Application de la classification en 5 formes aux données de l’obser-

Nous avons appliqué cette classification et défini chaque classe à partir des 2167 adultes atteints de DM1 présents dans DM-Scope. Les résultats sont présentés dans l’article « Un-ravelling the myotonic dystrophy type 1 clinical spectrum : A systematic registry-based study with implications for disease classification » [149].

Internationalmeeting of the French societyof neurology2016

Unravelling the myotonic dystrophy type 1 clinical

spectrum: A systematic registry-based study with

implications for disease classification

M.De Antonio^a,b, C. Dogan^a, D. Hamroun^c, M.Mati^a, S. Zerrouki^a, B.Eymard^d, S. Katsahian^b, G. Bassez^a,*, and theFrench Myotonic Dystrophy Clinical Network¹

aCentredere´fe´rencemaladiesneuromusculaires,CHUHenri-Mondor,51,avenueduMare´chal-de-Lattre-de-Tassigny, 94010Cre´teil,France

bInsermUMRS1138,team22,centrederecherchedescordeliers,15,ruedel’E´coledeMe´decine,75006Paris,France cInstitut universitaire de recherche clinique, CHU de Montpellier, 191, avenue du Doyen-Gaston-Giraud, 34090Montpellier,France

dCentre de re´fe´rence maladies neuromusculaires Paris-Est, institut de myologie, hoˆpital Pitie´-Salpeˆtrie`re, 47-83,boulevarddel’Hoˆpital,75013Paris,France

revue neurologique 172(2016) 572–580

info article Articlehistory:

Received8July2016 Receivedinrevisedform 15July2016

Accepted22August2016

Availableonline21September2016 Keywords:

Myotonicdystrophy Myotonicdystrophytype1 Steinertdisease Diseaseclassification Registry Rarediseases Medicalcare Clinicaltrials Healthcare abstract

Thebroadclinicalspectrumofmyotonicdystrophytype1(DM1)createsparticular chal-lengesforbothmedicalcareanddesignofclinicaltrials.Clinicalonsetspansacontinuum frombirthtolateadulthood,withsymptomsthatarehighlyvariableinbothseverityand natureoftheaffectedorgansystems.Intheliterature,thiscomplexphenotypeisdivided into three grades (mild, classic,and severe) and four or five main clinical categories (congenital,infantile/juvenile,adult-onsetandlate-onsetforms),accordingtosymptom severityandageofonset,respectively.However,theseclassificationsarestillunder dis-cussion with no consensus thusfar. While some specific clinical features have been primarily reportedin someforms ofthe disease,there are noclear distinctions.As a consequence,nomodificationsinthemanagementofhealthcareorthedesignofclinical studieshavebeenproposedbasedontheclinicalformofDM1.Thepresentstudyhasused theDM-Scoperegistrytoassess,inalargecohortofDM1patients,therobustnessofa classificationdividedintofiveclinicalforms.Ourmainaimwastodescribethedisease spectrumandinvestigatefeaturesofeachclinicalform.Thefivesubtypeswerecomparedby distributionofCTGexpansionsize,andtheoccurrenceandonsetofthemainsymptomsof DM1.Analysesvalidatedtherelevanceofafive-grademodelforDM1classification.Patients wereclassifiedas:congenital(n=93,4.5%);infantile(n=303,14.8%);juvenile(n=628,30.7%); adult(n=694,34.0%);andlate-onset(n=326,15.9%).Ourdatashowthattheassumptionofa continuumfromcongenitaltothelate-onset formisvalid, andalsohighlights disease featuresspecifictoindividualclinicalformsofDM1intermsofsymptomoccurrenceand chronologythroughoutthediseasecourse.Theseresultssupporttheuseofthefive-grade

*Correspondingauthor.

