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1、Medical Genetics13 线粒体疾病mitochondrial diseases Medical GeneticsMutations(changes)inthemitochondrialchromosomeareresponsibleforanumberofdisorders.Medical GeneticsMitochondrialdiseaseisachronic,geneticdisorderthatoccurswhenthemitochondriaofthecellfailstoproduceenoughenergyforcellororganfunction.Medica
2、l GeneticsTheincidenceabout1:3000-4000individualsintheUS.Medical GeneticsCharacteristicsUnlikenucleargenes,whichareinheritedfrombothparents,mitochondrialgenesareinheritedonlyfromthemother.Inmammals,99.99%ofmitochondrialDNA(mtDNA)isinheritedfromthemother.Thisisbecausethespermcarriesitsmitochondriaaro
3、undaportionofitstailandhasonlyabout100mitochondriacomparedto100,000intheoocyte.Medical GeneticsMedical GeneticsThreshold effect%ofmutantmtDNAsmustbeaboveathresholdtoproduceclinicalmanifestations%ofmutantmtDNAsneededtocausecelldysfunctionvariesaccordingtotissueoxidativerequirementsDiseasesignsespecia
4、llymanifestinTissueswithahighenergyexpenditure:DependentonoxidativemetabolismSpecifictissues:Brain,Heart&MuscleMedical GeneticsMitotic segregation%ofmutantmtDNAsindaughtercellscanshiftatcelldivisionProducesrapidchangesofgenotypethatmayleadtocrossingofthresholdMedical GeneticsTherearemanyformsofmitoc
5、hondrialdisease.Mitochondrialdiseasepresentsverydifferentlyfromindividualtoindividual.Medical GeneticsMitochondrialdiseaseisinheritedinanumberofdifferentways.Theremaybeoneindividualinafamilyormanyindividualsaffectedoveranumberofgenerations.Medical GeneticsIfthereisamutationinamitochondrialgene,itisp
6、assedfromamothertoallofherchildren;sonswillnotpassiton,butdaughterswillpassitontoalloftheirchildren,andsoon.Medical Genetics3.LHONLHON = Lebers;Hereditary;Optic;NeuropathyMedical GeneticsGenetic-Clinical correlations: Maternal InheritanceRecurrencerisks:Brother30%;Sister8%;Nephew46%;Niece10%;Malecou
7、sin31%;Femalecousin6%40%ofpatientswithcommonestmutation(G11778A)havenegativefamilyhistoryLargefamilieswithmaternalinheritance:G11778&T14484CmutationsMedical GeneticsMutations (General)3Mutationsaccountfor96%ofcasesAllinComplexIgenesMutations:G11778A(69%),G3460A(13%),T14484C(14%)Medical GeneticsClini
8、cal features(General)Malepredominance:NorelationtoanyX-linkedgenesOnset:Midlife:Mean30years;Range1to70VisuallossClinicalfeaturesPainlessVisuallosspatternSeverity:Maydeteriorateto20/200orlessProgression:Mean4months;Intervalbetweeneyesaffected:2monthsTendencytorecoverdependsonmutationPupillaryreaction
9、s:MayberelativelysparedfordegreeofvisuallossOcularpathologyOtherfeatures:SomefamiliesCardiacconductiondefects;Spasticdystonia;Spasticparaparesis;DystoniaMedical GeneticsMedical GeneticsLaboratoryMusclepathologyNoraggedredfibersEOMmitochondria:Diffuseincreaseinnumberandsize;DisorganizedcristaePreserv
10、ationofmyofibrilsMRI:OpticnervemayenhanceonT2weightedimagesMedical Genetics4.MERRFMERRF=MyoclonicEpilepsy;RaggedRedFibersMedical GeneticsmtDNA point mutations:tRNALys:A8344G(Frequent);T8356C;G8363A;G8361ASyndromes:MERRForMERRF/MELASoverlaptRNASerSyndromes:MERRF/MELASoverlap;EpilepsiaPartialisContinu
11、a;tRNALeuMedical GeneticsOnsetLateadolescence-EarlyadultMedical GeneticsClinical syndrome:CNSMyoclonus(60%)Epilepsy(45%)Cerebellardysfunction:AtaxiaDementiaOpticatrophy(20%)Polyneuropathy(20%)Distalsensoryloss(largefibermodalities)Hearingloss(40%)MyopathyShortstature(10%)Lipomata(10%)Medical Genetic
12、sMedical GeneticsLaboratory Lacticacidosis:VariablePathologyofmuscleRaggedredfibersMedical Genetics5.MELASMELAS=MitochondrialEncephalomyopathy;LacticAcidosis;StrokeMedical GeneticsmtDNA point mutations tRNALeu(common)A3243Gmutation:80%ofMELASsyndromesOtherMELASmutationloci:T3271Chaslaterageofonset;3
13、291Medical GeneticsClinical Syndrome OnsetMean=10years;Range=2to40Encephalopathy:OftenepisodicSystemicfeaturesMyopathyPolyneuropathyMorecommoninpatientswithmyopathyMeanlifespanwithfullclinicalsyndrome2to4decadesMedical GeneticsScattered abnormal, vacuolated fibers with clear rim:H&EScattered ragged
14、red muscle fibers:GomoritrichromeMedical GeneticsRagged red muscle fibers:GomoritrichromeMedical GeneticsGenetic counseling: A3423G mutation%ofaffectedoffspring:IncreasedwithhighermutantloadinmaternalbloodMutantload1%to19%:20%chanceofaffectedoffspringMutantload20%:50%chanceofaffectedoffspringFullexp
15、ressionofphenotypeinmultiplefamilymembers:RarePartialexpressioninmultiplefamilymembers:CommonMedical GeneticsLaboratory Lacticacidosis:Blood&CSFEMG:MormalorMyopathicSerumCK:Normalto2xhigh(32%)MRI:StrokesBiochemistryRespiratorychaindysfunctionReducedactivityofComplexesI&IVPathology(A3243Gmutation)Med
16、ical Genetics6.Kearns-SayreSyndromeFamily history Sporadic:MostpatientsFamilialcases:Rare;MothertooffspringMedical GeneticsmtDNA mutation typesSinglelargemtDNAdeletion(2to8kb)Mostcommonmutationtype(80%)CommondeletionsMostcommon:4977basepairsfrom8488to13460;13basepairrepeatatmutationbreakpointThaipat
17、ients:3558bpdeletion;10204to13761,or10208to13765MostdeletionspreservePromotersoftranscriptionofheavy&lightstrands12S&16SribosomalRNAgenesOriginofheavystrandreplicationChangeinnumberofdeletionsovertimeIncreasedinmuscleReducedinrapidlyturningovercells(hematopoetic)LargescaletandemduplicationMedical Ge
18、neticsClinical featuresGeneralCharacteristicsigns:PEO;Pigmentarydegenerationofretina;Heartblock;MitochondrialmyopathyOnset:Distal;SymmetricOccasionalfatigueorpainonexertionCNSHearingloss(95%)Ataxia(90%)SystemicfeaturesMedical GeneticsMedical GeneticsMedical GeneticsLaboratory MusclepathologyRaggedredfibers(98%):COX+andCOX-VariationinmusclefibersizeLacticacidosis(80%)HeadCT:Basalgangliacalcifications(5%)CSFProtein:High
