Patient-Reported Symptom Burden of Charcot–Marie–Tooth Disease Type 1A: Findings From an Observation by VITACCESS

k FilippoGenovese,PhD,**

††† ChengyuOuyang,MSc,†††

Thereisalackofdataaboutthepatient experienceofCMT1Atohelpmakeinformed decisionstoimprovediseasemanagement andoutcomes.Theroleofpatient-reported outcome(PRO)dataisbecomingincreasingly recognizedasstrengtheningdiseaseunderstandingandinthedevelopment,regulatory approval,reimbursement,anduseof

Abstract Objectives: ThisstudyaimstoexploretheimpactofCharcot Marie Toothdiseasetype1A(CMT1A)andits treatmentonpatientsinEuropean(France,Germany,Italy,Spain,andtheUnitedKingdom)and USreal-worldpractice. Methods: AdultswithCMT1A(n ¼ 937)wererecruitedtoan ongoingobservationalstudyexploringtheimpact ofCMT.DatawerecollectedviaCMT&Me,anapp throughwhichparticipantscompletedpatientreportedoutcomemeasures.

PublishedbyWoltersKluwer

Conclusions: Patient-reportedburdenofCMT1Aishigh,influenced bydifficultiesinusinglimbs,fatigue,pain,and impairedqualityoflife.Burdenseverityappearsto differacrossthepopulation,possiblydrivenbydifferencesinrehabilitativeandprescription-basedinterventions,andcountry-specifichealthcarevariability.

KeyWords:burdenofillness,Charcot Marie Tooth disease,international,observational,patientreportedoutcomes ( JClinNeuromuscDis 2022;24:7 17)

Journalof CLINICAL NEUROMUSCULAR DISEASE Volume24,Number1 September2022

OriginalArticle 7

†

kk CourtneyHollett,BS,kk XavierPaoli,MSc,***

FlorianP.Thomas,MD,PhD,*MarioA.Saporta,MD,PhD, ShahramAttarian,MD,PhD, RafaelSivera,MD,¶GianM.Fabrizi,MD,PhD, AmyJ.Gray,BSc, AllisonMoore, ThomasSénéchal,MS,***LauraDay,MSc, SamuelLlewellyn,MPH, andYoucefBoutalbi,MD***

Patient-ReportedSymptomBurdenof Charcot–Marie–ToothDiseaseType1A: FindingsFromanObservationalDigital LifestyleStudy

††† MarkLarkin,PhD,†††

CMTcompromisespatientlifestyles, everydayactivities,andcareerandfamily choices.4 Thereiscurrentlynopharmacologic treatmentforCMT1AorCMT.2 Treatment focusesonphysicaltherapytomaintainmovement,musclestrength,andflexibility,combinedwithoccupationaltherapy,orthotics, painmanagement,andpsychologicaland socialsupport.5 Surgicalinterventionmaybe requiredformoresevereformsofthedisease.

‡ TeresaSevilla,MD,PhD,§

INTRODUCTION Charcot Marie Toothdiseasetype1A (CMT1A)isararediseasebelongingtothe groupofinherited,chronic,progressivemotor andsensoryneuropathiesreferredtoas Charcot Marie Toothdisease(CMT).CMT1A hasanestimatedprevalenceof1in5000 people.1,2 Itpredominantlycausesdistalmuscleweakness,atrophy,sensoryloss,andprogressivelimbdeformities.3

Results: Symptomsrankedwithhighestimportancewere weaknessintheextremities,difficultyinwalking, andfatigue.Almosthalfofparticipantsexperienceda worseningofsymptomseveritysincediagnosis. Anxietyanddepressionwereeachreportedbyover one-thirdofparticipants.Useofrehabilitativeinterventions,medications,andorthotics/walkingaids washigh.

Fromthe*HackensackMeridian SchoolofMedicine,Hackensack UniversityMedicalCenter, Hackensack,NJ; †Universityof MiamiMillerSchoolofMedicine, Miami,FL; ‡HospitalUniversityla Timone,FilnemusERN-NMD, Marseille,France;§Hospital UniversitariiPolitècnicLaFe, UniversitatedeValencia, CIBERER,Valencia,Spain; ¶HospitalUniversitariiPolitècnic LaFe,CIBERER,Valencia,Spain; kDepartmentofNeurosciences, Biomedicine&Movement Sciences,UniversityofVerona, Verona,Italy;**ACMT-Reteperla malattiadiCharcot-Marie-Tooth OdV,Bologna,Italy; ††CharcotMarie-ToothAssociation, Glenolden,PA; ‡‡Charcot-MarieToothUK,Christchurch,United Kingdom;§§CMTFrance,SaintAlban,France;¶¶Federación EspañoladeEnfermedades Neuromusculares,Barcelona, Spain; kkHereditaryNeuropathy Foundation,NewYork,NY; ***Pharnext,Paris,France;and †††Vitaccess,Oxford,United Kingdom. Theauthorsreportnoconflictsof interest. Thisisanopenaccessarticle distributedunderthetermsofthe CreativeCommonsAttributionNonCommercial-NoDerivatives License4.0(CCBY-NC-ND), whereitispermissibleto downloadandsharethework provideditisproperlycited.The workcannotbechangedinany wayorusedcommercially withoutpermissionfromthe journal. Reprints:SamuelLlewellyn,MPH, Vitaccess,TheOxfordScience Park,MagdalenCentre,Robert RobinsonAvenue,OxfordOX4 4GA,UnitedKingdom(e-mail: samuel.llewellyn@vitaccess.com).

