王建设儿童肝病遗传咨询

肝脏遗传病的诊断和遗传咨复旦大学附属金山医院儿复旦大学附属儿科医院分子诊断中复旦大学附属儿科医院肝病中1:30-肝脏遗传病的特各 阶段均可发病，以儿童期为起病形式多多数为 隐性遗传，或De 近年来进展非常肝脏遗传病的诊断和鉴别诊是肝脏病肝细vs胆汁淤Type1、2、3MDR3（ABCB4）deficiency缺陷AlagillesyndromeNeonatalsclerosing新生儿硬化性胆管Alagille综合ABCB4缺陷Citrin 隐性遗传7q21.3上 突变引Kobayashietal.NatGenet1999;Yasudaetal.HumGenetOhuraetal.HumGenet2001;Tazawaetal.JPediatr2001;Tomomasaetal.JPediatr2001;Yamaguchietal.HumMutat2002;Saheki&KobayashiJHumGenet.AworldwideMainlyinEastAsia,IncludingJapan(1/69&MainlandChina(1/65),Korea(1/112)andVietnamYehJN,etal.JPediatr.SongYZ,etal.ZhongguoDangDaiErKeZaZhiKoJS,etal.JKoreanMedSciLuYB,etal.JHumGenet.AlsoinIsreal,USA,CanadaandBen-ShalomE,etal.MolGenetMetalDimmockD,etal.Pediatrics.DimmockD,etal.MolGenetMetabHutchinT,JInheritMetabDis,2009,FrequencyandDistributionofCarriersinEast Kobayashietal.MolGenetMetab2003Luetal.JHumGenet2005Tabataetal.JHumGenet2008Gaoetal.inpress

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Wefoundaremarkabledifferenceincarrierratesinbetweennorth(low)andsouth(high)oftheYangtze携带福1638-1660dup(3)和IVS6+5GtoA(3)12/450 分析exons6,9,11,16,17和 .Lin等.ClinChimActa.2011;412(5-6):460婴儿肝内胆汁淤积症最常见原115名肝内胆汁淤积症婴儿，10名存在突婴儿肝内胆汁淤积症最常见原因（续21例杂合突变——可疑citrin缺陷明确+FuHY.WJG.FuHY.JGastroenterol.GeographicdistributionofSLC25A13SLC25A13突变地理分布（400例结果 早期发现—外NICCDandAnyaminoacidelevated2timesUNL,ormorethanoneaminoacidelevated1.5timesUNL酸）Dec2003-Spet2009,39casesincluded 年月 NICCDand无氨基酸谱异常不能除外Citrin缺 :17名不明原因伴脂肪变性婴肝,14名 :11名肝内胆汁淤积症伴脂肪变性,6名行研究,11/12allelesSLC25A13 Steatosisisthemostimportant69intrahepaticcholestasisreceivedliverbiopsyandSteatosis63Steatosis05Allthehomozygotesorcompoundheterozygetsharborhepaticsteatosis所有NICCD均有明显脂肪变性PatientswithoutsteatosisexcludethediagnosisofCitrinDeficiency无脂肪变性可除外NICCDHYFu,JSWang.UnpublishedFocalmacrovesicularsteatosiswithgiantcell.Adult-onsettypeII presentintractablemetabolicencephalopathyandmostpatientshaddiedofseverebrainedemaClinicalpicturesofCTLN2临床表Neurologicalsymptoms神经系统症Consciousnessdisturbance(disorientation,delirium,syncope,coma) Seizure,CognitiveBehavioralaberrations Depression,Characteristicfoodfondness食物偏好特征 Likeprotein-richand/orlipid-richfoods(peanuts,meat,milk,tofu,fishroe)Dislikecarbohydrate-richfoods(rice,Disliketodrinksometimeshaveahistoryofpancreatitis,fattyliver,and/orliverdysfunctionsbeforeonsetofCTLN2physicalexamination体格检Mostpatientsarethin消瘦(BMI震颤、共济失调、反射亢Nosignsoficterus,ascites,or无黄疸、腹水、脾 检Highlevels:ammonia,citrulline,arginine,triglycerides,AST,ALT血氨、瓜氨酸、精氨酸、甘油三酯、转氨酶升FrequencyFrequencyandDistributionof12SLC25A13MutationsinEast-SouthJ:Japanese,K:Korean,C:Chinese,V:Vietnamese,M:Malaysian,T: numberofI744---311-21---V2-------1-62----3-2-1-X1-22-1-2----4---2-治疗-肝移 精氨酸钠血亲亲属（尤其兄弟姐妹）监RestrictRestrictproteininthedailydiet(40Giveoralantibiotics口服抗生素Givelactulose口服乳果糖Administerbranchedchainamino