E-mailaddress:guillaume.bassez@aphp.fr(G.Bassez). Availableonlineat

ScienceDirect

1. Introduction

Myotonic dystrophy type 1 (DM1 or Steinert disease) is remarkableduetoitswideclinicalspectrumandunderlying molecularmechanisms,makingDM1oneofthemostcomplex genetic disorders. It is a pleiotropic disease that predomi-nantlyaffectsthemusclesthroughdelayedmusclerelaxation (myotonia)andprogressivemuscleweakness,butalsoother organs,suchastheheart,lungs,gastrointestinaltract,eyes, endocrinesystem andbrain[1]. Itsbroadclinicalspectrum reflectsthevariabilityofexpressionofthephenotype,which differsbyageofonsetaswellasthenature,severityandorder ofsymptomoccurrence.Thisvariabilityislinkedmainlytothe particularcharacteristicsoftheunderlyingmutation.DM1is causedbyanunstabletrinucleotide cytosine–thymine–gua-nine(CTG)repeatexpansionintheDMproteinkinase(DMPK) gene[2–5],whichshowsacleartendencytoincreaseinsize: oversuccessivegenerations,whichispositivelycorrelated withoverallseverityofsymptomsandinverselywithageof onset[6–8];

insomatic tissues,withdiffering ratesofCTGexpansion between differenttissuesand differentpatients.Such an unstablemutationexplainsinpartitswideobserved intra-andinterindividualvariability[9–18].

The unusually wide clinical spectrum poses particular challenges for medical care and the establishment of homogeneous groups of DM1 patients in clinical studies. Themaindifficultyresultsfromdisparitiesindistinguishing particular phenotypes inguidelines ofhealth management and in translational research. In the literature, the DM1 clinicalspectrumis variouslydivided into threesomewhat overlappingphenotypes(mild,classic,severe)[19–23]andfour orfivemainclinicalcategories(congenital,infantile/juvenile, adult-onsetandlate-onset)[24–29].Thelackofconsensuson DM1clinicalclassificationleadstolimitations,including: non-standardized medical care, in particular the lack of

uniquecareguidelinesforadultDM1patientsregardlessthe ageofonset[30–38];

avoidanceofclinicalformasakeycriterioninthedesign andinterpretationofclinicalstudies[39–47];

aninabilitytoperformmeta-analyses.

In thepresent study,the French DM-Scoperegistrywas usedtodescribe,inalargecohortofpatients,theDM1clinical spectrum.Ourmainaimwastoassessthe robustnessofa classificationusingfive clinicalforms(congenital,infantile, juvenile, adult-onset and late-onset). Different approaches wereused to compare the five clinical grades in terms of

distributionofCTGexpansionsize,andtheoccurrenceand onset of the main symptoms of DM1. Thus, our study addressestheissueofDM1clinicalspectrumand classifica-tion,anddiscussestheimplicationsofcorrectidentificationof clinicalformsforpatients’caremanagementandthedesignof clinicaltrials.

2. Materialsandmethods

2.1. Patientsandeligibility

Thisstudywasperformedwithstandardizeddatacollectedin the French DM-Scope Registry from 2167 French patients during their yearly follow-ups at 28 adult neuromuscular expertcenters.Allpatientswereaged18yearsandhadbeen givenageneticdiagnosisofDM1.

2.2. Definitionsandclassification

2.2.1. Clinicalmanifestations:measuresanddefinitions

Musclestrengthwasmeasuredusingthe:

 modifiedMedicalResearchCouncil(MRC)scaletoevaluate neckflexors,shoulderabductors,elbowflexorsand exten-sors,wristextensors,fingerflexors,hipflexors,kneeflexors andextensors,posteriorfootflexorsandplantarflexors;  validated muscular impairment rating scale (MIRS) to

quantifyDM1-relatedmotorimpairment[48].