†† SimonBull,BSc,‡‡ DanielTanesse,§§ManuelRego,¶¶

treatments.6 8 Todate,muchPROevidence hasbeengeneratedinrandomizedcontrolled trials(RCTs),withlittledatacollectedfrom patientsmanagedinreal-worldclinicalpractice.Real-worldevidence(RWE) whichcan begatheredaspartofdecentralized/remote datacapture(ie,awayfromhospitalsand doctors’ offices) canprovidemoregranular,longer-termdata,fromabroaderpatient population,thanistypicalinRCTs,sothereis clearvalueinitscollectionandanalysis. Theobjectiveofthisstudyisto provideadetailedviewoftheimpactof CMT1Aanditstreatmentonpatientsinthe real-worldsetting(includingfactorssuchas epidemiology,naturalhistory,andclinical andhumanisticburden)andtodefinethe economicimpactofthediseaseonhealth carefacilitiesandsystems.

MATERIALSANDMETHODS StudyDesign Thisisaprospective,longitudinal, observational,patient-reportedlifestylestudy. Adultswithaself-reporteddiagnosisofCMT (CMT1Aorothersubtype)residinginoneof thestudycountries(ie,France,Germany, Italy,Spain,theUnitedKingdom,orthe UnitedStates)useasmartphoneapp, CMT&Me(Vitaccess,Oxford,UnitedKingdom),tobothenrollandprovideinformed consenttoparticipateinthestudyandenter regulardataaboutCMT,itsmanagement,and itsimpactontheirlives.Datacollected betweenOctober15,2018,andJune1, 2021,fromCMT1Apatients themostfrequentlyreportedCMTtype1,2 arepresented inthisinterimanalysis. DataCollection

options:hadnocramp,1

moderate,severe,andverysevere.Higher scoresonbothitemsrepresentgreatercramp frequencyandintensity,respectively. QuickDASH TheQuickDisabilitiesofArm,Shoulder

healthyoucanimagine.

Shortlyafterenrollment,participants areaskedtocompleteaprofile,which includesdataondemographics,lifestylecharacteristics,anddiagnosis manyofwhichare expectedtoremainfairlystableoverthe durationofthestudy.Forthosedatathat maychangeoverthedurationofthestudy (eg,treatments,healthcarevisits),

participantsareable andencouraged to makeadditionsorupdates. Participantsarealsoaskedtocompletea numberofPROinstruments.Summary descriptionsofthePROinstrumentsincluded inthisstudyareprovidedbelow. EQ-5D-5L

itemasks,

TheEQ-5D-5Lcomprises2parts:the EQ-5D-5LdescriptivesystemandtheEQ visualanalogscale.9 Thedescriptivesystem comprises5dimensions(mobility,self-care, usualactivities,pain/discomfort,and anxiety/depression),eachwith5levels(no problems,slightproblems,moderateproblems,severeproblems,andextremeproblems ie,higherscoresrepresentworse health).Thescoresforthe5dimensionsare combinedina5-digitnumberdescribingthe participant’shealthstate. TheEQvisualanalogscalerecordsthe participant’sself-ratedhealthonavertical scale,withendpointslabelled “thebest ” and “theworst ” Higherscoresrepresentbetterself-perceivedhealth. BespokeInstrumentsforthisStudy Crampisacommonsymptomamong CMT1Apatients.10 Twocramp-specificitems crampfrequencyitemasks, “Inthepast 7days,howmanydaysdidyouexperience anycramp?” andhas5possibleresponse 2days,3 4days, 6days,andeveryday.Thecrampintensity “Inthepast7days,howintense wasyourcrampatitsworst?” andhas5possibleresponseoptions:hadnocramp,mild, andHand(QuickDASH)measureuses11

measuringfrequencyandintensitywere developedforinclusioninthestudy.The

itemstogaugephysicalfunction(eg, openingatightornewjar)andsymptoms Thomasetal Copyright©2022TheAuthor(s).PublishedWoltersKluwerHealth,Inc. Journalof CLINICAL NEUROMUSCULAR DISEASE Volume24,Number1 September2022 8

healthyoucanimagine

ThePROMISPainInterference6b instrumentassessestheextenttowhichpain hindersengagementwithsocial,cognitive, physical,andrecreationalactivitiesaswellas enjoymentinlifeoverthepast7daysusinga 5-pointscale.14 Possiblescoresrangefrom6 to30,wherehigherscoresrepresentgreater interference.Thismeasureisgenericrather thandiseasespecific.

