王建設(shè)兒童肝病遺傳咨詢

肝臟遺傳病的診斷和遺傳咨復(fù)旦大學(xué)附屬金山醫(yī)院兒復(fù)旦大學(xué)附屬兒科醫(yī)院分子診斷中復(fù)旦大學(xué)附屬兒科醫(yī)院肝病中1:30-肝臟遺傳病的特各 階段均可發(fā)病，以兒童期為起病形式多多數(shù)為 隱性遺傳，或De 近年來進展非常肝臟遺傳病的診斷和鑒別診是肝臟病肝細(xì)vs膽汁淤Type1、2、3MDR3（ABCB4）deficiency缺陷AlagillesyndromeNeonatalsclerosing新生兒硬化性膽管Alagille綜合ABCB4缺陷Citrin 隱性遺傳7q21.3上 突變引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攜帶福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嬰兒肝內(nèi)膽汁淤積癥最常見原115名肝內(nèi)膽汁淤積癥嬰兒，10名存在突嬰兒肝內(nèi)膽汁淤積癥最常見原因（續(xù)21例雜合突變——可疑citrin缺陷明確+FuHY.WJG.FuHY.JGastroenterol.GeographicdistributionofSLC25A13SLC25A13突變地理分布（400例結(jié)果 早期發(fā)現(xiàn)—外NICCDandAnyaminoacidelevated2timesUNL,ormorethanoneaminoacidelevated1.5timesUNL酸）Dec2003-Spet2009,39casesincluded 年月 NICCDand無氨基酸譜異常不能除外Citrin缺 :17名不明原因伴脂肪變性嬰肝,14名 :11名肝內(nèi)膽汁淤積癥伴脂肪變性,6名行研究,11/12allelesSLC25A13 Steatosisisthemostimportant69intrahepaticcholestasisreceivedliverbiopsyandSteatosis63Steatosis05Allthehomozygotesorcompoundheterozygetsharborhepaticsteatosis所有NICCD均有明顯脂肪變性PatientswithoutsteatosisexcludethediagnosisofCitrinDeficiency無脂肪變性可除外NICCDHYFu,JSWang.UnpublishedFocalmacrovesicularsteatosiswithgiantcell.Adult-onsettypeII presentintractablemetabolicencephalopathyandmostpatientshaddiedofseverebrainedemaClinicalpicturesofCTLN2臨床表Neurologicalsymptoms神經(jīng)系統(tǒng)癥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體格檢Mostpatientsarethin消瘦(BMI震顫、共濟失調(diào)、反射亢Nosignsoficterus,ascites,or無黃疸、腹水、脾 檢Highlevels:ammonia,citrulline,arginine,triglycerides,AST,ALT血氨、瓜氨酸、精氨酸、甘油三酯、轉(zhuǎn)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-治療-肝移 精氨酸鈉血親親屬（尤其兄弟姐妹）監(jiān)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飲–：低蛋白高碳水化合物肝移精氨酸鈉血親親屬（尤其兄弟姐妹）監(jiān)治療-肝移 精氨酸鈉血親親屬（尤其兄弟姐妹）監(jiān)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-自身免疫抗銅藍蛋正ERCP和CT：提示肝硬化，無膽道異病Cirrhosis;pan-lobularmetallothionein(Cu)–usualcopperdepositsareperiportalonlyin “Cholangiocytedisarray”andcholesterol病TB42mol/L,DB20ALT103U/L