Protein80g/dayPatient低碳水化低碳水化合物饮–：低蛋白高碳水化合物肝移精氨酸钠血亲亲属（尤其兄弟姐妹）监治疗-肝移 精氨酸钠血亲亲属（尤其兄弟姐妹）监Brainedema,maincauseof Jan Jan

酸 Dr.Dr.K.Kobayashi,whodiscoveredSLC25A13,thecausativegenefoCTLN2andNICCD,deceasedonDec.21st,2010.Citrin缺陷PaucityofBileprevioussyndromicpaucityofbileAlagilleAutosomaldominantdisorderwithhighlyvariableexpressivityliver,heart,eye,skeleton,face,andtoalesserdegreethekidney,vasculature,andpancreasInthepresenceofpaucityofinterlobularbileduct,3ormoreofthe5majorfeatures,namedascholestasis,cardiacmurmur,eyeabnormality,butterflyvertebrae,facialcharacteristics(renalIfbiopsynotdone,orpaucityofinterlobularbileductnotconfirmed,4ormoreofthefivealsoreachthediagnosisIfpositivefamilyhistory,orknownJagged1mutation,twomajormanifestationsusuallyenoughfordiagnosisLiverpresentation-MisdiagnosedasAcholicstoolseenin5/6within1wkafterLaparoscopiccholangiography:1/1/6diagnosedasHidascan:3/4/6noJaundicefadeinsomecasesalongtheageWJP Jaundice-followLastfollowOtherliverDysfunctionofsyntheticCardio-vascularPulmonary70%8.8％tetralogyofSkeletalbutterflyvertebraeandothervertebralanomaliesin33-87%rarelycauseclinicalproblemsanddonotrequirefollow-upProminentDeep-setSmallBulbBigorerectedChangewith Characteristic BloodvesselAccountingfor1/3Intracranialhemorrhageisthemostimportantcomplication,occurringindifferentpartofskull.MostoccurinptwithoutobviousHeadinjury,evenmild,couldleadtoAssociatedwithabnormalvesselstructure,seenin15%Abnormalityseenin40-50%USforstructuralmesangiolipidosis,RTACanbefirstpresentationinJagged1AligandintheNotchsignalingfunctionsincellfatelocatedwithin20p12andconsistsof26exonsthatcover38,000kbofgenomicDNA94%(232/247)of93%(216/232)canbedetectedbydirect14deletionsbyFISH,1byqPCR,1byWarthenDM…SpinnerNB.HumMutatJAG1variantinChineseWangHL…,WangJS,XingQH.GeneJAG1variantinChinese10/15infourexons(3,4,6,Mutationwasnotfoundintwo5/5deAccountforlessthan1%ALGSTwenty-twoindividualswith edALGSandnomutationsinJAG1,8detected6missense,1splicing,1533inherited,1denovo,4KamathBM,…,SpinnerNB.JMedGenetAllLiverSimilarprevalenceofophthalmologicandrenalanomaliesLesscardiacinvolvement(60%vs100%inJAG1)Lessvertebralabnormalities(10%vs.64%)andfacialfeatures(20%vs.featuresNOTCH2Phenotypeishighlycharacteristicfacial,kidneysAutosomalJagged1geneMostdeNotch2病女，7性肝炎A-自身免疫抗铜蓝蛋正ERCP和CT：提示肝硬化，无胆道异病Cirrhosis;pan-lobularmetallothionein(Cu)–usualcopperdepositsareperiportalonlyin “Cholangiocytedisarray”andcholesterol病TB42mol/L,DB20ALT103U/L