(eg,hand,shoulder,orarmpain)inpeople withanyormultiplemusculoskeletaldisordersoftheupperlimbs.11

Allquestionsare rated1 5(nodifficulty/none/notatallto unable/extremedifficulty).Possiblescores rangefrom11to55,wherehigherscores representgreaterdifficultieswithphysical functionandsymptoms. BFI TheBriefFatigueInventory(BFI) assessesparticipants’ fatigueseverity.12 The measureusesa10-pointnumericratingscale andarecallperiodof24hours.Aglobal fatiguescoreiscalculatedbyaveragingall9 items.

Symptomcharacteristicsofparticipants areprovidedinTable2.Participantsreported thattheyhadspentalmost30yearsexperiencingCMT1Asymptomsandhadbeen

Missingdatawerehandledassetoutin thescoringguidelinesforthePROinstruments andaccordingtobestpracticeforprofile questions.Allmissingdatawereassumedto bemissingatrandom,andnoadjustments weremadetoaccountformissingdata.

DemographicandclinicalcharacteristicsofparticipantsareprovidedinTable1. Themeanageofparticipants(n ¼ 782)was 45(SD13.8)years,andthemajorityofparticipants(n ¼ 781)werefemale(n ¼ 553, 70.8%).Theageandsexofparticipantswere comparableacrosscountries,althoughthe percentageoffemaleparticipantsinItaly andSpainwascloserto60%.Themajority ofparticipantsreportedmoderateorsevere symptomseverityatthetimeofsurveycompletion.Justmorethan40%ofparticipants reportedthattheyexercise(definedasat least20minutes,raisingpulseandbreathing rate)oncepermonthorless.Morethanhalf ofparticipantsresidedineithertheUnited StatesortheUnitedKingdom. Symptoms

StatisticalAnalysis

Dataanalysisfollowedapredefined statisticalanalysisplan.Allanalyseswere descriptive,andnohypothesesweretested. Aggregated,deidentifieddataweresummarizedasfollows:

Descriptivedistributionstatisticsfor eachPROinstrumentscore,ordomainscore, arepresentedforbaseline(firstdataentry timepoint)andateachtimepointthereafter upuntilJune1,2021.

ThePatient-ReportedOutcomesMeasurementInformationSystem(PROMIS)Pain Intensity3ainstrumentincludes2itemsthat assesspainintensityoverthepast7days (averageandworstpain)andoneitemthat assessespainintensity “rightnow,” each scoreusinga5-pointscale.13 Possiblescores rangefrom2to10,wherehigherscoresrepresentworsepain.Thismeasureisgeneric ratherthandiseasespecific.

• Forcategoricalvariables,summaries:n,frequency,proportion.

PROMISPainIntensity3aand Interference6b

• Forcontinuousvariables,distributions: number,mean,SD,median,minimum, maximum,SE,firstandthirdquartiles;and

Themeanageatwhichstudyparticipantshitcertainmilestonesisreportedin Figure1.Meanageatreportedsymptom onsetwasjustmorethan17years,with themeanageatdiagnosisalmost10years later.

SymptomBurdeninCMT1A www.jcnmd.com Journalof CLINICAL NEUROMUSCULAR DISEASE Volume24,Number1 September2022 9

Ninehundredandthirty-sevenCMT1A participantsrespondedtoatleastoneitemin anysurveyandwereincludedinthisinterim analysis. Demographicand ClinicalCharacteristics

RESULTS

None

TheproportionofparticipantsreportingcomorbiditiesispresentedinFigure3. Themostfrequentlyreportedcomorbidities, inadditiontoCMT1A,wereanxiety(most frequentlyreported),depression,gastrointestinalproblems,respiratoryproblems,andthyroidproblems.