Educational levels were based on the International StandardClassificationofEducation(ISCED)orInternational Classification of Type of Education (CITE). The following definitionswereused:severemyotonia=timetoopenhands after contraction3sec; respiratory insufficiency=forced ventilationcapacity(FVC)<70%;cardiac conduction defect-s=electrocardiography(ECG)showingarrhythmia, atrioven-tricular blocks (type 1, 2 or 3) or left hemiblock or bundle branch block; somnolence=Epworth Sleepiness Scale score>10; dysphagia=coughing during eating or drinking more than twice a month, 80-mL swallowing-time test>6sec and coughing during the drinking evaluation [1];gastrointestinal(GI)troubles=diarrhoeaorconstipation; muscle impairment=MIRS score>3; couple’s hypofertili-ty=delayof>18monthsingettingafirstchild;overweight/ obesity=bodymassindex(BMI)25kg/m²;andlow educa-tionallevel=ISCED/CITElevel3.

2.2.2. Clinicalclassification

Our DM1 subjects were classified into five clinical forms according toageat onset ofthefirst clinicalmanifestation (adaptedfromAslanidisetal.[2]):

modelfordiseaseclassification,andthedistinctclinicalprofilessuggestthatageofonset andclinicalformmaybekeycriteriainthedesignofclinicaltrialswhenconsideringDM1 healthmanagementandresearch.

#2016ElsevierMassonSAS.Allrightsreserved.

 congenital form=mild to severe neonatal symptoms, includinghypotonia,respiratorydistress,suckingor swal-lowingdifficulties,orskeletaldeformitiesdetectedatbirth orduringthefirstmonthoflife;

 infantile form=clinical onset between 1 month and 10 years;

 juvenileform=onsetbetween10and20years;  adultform=onsetbetween20and40years;  late-onsetform=onsetafter40years.

2.2.3. Designofthestudy

Thefiveclinicalformswerecomparedfor:  distributionofCTGexpansionsize;

 frequencyofmainDM1features(facialdysmorphism,CITE level>3, muscle weakness, severe myotonia, abnormal ECG, respiratory insufficiency, dysphagia, GI symptoms, cataract,somnolence,diabetesandoverweight/obesity);  age of onset of symptoms (cataracts, cataract surgery,

pacemaker,cardiacdefects,respiratoryinsufficiency, endo-crinedisorders,GItroubles, myotonia and muscle weak-ness)orageattimeofmedicaldeviceuse.

2.3. Statisticalanalyses

Descriptionsareexpressedasnumber(n)andpercentage(%) forqualitativevariables,andasmeansandstandarddeviation (SD)forquantitativevariables.TheChi2orFishertestwasused to assess dependence between two qualitative variables. Quantitative variables showing Gaussian (or non-Gaussian) distributionswerecomparedbetweengroupsusinganalysisof variance(ANOVA)(orthenon-parametricKruskal–Wallistest), andTukey’shonestsignificantdifference(HSD)test(orDunn’s test) was usedforpost-hoc multiplecomparisons. Logistic-regressionmodels,adjustedforage,wereusedtodetermine theeffectofclinicalformonclinicalmanifestations.Clinical formdifferenceswereexpressedasoddsratios(ORs),withthe clinicalmanifestationmorelikelytooccurinanearlierformif the OR is>1 and inversely if the OR is<1. All statistical analyses were performed usingR version 3.2.3 software(R FoundationforStatisticalComputing,Vienna,Austria)and,for alltests,thelevelofsignificancewassetat5%.

3. Results

3.1. Characteristicsofthestudycohort

(n=694,34.0%)andlate-onset(n=326,15.9%)forms(Table1). Theaverageageofpatientsdifferedacrossthefiveclinicalforms (P<0.0001,ANOVA) and there was no difference in gender distribution in eachform (Chi2 test, P=0.09). Thus, the five clinicalgradeswerecomparableafteradjustingforpatientage.

3.2. DistributionofCTGexpansionsizeamongthefive

clinicalgrades

CTGexpansionsizeswerebroadlydistributedineachclinical formwithoverlappingbetweensubtypes,thusdemonstrating the wide variability of DM1 genetic characteristics (Fig. 1). However,thedistributionsizeoftherepeatexpansiondiffered significantly among the five clinical grades (P<0.0001, Kruskal–Wallistest).CTGsizedecreasedfromthecongenital tolate-onsetform(allP<0.05,Dunn’spost-hoctest).

