型肌营养不良症课件

MuscularDystrophy DrNeha Objectives Recognizepatientsthatrequirereferralfordiagnosisandmanagementofmusculardisorders Performthehistoryandphysicalexamtoscreenforneuromusculardisorderforpatientsofallages Describecurrentmethodsofdiagnostictestingforneuromusculardisorders Discusscurrenttherapyandtreatmentoptionsavailableandtheaffectonprognosis Presentationsofpatientswithneuromusculardisorders Case1Calledtoevaluatenewborninfantwithhypotonia Pregnancycomplicatedonlybyflu likeillnessin2ndtrimesterandquestionofdecreasedstrengthoffetalmovementscomparedtofirstpregnancy Laboranddeliverycomplicatedbyprecipitousdelivery Case1con tPhysicalexamrevealshypotonicinfantwithhigharchedpalate Physicalexamisotherwisenormal LaboratorysuchasCBCandelectrolytesarenormal Case24yearoldpresentstoclinicwithchiefcomplaintoftoewalkingandfalling Theparentsalsostatethathehastroublewithstairsandrunning Sataloneat8months walkingby15months Onphysicalexamhedemonstrateswalkinguplegswithhandsinordertorisefromseatedpositiononfloor Calvesareprominent Case314y owithdifficultyliftingarmsabovehead Onreviewofsymptoms thisadolescentstateshehasneverbeenabletoblowupaballoon Onphysicalexam scapularwingingisnoted Case4Infantpresentswithnarrowfacies shapedupperlip andrespiratorydistressafterbirth PoorfeederrequiringOGtubeassistance Motherhassimilarfacialfeatures Whenyoushakeherhand shecan tletgoeasily HistoryandPhysicalExamintheNewbornandOffice HistoryNewborn floppyinfant termorpreterm poorheadcontrol poorfeeding prolongedlabor maternalcomplicationsChildhooddevelopment delayinsitting standing walking toewalking difficultystairclimbingorrunningTeenoradult difficultyinself care swallowing athletic enduranceactivity FamilyHistoryIncludeenoughoffamilytreetopickupautosomalrecessivedisordersandX linkedorADdisorderswithvariablepenetranceManyx linkedorADrepresentnewmutationsPastdiagnosesinolderfamilymembersmaynotbeaccurateReviewofSystemsSchoolfunctioning cognitivedevelopmentCardiacfunction arrhythmias syncopeRespiratory PhysicalexamfindingsMusclemass signsofwastingorhypertrophy pseudohypertrophyMusclestrength power generationofforceagainstresistanceorgravityObservereaching gettingupfromfloorObservetrunkandhead neckcontrolTestspecificproximalgroups positionsoagainstgravityTone resistancetopassivemovementNotehypervs hypotoniainweakareasDeeptendonreflexes normalordecreasedNormalsensation rememberproprioceptionJointcontracture reducedpassiverangeofmotionnotduetotone WhatisMuscularDystrophy MD MuscularDystrophy groupofgeneticdisordersthatarecharacterizedbyprogressivelossofmuscleintegrity wasting andweakness Characterizedbydegenerationandregenerationofmusclefibers incontrastwithstaticorstructuralmyopathies MuscularDystrophyAssociationCoversallmusculardystrophiesandmyopathiesMultisystemdiseases ALSorFriedreichAtaxiaNeuropathy HSMN CMTD Dystrophinopathy disordersinvolvingdystrophinDuchenneMDandBeckerMDarethemusculardisorders thetwomostcommonandseveredystrophiesDystrophinisaverylargegeneontheX chromosome ubiquitousinthehumanbodyDystrophin AssociatedProtein DAP Complex composedoftheextracellular transmembrane andintracellularcomponents TheLancetNeurologyVolume2 Number5 May2003Copyright 2003Elsevier GeneralDiagnosticTesting Creatinekinase Aidsinnarrowingthedifferentialdiagnosisifgreatlyelevated 50timesnormal IncreasedinDMD BMD polymyositis andrhabdomyolysisNonspecificifmildlyelevated2 3xnormalLowerlateinMDcourseduetoseverelyreducedmusclemassNothelpfulforcarrierdetection MusclebiopsyDystrophicchangesincludenecrosis degeneration regeneration fibrosisandfattyinfiltration sometimesmildinflammationSpecificdiseasesmayhaveinflammation