TABLE1. DemographicandClinicalCharacteristicsofStudyParticipants Characteristicn(%) Age,y(n ¼ 937) Mean(SD) 44.8(13.8) Median(range)45.0(18 83) Sex(n ¼ 781) Female 553(70.8) Male 228(29.2) Symptomseverityatthetimeofsurveycompletion(n ¼

Italy

Moderate

Severe

Mild

Spain

Daily

Almosthalfofparticipantsreportedthat theirsymptomseverityhadworsenedbetween diagnosisandthetimeofthesurveyresponse. TheCMT1Asymptomsrankedwithhighest importancebyparticipants(Fig.2)wereweaknessinhandsandfingers(mostimportant), difficultywalking,weaknessinthefeet,fatigue, weaknessinthelegs,andproblemswithbalance(sixthmostimportant).Painwasreported astheeighthmostimportantsymptom,andit isreflectedinthefactthatmorethan70% (Table3)ofparticipantsreportedcurrently takinganalgesics/painkillers.Resultsweresimilaracrosscountries. Comorbidities

Ofthosewhoreporteddepression, approximately47%and30%reportedmoderateorsevereCMT1Asymptomseverity, respectively.Reporteddiagnosisofdepressionvariedconsiderablybycountry.Highest rateswereamongparticipantsintheUnited StatesandtheUnitedKingdom,whereas 684) 108(15.8) 400(58.5) 167(24.4) 9(1.3) ¼ 612) 80(13.1) 6timesperweek72(11.8) Onceaweek95(15.5) Onceamonth25(4.1) Seldom 112(18.3) Donotexercise21(3.4) Cannotexercise19(3.1) Cannotexercisebecauseofdisability77(12.6) Countryofresidence(n ¼ 937) UnitedStates289(30.8) UK 241(25.7) 133(14.2) 119(12.7) 89(9.5) 66(7.0)

receivingmedicalcareforCMT1Aformore than20years.Participantsreportedfirstseekingmedicalcareapproximately8yearsafter symptomonset,whereasthetimedifference betweensymptomonsetanddiagnosiswasa meanofapproximately11years.

Exercisefrequency(n

3timesperweek111(18.1)

France

Germany

Timespentwithsymptoms,y(n ¼ 932)

EQ-5D-5Lmobilitydomainscoresare presentedinFigure4.Almost60%ofstudy participantsreportedatleastmoderateproblemswithmobility.Thisvariedacrosscountries,withthehighestfiguresinFranceand lowestintheUnitedStates.

TimespentreceivingmedicalcareforCMT1A,y(n ¼ 933)

Mean(SD) 11.3(12.8) Median(range)6.0(0 78) SymptomBurdeninCMT1A www.jcnmd.com Journalof CLINICAL NEUROMUSCULAR DISEASE Volume24,Number1 September2022 11

Mean(SD) 27.9(16.0)

PROMISPainIntensity3ascoresand PROMISPainInterference6bscoresare presentedinFigure5CandFigure5D, respectively.ThePROMISPainIntensity3a medianscoreisindicativeofmildpainintensity,whereasthePROMISPainInterference Meanageatwhichstudyparticipants(n ¼ 937)reportedcertainmilestones. SymptomCharacteristicsofStudyParticipants

79)

Mean(SD) 21.3(14.9) Median(range)20.0(0 79)

TimebetweensymptomonsetandfirstseekingmedicalcareforCMT1A,y(n 896)

Ofparticipantswhoreportedthefrequencybywhichtheyexperiencedcramp, justlessthan75%experienceditonatleast 1dayperweek.Thisvariedacrosscountries highestintheUnitedKingdomandlowest inItaly.Morethanhalfofparticipantsrated

PROInstrumentScores

theseverityofthecrampingtheyexperiencedaseithermoderateorsevere.

lowestrateswereamongparticipantsin FranceandItaly.

FIGURE1.

TABLE2.

Characteristicn

Median(range)27.0(0

Mean(SD) 7.8(11.0) Median(range)3.0(0 71)

TimebetweensymptomonsetandCMT1Adiagnosis,y(n ¼ 882)

QuickDASHscoresarepresentedin Figure5A,withthemedianscoreindicating somelevelofupperextremitydisabilityand symptomsaffectingthequalityoflife.BFI scoresforworstleveloffatigueduringthe past24hoursarepresentedinFigure5B, withthemedianscoreindicatinghighfatigue impactandseverity.

