TRISOMY21SYNDROMEDr XiaopingLuoProfessorandChairmanDepartmentofPediatricsTongjiHospitalofTongjiMedicalCollegeHuazhongUniversityofScienceandTechnologyWuhan China Downsyndrome asweknowittoday hasexistedsincethebeginningofhumankind Dept ofPediatrics TongjiHospital HUST Downsyndrome FirstdescribedinthemedicalliteraturebyDr JohnLangdonDowninEnglandin1866In1956 scientistsdiscoveredthatthetypicalhumancellhas46chromosomesIn1958 LejeunediscoveredthatthecellsfromanindividualwithDShadanextrachromosome21In1959 9peoplewithDSwerefoundtohaveanextrachromosome21 1 Dept ofPediatrics TongjiHospital HUST Maternalage 放射线Radiation Infection Chemicals Geneticfactors Mothercyesis Etiology TheincidenceofDS Maternalage Y Dept ofPediatrics TongjiHospital HUST MaternalAgeTheriskincreaseswiththematernalage Normal Thegenesofchromosome21 whatdoweknow Therearemorethan400genesonchromosome21 weusedtothinktherewerefewer Ofthese 170codeforproteinsthatarealsoencodedbygenesinmiceandotheranimalsWhengenesareconservedacrossspecies itistypicallybecausetheyareimportant Chromosome21proteins ArepredictedtodirectlyandindirectlyaffectlearningandmemoryinDownsyndromebyPreventingestrogenfromenteringbraincells lowestrogeninbraincanpromoteearlymenopauseandAlzheimerdisease ReducingsubstancesthatallowcellstocommunicatewithoneanotherReducingbraincellsurvivalintheadult Studyingchromosome21genesacrossspeciesallowsusto UnderstandtherolesofthesegenesinnormaldevelopmentandfunctionLearnhowtheproteinsencodedbythesegenesinteractwithotherproteinsinthebodyPredictwaysinwhichtheextrainformationencodedbythesegenescanbe turneddown or turnedoff bymedications genetherapy etc 2 TypesofDownSyndrome Trisomy21 92 95 MMoossaaiiccDDoowwnnSynnddrroommee 2 5 5 TranslocationTrisomy21 2 4 Trisomy21Foundin92 ofallDSindividualsCausedbynondisjuctioninmeiosis causingeggstohavetrisomy21Increasesinincidencewithmaternalage butalsofoundinyoungermothersChildrenbornimmediatelyafterDSchildrenhaveahigherchanceofalsohavingDS however forothersiblings theriskforhavingDSdoesnotincrease Nondisjunction MosaicDS2 4 oftheDSpopulationStartsoffwith23pairsofchromosomesineachcellErroroccursinanearlycelldivisionDuringembryonicdevelopment arandomcellwillacquiretrisomy21 creating2individualcelllines normalandtrisomatic Theearlierthemutationoccurs themoreprofoundtheeffects MosaicDS TranslocationDS3 4 oftheDSpopulationARobertsoniantranslocationoccurswhenonechromosome21attachestoanotherchromosome formingasinglenew chromosomeTherecipientchromosomeisusuallychromosome14andthecombinationofthe2chromosomesiscalledafourteen twentyonetranslocationCanalsoswitchwith13 15 or22 3 TranslocationDSAbout ofTranslocationDSisinheritedTheparentisthencalledatranslocationcarrierParenthasonenormalcopyof21andonecopyof21attachedtoanotherchromosomeBothcopiesarethenpassedonWhenfertilizationoccurs embryocontainsbothcopiesof21fromthecarrierparent andthenormalonecopyor21fromthenormalparentEffectsaresimilartoTrisomy21DS TranslocationDS RobertsonianTranslocationsCanresultinDownsyndrome 4 MedicalComplications EpilepsyHypothyroidismCrossedeyesCataractsHearingimpairmentHeartdefectsChildhoodleukemiais20 morecommon HerniasSterilityinmalesFemalesarefertilebutcanpassonDSAcceleratedAgingwithhighchanceofAlzheimer sdisease 1968 1974 1983 8 1988 NewTestforDownSyndrome 1959 1966 1933 1990 Screeningmilestones Trisomy21identifiedascauseofDownSyndrome Firstchromosomalanalysesfromamnioticfluid AssociationbetweenmaternalageandDownsyndrome Tripletestintroduced MaternalserummarkersforDownsyndrome Nuchaltranslucencyintroduced 1968 1974 1983 8 1988 1959 1966 1933 1990 1864 Langdon Downfirstdescriptionoftheclinicalfeaturesof mongolism NoninvasiveprenatalscreeningforDSDecember1 2008 Sequenom Inc announcedresultsfromacollaborativestudywithTheChineseUniversityshowingthatitispreliminarilypossibletodiagnoseDownsyndromeonabloodsampletakenfromexpectantmothersduringthefirstandsecondtrimestersofpregnancy ThemethodusestechnologythatextractsfetalRNAfrommaternalblood Studyisbeinglaunchedtoevaluateupto10 000pregnanciesatincreasedriskforDS Noninvasivetest cont Atfirst womenwithpositivescreenswillssttiilllluunnddeerrggoochorionicvillisampling CVS oramniocentesistoconfirmresults butthehopeisthatthenewtestwillultimatelyreplaceboth Thereissomeconcernthatthistestingwillbemarketed indemandbeforesufficientstudiesarecompletedtoproveaccuracy 5 Noninvasivetest cont ResearchersatStanfordhavepublishedpreliminaryresultsonamaternalblood basedDSscreenthatusesadifferenttechnologythanSequenomOthercompaniesarealsoworkingonnoninvasivetests 1968 1974 1983 8 1988 AlternativeTherapiesforChildrenwithDownSyndrome1959 1966 1933 1990 Alternativetherapies history1960 s HenryTurkelclaimedthatamixtureof48ingredientscouldimprovetheintelligenceofchildrenwithDS whichheadministeredtohispatientsformorethan40years Nodouble blindstudywaseverperformed Noevidenceemergedthatthiswasbeneficial Alternativetherapieshistory cont 1980 s RuthHarrell andassociatesreportedthatsupplementaryvitaminsandmineralsandthyroidhormoneimp