intracellularvacuoles rods andotherinclusionsonbiopsyBiochemicalmuscleproteinanalysisUsefulforspecificidentifiedproteinthatismissingandmanyspecificmutationsmaycausethesamedeficiencyImmunohistochemicalproteinstainingWesternblot quantitatespercentofnormalproteinpresent GeneticanalysisPCRforspecificknowndefectsSouthernblotfornucleotiderepeatsElectromyographyUsefulifdiagnosisnotclear biopsyhasmixedfeatures Differentiatesneuropathicvs myopathicCharacteristicmyotonicdischargesinadultswithmyotonia divebomber soundPerformaftertheCK DuchenneMuscularDystrophy Presentation 3 5y owithpseudohypertrophyofcalfmuscles frequentfalls slowrunning andwaddlinggaitPrevalenceof1 3500OtherorgansaffectedHeart cardiomyopathyRespiratoryIntellect 30 withimpairmentIQ 75TestingImmunostainingwithabsenceofdystrophinPCRtestingavailableforcommonmutations X21 2 BeckerMuscularDystrophy SlowlyprogressiveformwithsamegeneaffectedasDuchenneMDMusclebiopsyimmunostainingfordystrophinwithpatchystainingDisorderoffunctionordecreasedamountofdystrophinratherthanabsenceoftheprotein CongenitalMuscularDystrophy Presentation neonatalonsetofsevereweakness delayedmotormilestones contracturesMerosinnegative CMDA1WhitematterhypodensitiesonbrainscanbutnormalmentalcapacityDiagnosisbymusclebiopsyimmunohistochemistryshowinglossof 2 laminin AR chromosome6q22 23 NeuronalMigrationDisorders Withneuronalmigrationdisordersgetmentalretardation brainmalformations andclinicaleyeinvolvementFukuyama smusculardystrophy affectsfukutinprotein AR chromosome9q31 Muscle eye braindisease affectsPOMGnT1 AR chromosome1p32 34 WalkerWarburg affectsPOMT1 AR Glycosyltransferasesarealsoimportantinneuronaldevelopment OtherMerosinPositiveCMD MyotonicMuscularDystrophyorSteinert sdisease Presentation adultwithmultiplesystemsaffectedPrimarilydistalandfacialweaknessFacialfeatures frontalbaldinginmen ptosis low setears hatchetjaw dysarthria swanneck shapedupperlipMyotonia worseincoldweather afterage20Heart conductionblock evaluatesyncopeSmoothmuscle constipation carewithswallowing gallstones problemswithchildbirth BPlabilityBrain learningdisabilities increasedsleeprequirementOphthalmology cataractsEndocrine insulinresistance hypothyroidism testicularatrophy Genetics Motherscanhaveadultorcongenitalonsetoffspring fatherscanhaveadultonsetoffspringParentsmaynotbeawareofowndiagnosisMyotoningeneisaffectedaswellasadjacenttranscriptionfactorgeneSIX5byCTGrepeatinnoncodingregionofchromosome19q13 3 andanticipationseenwithincreasedrepeatsMusclebiopsywithinternalizednuclei type1fiberatrophy ringfibers andsarcoplasmicmassesCongenital severeform initialrespiratorydistressafterbirthwithventilatoryrequirementorapnea feedingdifficulty mentalretardation clubfeet scoliosis strabismus FascioScapularHumeralMuscularDystrophy Presentation Facialweaknesswithtroubleblowingupaballoon sippingthroughastraw whistling troubleclosingtheeyesatnight scapularwingingthatmaybeasymmetric painMayhaveabsenceofpectoralis biceps orbrachioradialisAlsoaffected mildhighpitchedhearingloss retinalabnormalities mentalretardationinearlyonsetGenetics TestingSouthernblottestingavailable chromosome4q35 fordecreaseinrepeatsnormallypresentMusclebiopsymayshowlymphocyticinfiltrates LimbGirdleMuscularDystrophy Presentation variableageofonsetwithweaknessandwastingofthelimb girdleMayhavecalfhypertrophy involvementofscapularmuscleanddeltoidinsarcoglycanopathiesManytypesinvolvedysfunctionalsarcoglycans transmembraneproteinsoftheDAPthatinteractwithcytoplasmicproteinsTable2 typesofLGMD OculopharyngealMuscularDystrophy Presentation mid adultwithptosis