DISCUSSION

Anxietyanddepressionwereeachreportedbymorethanone-thirdofparticipants. Thisissimilartoindividualswithother neurologicaldiseases,suchasamyotrophic lateralsclerosisandmultiplesclerosis,16,17 buthigherthantheprevalenceofanxiety anddepressioninthegeneralglobalpopulation(estimatedat4.4%and3.6%,respectively),18 althoughdifferentquantification methodologieswereused.Thefactthatdiagnosisofanxietyanddepressionishigherin thestudypopulationthaninthegeneralpopulationisnotsurprisingforadiseasewiththis symptomburden;however,anxietyordepressionascomorbidconditionsrepresentsignificantdiseaseburdenandcanaffecttreatment andoutcomesforCMT.Ofthosereporting depression,morethanhalfofrespondentscategorizedtheirCMT1Asymptomseverityas moderate,andmorethanone-thirdcategorizedtheirsymptomseverityassevere.Future researchcouldexaminetheinfluenceofthese comorbiditiesontheconditionofpatients (similartotheGAMEDISstudiesofchronic inflammatorydemyelinatingpolyneuropathy19),aswellasanypotentiallinksbetween reportedanxiety/depression,useofmedicationstotreatanxiety/depression,andEQ-5D5Lanxiety/depressiondomainscores.The prevalenceofanxietyanddepressionamong participantscouldalsobereflectiveofthefact thatthenumberoffemales who,according toglobalestimates,18 aremorelikelytosuffer frombothdisorders constitutemorethan 70%ofthestudypopulation. Ourresultsshowthattheprevalenceof anxietyanddepressionwashighestforparticipantsintheUnitedStatesandinthe UnitedKingdomandlowestforparticipants inFranceandItaly.Thehighincidenceof bothconditionsintheUnitedStateswhen CMT1Asymptomrankedasmostimportantbyparticipants(n

FIGURE2.

6bmedianscoreisindicativeofmoderate paininterference. Treatments

Currenttreatmentcharacteristicsof participantsareprovidedinTable3.The rehabilitativeinterventionsmostfrequently reportedbyparticipan tswerephysicaltherapy,occupationaltherapy,andmassage therapy.Themedicinesmostfrequentlyreportedbyparticipantswerepainkillers, antidepressants,andopioids/analgesics. Theorthotics/walkingaidsmostfrequently reportedbyparticipan tswereoff-the-shelf insoles,ankleorlegbraces,andcustom insoles.

Accordingtointerimfindingsfromthis prospective,observational,patient-reported lifestylestudy,patientswithCMT1A experienceahighlevelofsymptomburden. Thelonghistoryofsymptomsexperienced bypatientsinthestudy(mean27.9years) maybereflectiveoftheescalationofsymptomsbeingthemostrapidwithinthefirst10 years 15 andpatientslikelybeingawareof themlongbeforediagnosis.

Rehabilitativeinterventions currentlyreceived(n ¼ 445) Physicaltherapy385(86.5) Occupationaltherapy145(32.6) Massagetherapy93(20.9) Personaltraining81(18.2) Yoga59(13.3) Pilates57(13.3) Otherrehabilitativeinterventions68(15.3)

AccordingtoresultsfromthePROMIS PainIntensity3a,painintensitywasmildor moderateformostparticipants.Thisisin linewithpriorliterature;forinstance,a studyonpainassessmentinCMT 23 found thatmorethan65%ofparticipantsreported somelevelofpain,usuallywithamoderate severity.Althoughpainintensityfellwithin normallimitsforthemajorityofrespondents inthepresentstudy,itshouldbenotedthat painisstillaninterferingfactorinparticipants’ lives.Thisisreflectedinthefactthat morethanhalfofparticipantsreportedmoderateorsevereinterferenceofpainon engagementwithsocial,cognitive,physical, andrecreationalactivitiesviathePROMIS PainInterference6bandthatpainwas amongthetop10mostfrequentlyranked symptomsofimportancetoparticipants. Whetherthereareanylinksbetweenreportedpain,PROMISPainIntensity3aand PROMISPainInterference6bscores,anduse Participants Characteristicn(%)

Medicinescurrentlyreceived (n ¼ 404) Painkillers293(72.5) Antidepressants144(35.6) Opioids/analgesics84(20.8) Antianxieties72(17.8) Neurolepticmedications70(17.3) Codeine61(15.1) Cannabidioloil59(14.6) Naturalhomeopathicremedies49(12.1) Benzodiazepines21(5.2) Medicinalcannabis19(4.7) Othermedicines92(22.8) Orthotics/walkingaidscurrently used(n ¼ 477) Off-the-shelfinsoles232(48.6) Ankleorlegbraces197(41.3) Custominsoles192(40.3) Walkingstick/cane146(30.6) Walkingaids136(28.5) Crutches61(12.8) Nonmotorizedwheelchair60(12.6) Thickhandletools55(11.5) Walkingframe/walker49(10.3) Wristsplint45(9.4) Motorizedwheelchair33(6.9) Thumbsplints30(6.3) Standingframe4(0.8) Otherorthotics/walkingaids93(19.5)

comparedwithothercountriesisreflective oftrendsdescribedintheliterature.Astudy byLimetal20

SymptomBurdeninCMT1A www.jcnmd.com Journalof CLINICAL NEUROMUSCULAR DISEASE Volume24,Number1 September2022 13

Almostone-thirdofparticipantsreportedthattheyexperiencedgastrointestinal problems.Theseproblemsarepossibly sequelaeofdiet,lackofmobility,andmedicationstakentoaddressCMT1Asymptoms andwarrantfurtheranalysisandexploration.