3.3. SymptomoccurrenceinDM1isclinical

form-dependent

InDM1adults,thefrequencyofsymptomsvariesaccordingto ageofonsetandclinicalform(Fig.2).Fourtypesofsymptom patternscanbedistinguished:

 typeA(‘decreasing pattern’)shows morefrequent symp-toms in earlier-onset forms of DM1, including facial

Table1–Clinicalcharacteristicsofstudycohortbyclinicalformofmyotonicdystrophytype1(DM1).

Congenital <1month Infantile (1month–10years) Juvenile (>10–20years) Adult (>20–40years) Late-onset (>40years) DM1patients 93(4.5) 303(14.8) 628(30.7) 694(34.0) 326(15.9) Female 38(40.9) 151(49.8) 330(52.5) 382(55.0) 176(54.0) Age(years) 28.68.0 [18.0–54.0] 35.912.0 [18.0–68.0] 38.712.0 [18.0–68.0] 46.710.0 [21.0–79.0] 57.78.0 [34.0–81.0] Dataarepresentedasn(%)orasmeansSD[min–max].

revue neurologique 172 (2016)572–580

dysmorphism, cognitive impairment, muscle weakness, respiratoryinsufficiencyandinfertility;

type B (‘increasing pattern’) clinical features, including cardiacdefects,cataracts,diabetesandoverweight/obesity, aremoreoftenreportedinlaterformsofdisease;

typeC(‘bell-shapedpattern’),wheremyotoniaisthesole clinical sign, displays a particular median peak of pre-valenceinjuvenile-andadult-onsetforms;

typeD(‘stablepattern’),wheredysphagia,hypersomniaand GIproblems areequallyobservedamong thefiveclinical forms.

Toshedsomelightonthemuch-debatedsplittingofcases arising in childhood into different categories (congenital, infantile and juvenile), our focus was particularly on the symptomsmoreprevalentinearly-onset,age-matchedcases torefine differences indisease phenotype (Table 2). Initial comparisonsofcongenitalandinfantileforms(CFsandIFs, respectively)revealedthatCFpatientsmuchmorefrequently havespecializedprofessionalattention(OR:9.6,P<0.01)as wellasmorefrequentrespiratoryinsufficiency,severemuscle weaknessandfacialdysmorphism(OR:>1,P<0.05).

Ifpatientsdevelopmoreseverephenotypesthanjuvenile forms(JFs; Table 2), particularlywithcognitive impairment requiring more frequent specialized professional attention (OR:4.6,P<0.001).IFsalsomorefrequentlydisplaydysphagia, facialdysmorphism,cardiacconductiondefects,cataractsand muscleinvolvement,suchasmuscleweaknessand respira-toryinsufficiency(OR:>1,P<0.05).Incontrast,the probabi-lityof developing severemyotonia is higher inJF patients (OR:<1,P<0.05).

ThemildercognitiveimpairmentdescribedinJFsisoneof themaindifferencesbetweenthisformandtheadultform (AF; Table 2). In fact, despite the non-significant OR for

educational level, JF patients face greater employment challengesandmorefrequentlyrequirespecialized professio-nalattention.JFsalsopresentwithamoreseverephenotype including,inparticular,morepronouncedmyotonia,greater somnolence and, more frequently, dysphagia, respiratory insufficiency, muscle weakness and facial dysmorphism (OR:>1,P<0.05).

AFsdifferfromthelate-onsetform(LFs)bymorefrequently having muscle weakness and GIsymptoms, and a greater probabilityofdevelopingdysphagiaatthesameage(OR:>1, P<0.05).Facialdysmorphism,cognitiveimpairment,cardiac conduction defects,cataractsand severemyotoniaarealso morefrequentinAFpatients.

