfulsubstances.,SecondarypreventionToReducebirthdefectsinchildrenborn第2道防线减少出生缺陷儿的出生,1、产前筛查（Prenatalscreening）2、产前诊断（Prenataldiagnosis）,1、产前筛查（Prenatalscreening）,产前筛查是指通过简便、经济、微创的方法在妇群体中发现孕育某些先天畸形和遗传性疾病胎儿的高危孕妇，获得发病风险的估计。Prenatalscreeninghigh-riskpregnantwomengavebirthtosomecongenitalmalformationsandgeneticdiseasesofthefetusinthewomensgroupsthroughasimple,economicalandminimallyinvasivemethodtoobtainestimatesofrisk.常用指标（Commonlyusedindicators）PAPP-A/-HCG、AFP/-HCG注：PAPP-A妊娠相关血浆蛋白AAFP孕妇血清甲胎蛋白-HCG人绒毛膜促性腺激素亚单位,早孕期筛查（Earlypregnancyscreening）,游离-HCG、PAPP-A是早孕期生化筛查最好的指标NT是独立的早孕期筛查指标游离-HCG+PAPP-A+NT可以检出85%的胎儿染色体异常注：NT胎儿颈后透明组织厚度,中孕期筛查（Secondtrimesterscreening）,血清AFP+游离-HCG可以检出60%的胎儿染色体异常,0.06,1,16,0.25,4,64,正常人群Unaffected,脊柱裂Spinabifida,无脑畸形Anencephaly,AFP(MoM),15,20,25,30,35,40,45,50,55,孕妇年龄Maternalage,唐氏综合征Downssyndrome,正常人群Unaffected,仅以孕妇年龄为指标，检出率低,1520w母血清筛查,Downs风险1/270,胎龄正确,重新计算胎龄及MoM,定期产前检查,染色体核型分析/高分辨超声,提供遗传咨询,Downs风险=1/270,Downs风险=2.0MoM,定期产检,NTD高风险,羊水AFP、核型分析/高分辨超声/AchE,NTD确诊,筛查时注意问题（Attentiontotheproblemwhenscreening）,正确的孕龄Correctgestationalage孕妇体重Maternalweight其它：型糖尿病者、吸烟者、受孕方式等Other:Typediabetes,smokers,andconceivetheway风险率的估计、处理Estimatesoftheriskrate,processing有一定的漏检率、标本要求Undetectedrate,specimenrequirements,2、产前诊断（Prenataldiagnosis）,宫内诊断(intrauterinediagnosis)产前诊断是指在胎儿出生前用各种方法诊断胎儿是否患有某种遗传病或先天性疾病的一种手段，是由人类细胞遗传学、分子遗传学、生物化学和临床医学紧密结合的一门学科。Prenataldiagnosisisameansusedtodiagnosiswhetherthefetusissufferingfromageneticdiseaseorcongenitaldiseasesornot.,产前诊断指征Indicationforprenataldiagnosis,高龄，畸形胎儿、染色体或基因异常胎儿生育史；Oldage,fetalmalformations,chromosomalorgeneticabnormalityoffetalreproductivehistory先天性代谢疾病，或已生育过病儿的孕妇；Congenitalmetabolicdisorders,orpregnantwomanwhohasgivenbirthtoasickchild;遗传性家族史或近亲婚配史的孕妇；Pregnantwomenofthegeneticfamilyhistoryorthehistoryofnextofkinmarriage,原因不明的流产、死产、畸胎或有新生儿死亡史的孕妇；Unexplainedmiscarriage,stillbirth,birthdefectsorneonataldeaths,thehistoryofpregnantwomen妊娠早期接触过化学毒物、放射性物质或严重病毒感染的孕妇；Earlypregnancyexposuretochemicalpoisons,radioactivesubstancesorseriousvirus-infectedpregnantwomen羊水过多、羊水过少、发育受限等Polyhydramnios,oligohydramnios,growthrestriction产前筛查高危、形态学检查疑畸形Prenatalscreeninghigh-risk,morphologicalexaminationofsuspectedmalformation,产前诊断指征与染色体异常检出效率Indicationsofprenataldiagnosisandchromosomalabnormalitiesdetectedintheefficiency,产前诊断方法Methodofprenataldiagnosis,观察胎儿结构（Observationoffetalstructure）：超声、X线、胎儿镜、MRI染色体核型分析（Karyotypeanalysis）：细胞和分子遗传学方法基因检测（Genetictesting）：DNA分子杂交、FISH检测基因产物（Detectthegeneproduct）：蛋白质、酶和代谢产物等检测，神经管缺陷、先天性代谢性疾病。病理解剖（Pathologicalanatomy）,1、观察胎儿结构(Observationoffetalstructure)：以无创、可重复的超声检查应用最广。Non-invasive,repeatableultrasoundwasusedmostwidely.超声检查结果的分析需进行染色体检查Ultrasoundanalysisoftheresultsneedtoanalysischromosome.,超声检查发现胎儿一种结构异常时,染色体异常率为10%20%;多种结构异常时,染色体异常率为30%40%。Whentheultrasoundexaminationrevealedafetuswithastructuralabnormalities,chromosomalabnormalitieswas10%to20%;avarietyofstructuralabnormalities,chromosomalabnormalitieswas30%to40%.遗传性改变先于形态学改变，超声检查不能代替染色体检查Geneticchangesprecedemorphologicalchanges,ultrasonographycannotreplaceachromosome,2、染色体核型分析和基因检测（KaryotypeanalysisandGenetictesting）细胞遗传学核型分析、FISH/CGH、DNA分子杂交检测标本（Testspecimens）：胚胎细胞、绒毛Embryoniccells,villous羊水、脐血Amnioticfluid,umbilicalcordblood胎儿组织Fetaltissue母血中分离的胎儿DNAIsolationoffetalDNAinmaternalblood,（1）细胞遗传学核型分析Cytogenetickaryotypeanalysis利用绒毛、羊水或脐血的胎儿细胞培养、收集中期分裂相，通过G高分辨显带，核型分析。Usingchorionicvilli,cordbloodoramnioticfluidtoculturefetalcellandcollectcellsofmetaphasesthroughtheGhighresolutionbanding,thenkaryotypeanalysis.得到全部染色体核型的数目、明显的结构异常；Getallthechromosomenumber,obviousstructuralabnormality培养周期长，依赖细胞形态及数目；Trainingcycleislong,thedependenceofcellularmorphologyandnumber,（2）荧光原位杂交技术（FISH）利用已知核酸序列作为探针,以荧光素直接标记后与待检DNA进行杂交,在荧光显微镜下观察杂交信号，确定标记染色体数目、结构变化。Usingtheknownnucleicacidsequencesasprobes,labeledwithfluoresceindirectlyandtheinspectedDNAhybridization,hybridizationsignalswereobservedunderfluorescencemicroscopy,andthendeterminethemarkerchromosomenumber,structuralchange,47,XX,+18