investigatedtheprevalenceof depressionin30countriesbetween1994and 2014andfoundthatamongcontinents,South Americahadthehighestaggregateprevalenceat20.6%,followedbyNorthAmerica at13.4%,andEuropeat11.9%.Thefactthat theproportionofourstudypopulationwho resideintheUnitedKingdomshowedhigher incidenceofbothconditionsthanthosewho resideinItalyorFrance,however,doesnot matchrecentstatistics.Accordingtothe recentanalysisofglobaldepression21 and anxietyrates,22 theincidenceofbothconditionsishigherinItalyandFrancethaninthe UnitedKingdom.Ofcourse,medicalcomorbidityisaninfluencingfactor,andfurther analysisofourresultscouldrevealwhether studyparticipantsintheUnitedKingdom collectivelyhaveaworsehealthstatusthan thoseinItalyorFrance.However,understandingtheimpactoffactorssuchasfamily historyorsocialstatus orevenoftheglobal COVID-19pandemic,whichcoincidedwith thetimeperiodofourdatacut,anditsexacerbationoffactorswhichdeterminepoor mentalhealth isconsiderablymorecomplicated,thuslimitingourabilitytospeculateon thesefindings.

TABLE3. TreatmentCharacteristicsofStudy

Reportedsymptomburdenwasmostly similaracrosscountries,althoughtherewere someconsiderabledifferences.Theseare worthnotingassymptomsrankedashigher importancecoulddrivevariationbetween countriesinhealth-relatedqualityoflife, healthcareresourceuse,andcosts.No participantsinSpainrankedfatigueasthe mostimportantsymptomtheyexperienced, despiteitbeingthefourthhighestranked symptomoverall.Conversely,thehighest impactoffatiguewasreportedbyparticipants inGermanyandtheUnitedKingdom.Weaknessinthefeet,meanwhile,wasrankedasthe mostimportantsymptomby9%ofparticipantsintheUnitedStates,butby22%of participantsinSpain.Methodologicallimitationsofthestudyhavebeendiscussed FIGURE3. Proportionofstudyparticipants(n ¼ 628)reportingdifferentcomorbidities.Theremainingn ¼ 198studyparticipantswhorespondedtothissurveyquestionanswered“noother medicalcondition.”

FIGURE4. EQ-5D-5Lmobilitydomainscores (n ¼ 686).

Journalof CLINICAL NEUROMUSCULAR DISEASE Volume24,Number1 September2022 14

Reportedexerciselevelswerelow, mostlikelyduetosymptomsofCMT1A; similartoindividualswithotherneurological diseases.24,25 Almosttwo-fifthsofparticipantsreportedthattheydonotorcannot exerciseorthattheyexerciseinfrequently; thisishigherthanthequarteroftheworld

ofmedicationstotreatpainisasubjectto considerinprospectiveanalyses.

’s adultpopulationwhodonotmeetrecommendedlevelsofphysicalactivity26 (althoughitisdifficulttocomparethese2 figuresduetothecomplexityoftheWorld HealthOrganization’srecommendations). Previousresearchhasindicatedareduced lifeexpectancyamongpatientswithCMT, anditisunclearwhetherthisfindingisdue toCMTitselforduetotheaccumulationof comorbidities.27 Thelowactivitylevels describedinthisstudymaydemonstrate someunmetneedintermsofexercisethat wouldbesuitabletoavoidfurtheractivityrelatedhealthproblems.Itwouldbeinterestingforfutureresearchtoinvestigateapossiblelinkbetweenexerciselevels,theimpact ofcomorbidities,andthuschangesinthe mortalityofCMTpatients.

Thomasetal

FIGURE5. PROinstrumentscores.(A),QuickDASHscore(n ¼ 642),(B)BFIscore(n ¼ 592),(C) PROMISPainIntensity3ascore(n ¼ 628),(D)PROMISPainInterference6bscore(n ¼ 584). SymptomBurdeninCMT1A www.jcnmd.com Journalof CLINICAL NEUROMUSCULAR DISEASE Volume24,Number1 September2022 15

However,theaimofthisstudywasnotto reportseverityaccordingtoclinicalcriteria buttounderstandhowpatientsviewtheseverityoftheirownsymptoms,withtheunderstandingthatthisseverityassessmentmaybe verysubjectiveanddiffergreatlybetweenparticipants;forthisreason,participantswerenot askedtoreporttheirCMTneuropathyscore, whichistypicallymeasuredbyphysicians.