3.4. DM1clinicalspectrum:atemporalsuccessionof

distinctprofiles

AgraphicrepresentationoftheoverallageofonsetofDM1 manifestationsforeachclinicalformhighlightsthetemporal successionofeachdiscreteclinicalprofile(Fig.3).Theearliest symptomsappearwithCFsandshowclustersofmusclesigns, GItroubles,respiratoryinsufficiencyandcardiacdefects.The timewindowfortheappearanceofeachsymptomclustermay vary, with some symptom groups showing a ratio of 1:2 betweentheearliestandlatestageofonset.Surprisingly,LFs differfromtheotherformsbyhavingaspecificprofile,with DM1manifestationsarisingwithinaperiodof5years.Inspite ofthelimitedoverlapofsomesymptoms,whichisconsistent with a temporal DM1 continuum, several clinical features appear to have a specific time of occurrence according to clinicalform.

Inthethreeearly-onsetforms,musclesymptomsandGI troublesareexpressedearlyinthecourseofdisease.InCFs, muscle weakness typically arises before myotonia, and Fig.2–FrequencyofthemainDM1featuresacrossthefiveclinicalforms:(A)‘decreasingpattern’,characterizedbya decreasingfrequencyfromearlytolateforms;(B)‘increasingpattern’,characterizedbyanincreasingfrequencyfromearly tolateforms;(C)‘bell-shapedpattern’,wheresymptomsaremorefrequentinmedian-ageforms;and(D)‘stablepattern’, withnosignificantchangesinsymptomfrequencyacrossallDM1forms.*P<0.05;**P<0.01;***P<0.001.

Table 2 – Comparisons of clinical manifestations of myotonic dystrophy type 1 (DM1) clinical forms. Congenital (CF) n (%) Infantile (IF) n (%) CF vs. IF OR [95% CI] Juvenile (JF) n (%) IF vs. JF OR [95% CI] Adult (AF) n (%) JF vs. AF OR [95% CI] Late-onset (LF) n (%) AF vs. LF OR [95% CI]

Lower educational level 22 (100.0) 75 (67.0) N/A 157 (57.7) 1.58 [1–2.5]*

175 (59.5) 1.08 [0.8–Inf] 79 (53.4) 1.81 [1.1–2.9]*

Specialized professional attention 29 (93.5) 44 (60.3) 9.6 [2–45]** 34 (24.8) 4.58 [2.5–8.4]*** 18 (12.3) 2.19 [1.1–45]* 1 (2.8) 4.68 [0.6–39] Facial dysmorphism 23 (82.1) 77 (61.6) 2.65 [0.9–7.5]* 123 (46.1) 1.89 [1.2–2.9]** 101 (35.2) 1.65 [1.2–7.5]** 43 (25.9) 1.52 [0.9–2.5]* Respiratory insufficiency 37 (66.1) 97 (50.3) 2.76 [1.4–5.4]** 146 (36.3) 2.23 [1.5–3.2]*** 141 (32.0) 1.83 [1.3–5.4]*** 61 (31.9) 1.37 [0.9–2.1] Muscle weakness 36 (49.3) 106 (42.1) 2.68 [1.5–4.9]** 209 (39.1) 1.5 [1.1–2.1]* 258 (45.0) 1.44 [1.1–4.9]* 89 (33.8) 3.23 [2.3–4.6]*** Infertility 1 (6.2) 21 (25.3) 0.23 [0–1.9] 55 (24.8) 1.07 [0.6–1.9] 65 (21.5) 1.18 [0.8–1.9] 19 (11.8) 1.38 [0.7–2.6] Diabetes 1 (1.2) 19 (7.2) 0.31 [0–2.5] 43 (7.7) 1.19 [0.7–2.1] 65 (10.8) 1.09 [0.7–2.5] 33 (12.1) 1.3 [0.8–2.2] Overweight/obesity 26 (35.1) 105 (41.7) 1.1 [0.6–2] 217 (40.8) 1.15 [0.8–1.6] 271 (46.2) 1.07 [0.8–2] 134 (51.5) 1.02 [0.7–1.4] Cardiac conduction defects 19 (32.8) 96 (45.7) 0.76 [0.4–1.4] 165 (40.6) 1.47 [1–2.1]*

