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)255-8682Ext144syoussof@hotmail.com

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