Thestudywasdisproportionatelywomen;thispresentsariskofbias,but noinformationisavailablefortheasymmetric participationanditisinlinewithliterature indicatingthatwomentypicallyengagemore withdigitalhealthappsthanmen.29,30

Inthecontextofsymptomburden,one limitationoftheseresultsisthattheyarereliant onpatients’ self-reportedassessment.Subjectiveassessmentofsymptomseverity,forexample,maynotmatchphysician/objective assessment,asobservedinspinocerebellar ataxia,31 andcouldbedrivenbyotherfactors (eg,comorbidities,concomitantmedicines).

Althoughtheresultsofthemostfrequentlyreportedsymptomsrevealthoseof greatestimportancetoparticipants,itshould notbeinferredthatthelessfrequently reportedsymptomsdonotaffect

elsewhere.28

1.KedlayaD.Charcot-Marie-Toothdisease;2021.Availableat:https://emedicine.medscape.com/article/ 1232386-overview.AccessedNovember22,2021.

participants,andassuch,anygivenresultin isolationshouldbeextrapolatedwithcaution.Pain,forexample,wasonlytheeighth highestrankedsymptomofimportance,yet medianPROinstrumentscoresindicatethat patientsexperiencebothpainintensityand interference.Cramping,meanwhile,wasonly the14thhighestrankedsymptomofimportance,yetjustunderthree-quartersofparticipantsreportedexperiencingcrampatleast onedayperweek.

11.BeatonDE,WrightJG,KatzJN,etal.Developmentof theQuickDASH:comparisonofthreeitem-reduction approaches. JBoneJointSurg. 2005;87:1038 1046.

4.HereditaryNeuropathyFoundation.WhatIt’sLiketo LivewithCharcot-Marie-Tooth(CMT):TheStoriesof thoseWhoKnowBest;2015.Availableat:https:// www.hnf-cure.org/essential-guide/.Accessed November25,2021.

12.MendozaTR,WangXS,CleelandCS,etal.Therapid assessmentoffatigueseverityincancerpatients:useof thebrieffatigueinventory. Cancer.1999;85:1186 1196.

Patient-reportedburdenofCMT1Ais high,influencedbymajordifficultiesusing limbs,fatigueandpainsymptoms,and impairmenttoqualityoflife.Thelevelof burdenappearstodifferacrosstheCMT1A population,possiblydrivenbydifferencesin rehabilitativeinterventionsandmedicines received,orthotics/walkingaidsused,and country-specificdifferencesinhealthcare systems.Anxietyanddepression,frequently reportedcomorbidconditionsamongthe CMT1Apopulation,representsignificant additionaldiseaseburden.Itisapparentthat thereremainsahighunmetneedinCMT1A causedbytheburdenonpatients.

15.JohnsonNE,HeatwoleCR,DilekN,etal.Quality-oflifeinCharcot-Marie-Toothdisease:thepatient’sperspective. NeuromusculDisord. 2014;24:1018 1023.

ACKNOWLEDGMENTS

9.HerdmanM,GudexC,LloydA,etal.Development andpreliminarytestingofthenewfive-levelversionof EQ-5D(EQ-5D-5L). QualLifeRes. 2011;20:1727 1736.

10.JohnsonNE,SowdenJ,DilekN,etal.Prospective studyofmusclecrampsinCharcot-Marie-Toothdisease. MuscleNerve.2015;51:485 488.

8.CanadianAgencyforDrugsandTechnologiesin Health.UseofReal-WorldEvidenceinSingle-Drug AssessmentsEnvironmentalScan;2020.Available at:https://www.cadth.ca/use-real-world-evidencesingle-drug-assessments-environmental-scan.AccessedNovember25,2021.

5.PareysonD,MarchesiC.Diagnosis,naturalhistory, andmanagementofCharcot-Marie-Toothdisease. LancetNeurol. 2009;8:654 667.

CONCLUSION

6.FariaR,AlavaMH,MancaA,etal;NationalInstitute forHealthandCareExcellenceDecisionSupport Unit.Technicalsupportdocument17:theuseof observationaldatatoinformestimatesoftreatment effectivenessfortechnologyappraisal:methodsfor comparativeindividualpatientdata;2015.Available at:https://web.archive.org/web/20151223234314/ http://www.nicedsu.org.uk/TSD17%20-%20DSU% 20Observational%20data%20FINAL.pdf.Accessed November25,2021.

3.ReillyMM,ShyME.Diagnosisandnewtreatmentsin geneticneuropathies. JNeurolNeurosurgPsychiatry.2009;80:1304 1314.

7.USFood&DrugAdministration.Frameworkfor FDA’sreal-worldevidenceprogram;2018.Available at:https://www.fda.gov/media/120060/download. AccessedNovember25,2021.

