oculopharyngealmuscular dystrophy: clinical and research ... · temporalis muscle of patient with...
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Oculopharyngeal Muscular Dystrophy: Clinical and Research
UpdateSarahYoussof,MD,MS
NewMexicoNeuromuscularCenterNovember11,2017
InmemoryofHoushang Youssof “Youareextraordinary”
1. HistoryandBackground.
• Describedafamilialformoflate-onsetdysphagiawithptosis.Symptomswereslowlyprogressive,leadingeventuallytodeathbystarvation.
• “Justifiesitsclassificationasaclinicalentity.”
Patientawakeandfullyalert
TemporalismuscleofpatientwithOPMDshowsmuscledamage
TemporalismuscleofpersonwithoutOPMD
• Muscle,notnerve,disease
OPMDTypicalClinicalFeatures
MalnutritionAspirationpneumoniaFeedingtubePhysicaldisabilityDeathPhoto:Myology,AGEngel
• Autosomaldominant,onset40sor50s• Ptosis• Dysphagia• Dysphonia– hoarseness,changedpitch,
poorenunciation,decreasedvolume• Externalophthalmoplegia – ifpresent
mild.• Proximallimbweakness– laterthanptosis
anddysphagia,legsaffectedearlierandmoresothanarms
• 100%penetranceby70s• Variableseveritywithinsamefamily
Epidemiology
• Worldwide,OPMDprevalenceestimatedat1:100,0001– Casesreportedinover35countries
• GeographicclusterswithhighOPMDprevalence– FrenchCanadiansinQuebec(1:1000)2
– BukharaJewsinIsrael(1:600)3
– HispanicNewMexicans(1:10,000)4
– LargeMexicanclusterrecentlyreported(n=102)5
1 BrunetGetal.,RevNeurol (Paris)19902 BraisB.etal.,Semin Neurol,19993 Blumen SCetal.,Neuromuscul Disord.19974 YoussofS.etal.Neuromusc Disord 20155 Cruz-AguilarM.,JInvestig Med2016
RRM: RNA Recognition Motif
N-
Ala10
-CRRM
OPMD gene locus: 14q11.2Normal Ala10 PABPN1OPMD Ala11-18 PABPN1
N-Ala11-18
-CRRM
Short alanine expansion occurs in the ubiquitously expressed PABPN1 protein
Seminaldiscoveryin1998:GenemutationinOPMDisidentifiedinthePoly-ABindingProtein
Nuclear1(PABPN1)gene
Brais Betal.,NatGenet,1998
Aretherefeaturesaffectedbesidesmuscles?
Brain:Homozygoteshavecognitivedecline,psychoticmanifestationsandbrainatrophy
severeparietalcorticalatrophyslighttomoderateatrophyattheconvexityonthefrontallobe
Blumen SCetal.,Neurology,2009
Brain• Longestexpansionsizereported– 18alaninestretchin2heterozygoussisters–neuropsychiatricsymptomsobservedandearlierageofonset(Jouan L,etal.,CanJNeurol Sci.2014)
• ExecutivedysfunctioninheterozygoteswithGCNexpansionsranginginsizefrom13to16repeats–studyincluded11patientsand12age- andgender-matchedcontrols.Correlationfoundbetweenexpansionlengthandafewcognitivemeasures(Dubbioso R,etal.,JNeurol.2012)
Nostrongevidenceofheartinvolvement
• 10OPMDpatientsstudiedprospectively–nonehadcardiacsymptoms– EKG,Holter monitoring,andechocardiographywerenormalforage.
(WittingNetal.,Acta Neurol Scand.2014)
Possiblebreathinginvolvement
• Diaphragmmusclepathologyreportedinoneautopsiedcase(LittleBW&PerlDP,JNeurol Sci1982)
• Breathingfunctionwasexaminedin13OPMDpatients,andwasmildlyreducedinsome.(WittingNetal.,Acta Neurol Scand.2014)
• Aspirationpneumonia
PaininOPMD
• 19outof32OPMDpatientsinaDutchstudyreportedpain.
• 68%hadupperlegpain,63%hadneckorshoulderpain,47%hadupperarmpain,32%hadlowerbackpain,26%hadlowerlegpain,5%hadforearmpain
• About50%usedmedicationtotreattheirpain.
vanderSluijs BM,etal.Neuromuscul Disord.2016
FatigueinOPMD
• 54%ofOPMDpatientsinthestudywereexperiencingseverefatigue.
• People60yearsoldorolderhadseverefatiguemoreoftenthanyoungerpatients
• Therewasnotadifferenceinfrequencyofseverefatiguebetweenpeoplewhohavehadsymptomsforlongeramountsoftimecomparedtopeoplewhohavehadsymptomsforshorteramountsoftime.
vanderSluijs BM,etal.Neuromuscul Disord.2016
• 354unrelatedcasesidentifiedbetween1999and2014inseveralneuromuscularcentersinFrance
• Outcomeusedfordiseaseseverity:ageatdiagnosis
• PatientswithOPMDwithlongerPABPN1expansionswereonaveragediagnosedatanearlieragethanpatientswithshorterexpansions
RichardPetal.,Neurology2016
2.CurrentmanagementofOPMD.
