醫(yī)學(xué)遺傳學(xué)教學(xué)課件：Chapter 10 Mitochondrial genetics-2

2023/10/121MitochondrialdisorderMitochondrialGenetics-22023/10/122LHONMERRFMELASNARPKSSMitochondrialdisease

---duetomitochondrialDNAmutation★2023/10/123LeberHereditaryopticneuropathy(LHON)

(Leber遺傳性視神經(jīng)病)Firstrecognizedmtdisorder11778GtoA,3460GtoAand14484TtoC,respectivelyintheND4,ND1andND6subunitgenesofcomplexI2023/10/124Signs&symptoms

anacuteonsetofvisualloss

---firstinoneeye,afewweekstomonthslaterintheother.---Onsetisusuallyyoungadulthood,althoughagerangefrom8-60y.---verysevereopticatrophyandpermanentdecreaseofvisualacuity.2023/10/125GeneticsMutationsintheMT-ND1,MT-ND4,MT-ND4L,andMT-ND6genesThegenescodefortheNADHdehydrogenaseproteininvolvedinthenormalmitochondrialfunctionofoxidativephosphorylation.2023/10/126Epidemiology1:9000inNorthernEurope1:30,000to1:50,000inEuropeND4G11778Amutationwith70%ofEuropeancases;90%ofAsiancasesND6T14484Cmutationfor86%ofLHONcasesinQuebec,Canada>50percentofmaleswithamutationand>85percentoffemaleswithamutationneverexperiencevisionlossorrelatedmedicalproblems---Heteroplasmy,X-chromosome,haplogroup,……

2023/10/127PathophysiologyDegenerationintheretinalganglioncell(RGC)layerespeciallythemaculopapillarybundle.ImpairedglutamatetransportIncreasedreactiveoxygenspecies(ROS)causingapoptosisofretinalganglioncells.SOD2andglutathionerescueLHONRGCfromapoptoticdeath.2023/10/128Diagnosis&managementWithoutaknownfamilyhistoryofLHONthediagnosisisdifficultandusuallyrequiresaneuro-ophthalmologicalevaluationand/orbloodtestingforDNAassessmentThereisnoacceptedtreatment,buttheproposalforthisdiseaseGeneticcounselling,avoidnervetoxin2023/10/129MERRF:myoclonicepilepsyandragged-redfibersExtremelyrare1/400,000inEuropeHeteroplasmyRagged-redfiber(肌陣攣癲癇碎紅纖維病）2023/10/1210PresentationProgressivemyoclonicepilepsy"RaggedRedFibers"ShortstatureHearinglossLacticacidosisExerciseintolerancePoornightvision2023/10/1211CausesMutationatposition8344inover80%ofcasestRNA-LysmutationsodisruptssynthesisofproteinsessentialforoxidativephosphorylationMoreareinvolved:MT-TKMT-TL1MT-THMT-TS1MT-TS2MT-TF2023/10/1212TreatmentLikemanymitochondrialdiseases,thereisnocureforMERRFandtreatmentisprimarilysymptomatic.HighdosesofCoenzymeQ10andL-Carnitinehavebeentriedwithlittlesuccessastherapiesinhopesofimprovingmitochondrialfunction2023/10/1213MELAS:Mitochondrialencephalo-myopathy,lacticacidosis,andstroke-likeepisodes線粒體肌病腦病伴乳酸酸中毒及中風(fēng)樣發(fā)作綜合癥2023/10/1214PresentationOnsetinchildhoodInvolvingtemporarymuscleweakness,alteredconsciousness,visionabnormalities,seizures,andsevereheadaches,repeatedstroke-likeepisodeslacticacidosisLesscommonly,involuntarymusclespasms(myoclonus),ataxia,hearingloss,heartandkidneyproblems,diabetes2023/10/1215GeneticsNADHdehydrogenaseMT-ND1,MT-ND5TransferRNAsMT-TH,MT-TL1,andMT-TVInheritance

maternal,lesscommonlynewmutation2023/10/1216PrognosisNocure,progressiveandfataltreatMELASbyincreasingmitochondrialbiogenesisandfunction:nosuccessreport2023/10/1217NARP:Neuropathy,ataxia,andretinitispigmentosasignsandsymptomsvaryamongaffectedindividualsMutationsintheMT-ATP6geneHeteroplasmy70-90%,ormore（神經(jīng)病伴共濟(jì)失調(diào)和視網(wǎng)膜色素變性）2023/10/1218KSS:

Kearns-SayresyndromealsoknownasoculocraniosomaticdiseaseorOculocraniosomaticneuromusculardiseasewithraggedredfibers

（眼腦體?。㎡nsetbetween10-20ysamoreseveresyndromicvariantofchronicprogressiveexternalophthalmoplegia(CPEO)2023/10/1219EtiologyInheritedthroughmitochondrial,autosomaldominant,orautosomalrecessiveinheritance.Nopredilectionforraceorsex,andnoknownriskfactorsonly226casesasof19922023/10/1220SignsandSymptomsAunilateralptosisAbilateralptosisPigmentaryretinopathyCardiacconductionabnormalitiesOthers:Weaknessoffacial,pharyngeal,trunk,andextremitymuscles,hearingloss,smallstature,electroencephalographicchanges,cerebellarataxia2023/10/1221Genetics4,977-bpdeletion(1.3k-8k)inmtDNA,spansfromposition8469toposition13147onthegenome.Thisdeletionispresentinapproximately1/3ofpeoplewithKSSDeletioneffectsonATP8,ND5,andtRNAgenesHeteroplasmydependence(>85%)inaffectedtissues2023/10/1222TreatmentNocurativetreatmentcoenzymeQ10andotherreagentsenhancingmitochondrialfunctions2023/10/1223Mitochondrialdisease

---duetonuclearDNAmutation☆A(yù)lpersDisease☆15q25

Barthsyndrome☆X-linked

Beta-oxidationDefects

Carnitine-Acyl-CarnitineDeficiency☆CarnitineDeficiency☆CreatineDeficiencySyndromes☆Co-EnzymeQ10Deficiency☆ComplexIDeficiency☆ComplexIIDeficiency☆?ComplexIIIDeficiency☆?ComplexIVDeficiency☆?ComplexVDeficiency★COXDeficiency☆?CPEO★CPTIDeficiency☆CPTIIDeficiency☆FRDA☆GlutaricAciduriaTypeII☆KSS★L(fēng)acticAcidosis☆2p11.2LCAD☆2q34-q35

LCHAD☆LeighDiseaseorSyndrome☆★L(fēng)HON

★L(fēng)IC(LethalInfantileCardiomyopathy)☆LuftDisease?MAD☆4q32-qter

MCAD☆1p31MELAS★MERRF★MIRAS☆MitochondrialCytopathy

MitochondrialDNADepletion☆MitochondrialEncephalopathy

MitochondrialMyopathy

MNGIE☆15q25,22q13.32-qter

NARP★PDHC☆PearsonSyndrome★PyruvateCarboxylaseDeficiency☆PyruvateDehydrogenaseDeficiency☆POLGMutations★RespiratoryChain

SCAD☆SCHAD☆VLCAD☆………………/site/c.otJVJ7MMIqE/b.5692881/k.4B7B/Types_of_Mitochondrial_Disease.htm#Luft2023/10/1224TypesofmitochondrialdiseaseElectrontransferchaindisorderIrontraffickingdisorderMitochondrialentryMitochondrialexitKrebscycledisorderFe-S,Hemebiogenesisdisorder…………2023/10/1225QuestionsSizeofhumanmitochondrialgenome,howmanygenes?Howmanyproteinsareencoded?Whatmetabolicpathwayismainlyinvolvedbytheencodedproteins?CopynumbervariationMitochondrialinheritanceisnon-Mendelian,maternal.Structure:inner-,outer-membrane,inter-membranespace,and