13.RevickiDA,ChenW-H,HarnamN,etal.DevelopmentandpsychometricanalysisofthePROMISpain behavioritembank. Pain.2009;146:158 169. 14.AmtmannD,CookKF,JensenMP,etal.DevelopmentofaPROMISitembanktomeasurepaininterference. Pain.2010;150:173 182.

2.PareysonD,SaveriP,PisciottaC.Newdevelopments inCharcot Marie Toothneuropathyandrelated diseases. CurrOpinNeurol. 2017;30:471 480.

Theauthorsacknowledgethecontributionsofallparticipantswhoarecontributing datatothestudy,ACMT-Reteperlamalattiadi Charcot Marie ToothOdV(Bologna,Italy), Charcot Marie ToothAssociation(Glenolden, PA),Charcot Marie ToothUK(Christchurch, UnitedKingdom),CMTFrance(Saint-Alban, France),DeutscheGesellschaftfürMuskelkrankee.V.(Freiburg,Germany),European Charcot Marie ToothFederation(Brussels, Belgium),FederaciónEspañoladeEnfermedadesNeuromusculares(Barcelona,Spain), HereditaryNeuropathyFoundation(New York,NY),AnnabelNixonatChilliConsultancy(Salisbury,UnitedKingdom)forher workonthedevelopmentoftheCMT&Me appandstudydesign,andVitaccessstaff membersfortheirworkonthedevelopment oftheCMT&Meapp,studydesign,andimplementation. REFERENCES

26.WorldHealthOrganization.Physicalactivity;2020.Availableat:https://www.who.int/news-room/fact-sheets/ detail/physical-activity.AccessedNovember21,2021. 27.VaethS,VaethM,AndersenH,etal.Charcot-MarieToothdiseaseinDenmark:anationwideregisterbasedstudyofmortality,prevalenceandincidence. BMJOpen.2017;7:e018048. 28.ThomasFP,SaportaM,AttarianS,etal.PatientreportedimpactofCharcot-Marie-Toothdisease:protocolforareal-worlddigitallifestylestudy. NeurodegenerDisManag. 2021;11:21 33. 29.BolN,HelbergerN,WeertJCM.Differencesin mobilehealthappuse:asourceofnewdigital inequalities? InfSoc. 2018;34:183 193. 30.MontagniI,CariouT,FeuilletT,etal.Exploringdigital healthuseandopinionsofuniversitystudents:field surveystudy. JMIRMhealthUhealth.2018;6:e9131. 31.MaasRPP,SchutterDJL,vandeWarrenburgBPC. Discordancebetweenpatient-reportedoutcomes andphysician-ratedmotorsymptomseverityin early-to-middle-stagespinocerebellarataxiatype3. Cerebellum.2021;20:887 895.

20.LimGY,TamWW,LuY,etal.Prevalenceofdepressioninthecommunityfrom30countriesbetween 1994and2014. ScientificRep. 2018;8:1 10.

24.RazazianN,KazeminiaM,MoayediH,etal.The impactofphysicalexerciseonthefatiguesymptoms inpatientswithmultiplesclerosis:asystematicreview andmeta-analysis. BMCNeurol. 2020;20:1 11.

16.KurtA,NijboerF,MatuzT,etal.Depressionand anxietyinindividualswithamyotrophiclateralsclerosis. CNSDrugs.2007;21:279 291.

18.WorldHealthOrganization.DepressionandOther CommonMentalDisorders.GlobalHealthEstimates; 2017.Availableat:https://apps.who.int/iris/bitstream/ handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf. AccessedNovember16,2021.

17.BoeschotenRE,BraamseAM,BeekmanATF,etal. Prevalenceofdepressionandanxietyinmultiple sclerosis:asystematicreviewandmeta-analysis. JNeurolSci. 2017;372:331 341.

23.RibiereC,BernardinM,SacconiS,etal.PainassessmentinCharcot-Marie-Tooth(CMT)disease.

25.O’ConnorL,WesterbergE,PungaAR.Myasthenia gravisandphysicalexercise:anovelparadigm. Front Neurol. 2020;11:675.

19.MerkiesISJ,KieseierBC.Fatigue,pain,anxietyand depressioninGuillain-Barrésyndromeandchronic inflammatorydemyelinatingpolyradiculoneuropathy. EurNeurol. 2016;75:199 206.

SymptomBurdeninCMT1A www.jcnmd.com Journalof CLINICAL NEUROMUSCULAR DISEASE Volume24,Number1 September2022 17

21.WorldPopulationReview.DepressionRatesbyCountry 2022;2022.Availableat:https://worldpopulationreview. com/country-rankings/depression-rates-by-country.AccessedNovember2,2021.

22.OurWorldinData.MentalHealth.2022.Availableat: https://ourworldindata.org/mental-health.Accessed: November21,2021.

Ann PhysRehabilMed. 2012;55:160 173.