facialmuscleweaknesswithdifficultyswallowing proximalmuscleweakness mayhaveextraocularmuscleweakness morecommoninFrench CanadianandHispanicpopulationGeneticsMusclebiopsyshowsfilamentousnuclearinclusionsandubiquitincontainingvacuolesAffectspolyAbindingprotein2 PABP2 byexpansionofaGCGrepeatwithoutanticipationseen Southernblot chromosome14q11 13 Emery DreifussMuscularDystrophyScapuloperonealMD Presentation stiffjoints shoulderandupperarmweakness calfweakness cardiacconductiondefectsandarrhythmias contracturesGeneticsX linkedtypeaffectsemerinDiagnosebyproteinanalysisofleukocytesorskinfibroblastsDNAtestingavailable chromosomeXq28 ADaffectslaminAorlaminC chromosome1q21 Nuclearmembraneproteins DistalMuscularDystrophy Presentation weaknessinforearms hands andlowerlegsclinicallysimilartoaneuropathybutNCVnormalMusclebiopsywithautophagocyticvacuoles inclusionbodiesTable3 TypesofDMD Myopathies Centralcoredisease Ryanodinereceptor Cachannelthatmediatesexcitation contractioncoupling AD chromosome19q13 AssociatedwithMalignantHyperthermiaMyotubularmyopathyMyotubularin importantinmyogenesis Xq28 NemalineMyopathyCausedbymanydefects disorderofthinfilamentsRod likestucturesonmusclebiopsyInflammatoryJuvenileDermatomyositisInclusionBodyMyositis usuallydistal AdultPolymyositis associatedwithmalignancy Treatment Medications SteroidsBrieflyincreasestrength slowprogressionindystrophinopathyforwalking armuse andrespiratoryfunctionWeekendor15 20 monthaswellasprednisolone deflazacortmayminimizeSEDilantinandTegretolraisetherepolarizationthresholdandimprovemyotoniaMethylphenidateimprovesdaytimesomnolenceinDMAlbuterolmayhelpinFSHMDCreatineandglutaminemayhelpdelayprogression improveenergyinyoungestwithDMD Treatment futuretherapies GenetictherapiesRepairingthemutatedsequencesUsingcell sownrepairmechanismsbutaddingtemplateGentamicintrialforrelaxationinstopcodonrecognitionforDMDhasnotworkedReplacingthemutatedsequencesInsertingtruncatedgenesorwholegenewithvectorUpregulationofsimilarfunctioningproteinsUtrophininDMD Therapy ContracturepreventionStretchingexercisesandposturalchangingStretchthemostcontracturepronegroups gastrocnemius hipflexors iliotibialbands hamstrings AFOatnighttosupplement Strengthening conditioning enduranceGoalistomaintainorimprovemusclestrengthandmaximizefunctionalability slightimprovementispossibleAdditionalgoalistoavoidmusculardamagebyoverworkorinjuryNoeccentriccontractionordelayedsorenessVoluntaryactiveexercisesuchasswimming hydrotherapyorcyclinginambulatorychildrencurrentlyrecommended MobilityaidsWalkingorthoses KAFOStandingframes standingwheelchairs swivelwalkeroccasionallyusedWalkerswherearmstrengthlessaffectedTransferboardWheelchair powerneededforindependencePlanforindoorlift vanwithlift rollinshowerImprovingdailyactivitiesofdailylivingPhysicalandOccupationalTherapy teachingmodifiedtechniquesAntigravityorthosesarebeingdevelopedtoassistindailylivingactivitiesSplintingandtherapytopreventhandcontractures Surgerynotetheriskinherenttosurgery malignanthyperthermiaPalliativevs rehabilitativeTendonreleasesAchillesNeedKAFOtowalkpost opRelievespainandallowshoewearHamstringandiliotibialbandRelieveshipandkneepainorcontractureAllowsbettergaitcompensation Scoliosis spinestabilizationBracingisnoteffectivewithprogressiveneuromusculardiseaseTimelycorrectionofscoliosisisimportantforpatientcomfortandrespiratoryabilitySpineandscapularstabilizationmayaidfunctionofarmsOphthalmologyDeficienteyeclosureoculomaxillofacialMDandFSHMDmayrequireartificialtearsortarsorrhaphyTreatmentforcataractsinMyotonicMD RespiratoryPatientswithmorningheadache nightmares excessivedaytimesomnolence mentaldullne