CurrentStateofOPMDManagement:Surgicaltreatmentsareusedtoamelioratesymptoms
• Ptosis:– Retrospectivestudiesonvarioussurgicalapproachessuggest:
• frontalisslingprocedureisbestapproachformostpatients
• levator advancementalsomaybeused
• leasteffectiveis“cosmetic”simpleblepharoplasty
SurgicalOutcomes– Frontalis Sling
• Before • After
PhotocourtesyA.Joshi,MD
CurrentStateofOPMDManagement:Surgicaltreatmentsareusedtoamelioratesymptoms• Dysphagia:treattheconstrictioncausedbyahypertoniccricopharyngeal muscle(upperesophagealsphincter)
Hypertoniccricopharyngeal muscle
CurrentStateofOPMDManagement:Surgicaltreatmentsareusedtoamelioratesymptoms• Dysphagia:
– Cricopharyngealmyotomy fordysphagia– Cricopharyngeal dilatation– Cricopharyngeal botulinumtoxin– Evidenceforbenefitisbasedonretrospectivecaseserieswithnon-standardized,poorlyvalidatedoutcomemeasures
CricopharyngealMyotomy• Divisionofentireinferior
pharyngealconstrictormuscle,cricopharyngeus muscle,andtheupperpartofthecircularfibersofthecervicalesophagus
DilationProcedure• Conscioussedation• Endoscopyevaluationof
esophagus,stomach,andsmallintestine
• Awireispassedthroughthescopeandpositionedinthestomach.Thescopeisremovedandexchangedwiththewire
• Asavorydilatorispassedoverthewiretostretchthecricopharyngeus muscle
2.RecentResearchfromNewMexico.
Youssof S,Romero-ClarkC,WarnerT,PlowmanE.MuscleNerve2016
• Symptomswithhighburden:
• QualitativestudyofOPMDpatientstoobtaindirectpatientinputandidentifymostimportantthemesofdiseaseexperience
• 25interviews• 7mainthemes
ExperiencesofOPMDpatients
Dysphagia,impairedmobilityandadaptivestrategiesforcopingwithdysphagiawereprominentaspectsof
patientexperience
OPMDGlobalSeverityScoredevelopedbyourgroup
Totalsumscore:Range0-170 Asymptomatic1-5 Mild6-11 Moderate12-17 Severe
3.TherapydevelopmentforOPMD.
Périé SMol Ther 2014
• 12patients• Cellsgrownfrommusclestemcellsfrompatients’thighorneckmuscles
• Cellswereinjectedintothemusclesofthethroat
• Surgicalcricopharyngealmyotomyperformedatsametime
• 11to16injectionswereperformedineachpatient
• Musclestemcelltransplantation
Musclestemcellstudy:therapeuticeffect
– After2years,examinationofthroatmusclestrengthwasoverallunchanged
– At2years,thethroatsphincterfunctionwasconsiderednormalin8patients
– Appearssafe
Périé SMol Ther 2014
Trehalose
• EarlyphasestudybyBioblast inCanadaandIsraelshowedbenefitinmusclestrengthandswallowingwithweeklyintravenousTrehalose
• Thecompanyhasnewowners• TherearestillplansforaplacebocontrolledstudyinNorthAmerica-- furtherdiscussionswiththeFDAarepending
RecentAvenuestoGeneTherapiesinMuscularDystrophies
• Geneediting- “fixing”genemutations• ExampleisatechnologycalledCRISPR- Thecell's genome canbecutatadesiredlocation,allowingexistinggenestoberemovedand/ornewonesadded.
• CRISPRwasconsideredbreakthroughoftheyearin2015
RecentAvenuestoGeneTherapiesinMuscularDystrophies
• CRISPRwasstudiedinDuchennemusculardystrophyandcongenitalmusculardystrophywithgoodresultsinanimalmodels;notyetgiventohumans
• NotyetstudiedinOPMD;thegoalwouldbetofixthemutationbyshorteningtheexpandedregion
Geneediting:howwoulditbedeliveredtomuscle?Bighurdle.
• Cells derivedfrompatients,suchasstemcells,aregeneticallycorrectedoutsidethebody
• Then,thosecorrectedcellsareputbackindiseasedmuscletotrytomakethemusclehealthy
• Viralgenedelivery.Geneeditingtechnologiesaredeliveredtothebodyusingavirus,whichthentravelstothemuscles.
Nelson,CEetal.NatureReviewsNeurology2017.
Slideswillbepostedonwww.newmexiconeuromuscular.com
YoucanjoinOPMDRegistrybysendinganemailtoaddressbelow
NewMexicoNeuromuscular2741IndianSchoolRdNEAlbuquerque,NM87106(505)[email protected]
QuestionandAnswerSession
Questionssubmittedbeforetheconference
• Ifweallhavethesamething(OPMD)whydosomepeoplesuffermorethanothers?
– Other(unknown)geneticorenvironmentalfactorsaffecttheseverity.
ThickPhlegmatNight
• CommonprobleminOPMD• Phlegmthinnerssuchasguaifenesincanbeused
• SomepatientsarehelpedbyClaritin.• Otheroptions:RockyMountainThroatSyruphelps
• Wateroricechips• Humidifyroom
DoesOPMDcausepaininhipsorcrampingandnumbnessoflegs?Doesitcausetremorsor
fatigue?Doesitcauseintensefootpainatnight?
• Asdiscussed,painiscommonbuttendstobemuscular.
• CrampsandnumbnessarelikelytobeanerveproblemratherthanOPMD
• OPMDdoesnotcausetremors• OPMDdoescausefatigue
Trehalose/Cabaletta• Whatisthebenefit/harmofeatingordrinkingTrehalose?
• Trehalose isinshiitake,oystermushrooms,shrimp
• Likeeatingsugar;butiftoomuchingestedandyourgutcan’tdigest,canleadtobloatinganddiarrhea
OPMDandDiet
• Riskofpoornutritionduetoswallowingproblems– foodavoidances
• Maintainwell-balanceddietwithadequateprotein
• Seeyourdoctorifyoucannotmaintainyourweight– mayneedEnsureorsimilarsupplements
• Considerdailymultivitamin
Questions