248 (50.1) 1.13 [0.8–1.4] 126 (55.8) 1.49 [1–2.2]* Cataracts 29 (48.3) 127 (56.7) 1.67 [0.9–3.3] 253 (57.0) 1.48 [1–2.2]* 397 (72.4) 1.03 [0.8–3.3] 223 (78.5) 1.67 [1.1–2.5]* Severe myotonia 26 (36.6) 96 (37.9) 0.92 [0.5–1.6] 236 (44.3) 0.76 [0.6–1]* 170 (30.7) 1.68 [1.3–1.6]*** 53 (19.8) 1.42 [1–2.1]* Dysphagia 45 (60.8) 148 (56.9) 1.5 [0.9–2.6] 264 (49.2) 1.51 [1.1–2]** 297 (51.7) 1.26 [1–2.6]* 143 (51.6) 1.47 [1.1–2]* GI symptoms 26 (34.2) 121 (47.5) 0.66 [0.4–1.2] 227 (44.2) 1.19 [0.9–1.6] 251 (45.1) 1.21 [0.9–1.2] 111 (41.3) 1.62 [1.2–2.3]** Somnolence 7 (15.2) 48 (26.2) 0.64 [0.3–1.6] 100 (25.9) 1.1 [0.7–1.6] 89 (22.1) 1.41 [1–1.6]* 43 (24.3) 0.91 [0.6–1.4] r e v u e n e u r o l o g i q u e 1 7 2 ( 2 0 1 6 ) 5 7 576

respiratoryandcardiacdefectsareearlyevents(ataround20 years). In contrast, in IFs, myotonia is the first muscle symptom.Inaddition,JFsarefurtherdistinguishedfromthe otherchildhoodformsbyearlycardiacdefects.AFsdifferfrom JFsbythenatureofthesecond-occurringsymptoms,which, insteadofGItroubles,arecataractsandendocrinedisorders. Moreover, in AFs, cataract surgery is needed considerably soonerafterthediagnosisofcataract.LFspresentatemporal profile somewhat similar to AFs,with the maindifference beingashorterdelayintheappearanceofallsymptoms.

4. Discussion

ThispresentworkhighlightstheclinicalspectruminDM1and providesstrong evidence fora disease classification model basedonfive clinicalforms.Our datademonstratethatall formsofDM1differintermsofCTGexpansionsize,frequency ofsymptomsandageofonsetofdiseasemanifestations.

Previousstudieshavereportedabroadlyinverse correla-tionbetweenCTGrepeatsizeandageofonset[7,8].However, thehighgeneticvariability,highlightedinouranalysisbythe overlap in CTG size distribution, raises some relevant questions about the use of genetic results for disease prognosis.Indeed,ourpresentstudyhasshownthatmutation sizecan haveprognosticvaluewhenassociatedwithother criteria,suchasgender[49],andhelptopredicttheseverityof thephenotype.

Ourmaingoalwastodefinetheclinicalfeaturesofthefive diseasegrades,which have demonstratedthat, beyondthe clinicalcontinuumfromCFstoLFs,specificcharacteristicsare presentineachclinicalform.First,ourstudyshowedthatthe occurrenceandageofonsetofDM1symptomsarerelatedto clinicalgrade.Thisfindingindicatesthatthemedicalcareof patients should be adapted according to clinical form, including both the type and frequency of recommended

clinicalinvestigations.Ourresultsalsohighlightthefactthat symptomscommonlycorrelatedwithagingcandevelopvery earlyincertainclinicalforms,asseenwithcataractsinCFs andIFs,aswellasendocrinedisordersinJFs.Thiswasalsothe casewithotherfeatures,ascardiac defectsand pacemaker implantation maybe necessary at 20 and 23 years ofage, respectively,inearly-onsetforms(CFs,IFs,JFs).Strikingly,a verynarrowtimeintervalwasnotedwiththeappearanceofall DM1 symptoms in LFs, which should translate to greater medicalattentionduringclinicalfollow-upsofthesepatients, whoareoftenotherwiseconsideredmildlyaffected.

Our study also refines the clinical description of the childhoodperiod. Besidestheknowncharacteristics ofCFs andIFs[19,24],someremarkableclinicalspecificitieswerealso identified. Such findings may be of importance for the healthcaremanagementofearly-onsetDM1patients.Itwas alsoshownthatCFpatients,characterizedbyseverecognitive impairment,candevelopearlyrespiratory insufficiencyand cardiacdefectswhereasIFpatients,whoexpresslessmarked cognitiveimpairment,differfromtheotherpatientgroupsby early-onsetofmyotonia.JFsspanthecontinuumbetweenIFs andAFs,andsharesomeoverlappingfeatures.Nevertheless, JFpatientsdifferfromIFsbyhavingmoreseveremyotoniaand earlierendocrinedisorders,whiledifferingfromAFpatients byhavingoftenunderdiagnosedcognitiveimpairment,earlier GIandcardiacissues,andearlierrespiratoryinsufficiencyand muscledefects.

5. Conclusion

The present study has shown that the unique DM-Scope registrycanmeaningfullycontributetoinvestigationsofthe wide clinical spectrum and assessments of DM1 disease classifications. Our findings support a five-grade clinical model of disease classification and confirm the clinical Fig.3–AgeofonsetofDM1manifestationsinthefiveclinicalforms.Eachsquarecorrespondstothemeanageofonsetand 95%confidenceinterval.

continuumof DM1,which spansthe time ofbirth tolate adulthood.Interestingly,ourstudyresultsindicatethatthe clinicalspectrumcomprisesnotonlyatemporalsuccession ofsimilarpatternsofsymptoms,butalsodifferentclinical specificitiesfor eachclinical form, resultingin distinguis-hable, discrete profiles. The distinctive findings for each clinical form have prompted us to propose that optimal classificationofDM1patientsisakeysteptowards impro-vementsinboththedesignofclinicalstudiesandpatients’ caremanagement.

Disclosureofinterest

Theauthordeclaresthathehasnocompetinginterest.bœuf

AppendixA. FrenchMyotonicDystrophyClinical Network

AmarofKhadija(centrehospitalieruniversitairede Fort-de-France,unite´ deneuromyologie,routede Chaˆteaubœuf-La-Meynard, BP 632, 97261 Fort-de-France cedex – khadija. amarof@chu-fortdefrance.fr),MarieChristineArneBes (neu-rologie,poˆleneurosciences,hoˆpitalPierre-Paul-Riquet,place duDocteur-Baylac,TSA40031,31059Toulousecedex9,Hall B – arne-bes.mc@chu-toulouse.fr), Anne-Catherine Aube-Nathier(consultationmultidisciplinairemaladies neuromus-culaires pour adultes, de´partement de neurologie, CHU d’Angers, 4, rue Larrey, 49933 Angers cedex 9, France – acaube-nathier@chu-angers.fr),Anne-LaureBedat-Millet (ser-vice de neurologie, 5^e e´tage, pavillon Fe´lix-De´ve´s 1, CHU Nicolle,76031Rouencedex,France–anne-laure.bedat-millet@ chu-rouen.fr),Anthony Behin (institutde myologie,hoˆpital Pitie´-Salpeˆtrie`re, 47-83, boulevard de l’Hoˆpital, 75013 Paris, France– anthony.behin@psl.aphp.fr),Remi Bellance (centre hospitalieruniversitaire de Fort-de-France,unite´ de