Development of a decision-analytic model for the economic evaluation of newborn screening for spinal muscular atrophy

Abstracts/NeuromuscularDisorders28(2018)S29–S146 S59 forpatientswith≥6monthsoffollow-up(N=73).TheNNTtopreventone

death,oneevent(deathoruseofpermanentassistedventilation),orforone patienttoimprovemotorfunctionrelativetonusinersenwascalculatedasthe reciprocalofthedifferencebetweenAVXS-101andnusinersenineventrates ormotorfunctionachievementrates.Patientmeanageatfirstdosewas3.4 (0.9-7.9)and 5.3(1.7-7.9) monthsin theAVXS-101and nusinersentrials. NNTanalyses suggeststhattreating6.2patientswithAVXS-101insteadof nusinersenwouldprevent1moredeathbythelastvisit;treating2.6patients withAVXS-101versusnusinersenwouldprevent1moreevent;andtreating 3.5patientswith AVXS-101versusnusinersenwouldallow1morepatient to improvemotorfunction(atlastvisitand ata medianof9months). Ef-ficacy inpreventingdeathanduseofpermanent assistedventilationandin improvingmotorfunctionismuchhigherwithAVXS-101versusnusinersen. http://dx.doi.org/10.1016/j.nmd.2018.06.124

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Development of a decision-analytic model for the economic evalua- tion of newborn screening for spinal muscular atrophy

T.Dangouloff1_{,M.Hiligsmann}2_,J.Caberg1_,F.Boemer1_,L.Servais1

1_{CHU Liege, Liege, Belgium;} 2_{Maastricht University, Maastricht, The}

Netherlands

Economicconsiderationsareincreasinglyimportanttohelpdecision mak-erstoefficientlyallocatehealthcareresources.Todate,verylittleinformation isavailableonthecost-effectivenessofspinalmuscularatrophy(SMA) treat-mentandnewbornscreening;yetmoreandmorescreeningprogramsare be-ingimplementedintheUSAandinEurope.Theaimofthisstudyistherefore todevelopadecision-analyticmodeltoassessthecost-effectivenessof new-bornscreeningandpre-symptomatictreatmentofSMAascomparedto post-symptomatictreatment.NewbornscreeningforSMAhasstartedsinceMarsh 05thin SouthernBelgium.Wearedevelopingadecision-analyticmodelin Excelwithalifetimehorizonandasocietalperspective.Thismodelincludes events (such as death,permanent ventilation,etc), transition, utilities, and costs. Data was retrieved from literature reviews, available non-published data from Nurture, and data collected from theEuropean NaturalHistory Study in SMA. We also collected data from the large post symptomatic treatedcohortofLiege,Belgium.Allsuchdatawasacquiredincenters ap-plyingupdatedstandardsofcare.Thequalityoflifeofpatientsandparents was includedin theanalysis,as wellas theproductivity lossesofparents. Themodelthusestimatesthecostsandeffects(expressedinquality-adjusted lifeyears)ofnewbornscreeningandtocompareitwithasituationwhereall patientsarediagnosedpost-symptomatically.Initialdatasuggestspromising resultsand revealkeyfactorsonthecost-effectivenessofNBS.Themodel requiresadjustmenttobefullyvalidated.

http://dx.doi.org/10.1016/j.nmd.2018.06.125

LGMD

AUTOSOMAL

RESSESSIVE

AND

DOMINANT

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AAV-mediated gene transfer of FKRP for therapy of LGMD2I E.Gicquel1_,S.C.Brown2_,I.Richard1

1_{Genethon,Evry,France;}2_{RoyalVeterinaryCollege,London,UK}

Dystroglycanopathies constitute a group ofgenetic diseases causedby defective glycosylation of alpha-dystroglycanα, a membrane glycoprotein involvedinthecell/matrixanchoringofmusclefibers.TheaDG glycosyla-tion,averycomplexprocess,requiresmanyproteinswhosefunctionsarenot fullyelucidated.Inparticular,mutationsintheFKRPgeneencodingFukutin relatedproteinleadto hypoglycosylation ofα,resulting indifferentforms of dystroglycanopathies, among which Limb Girdle Muscular Dystrophy type2I(LGMD2I).Weand othershavepublished theproofofconceptof FKRP genetransferusing an AAV vectorfor treatingFKRP deficiencies. Astheknock-inmousemodelsusedinthesestudiesarenotsevereenough

toevaluateproperlythedose-effectofAAV-FKRPadministration,we devel-opeda musclespecificFKRPknock-down mousemodel.This newmouse model,namedHSA-FKRPdel,presentsamuchmoreseverephenotypethan observed in knock-inmouse. Defects of glycosylation of αDG and ofits bindingtolamininwereobserved,aswellashistologicaldystrophicsignsas centronucleation and inflammation. Functional evaluation also showed a reduced force of HSA-FKRPdel mice. AAV-FKRP was systemically administrated to this new mouse model at different doses. Depending of thedose,positive effectswere observed atthemolecular, histologicaland functional levels. Full animal characterization and therapeutic effects will bepresented.DevelopmentofAAVproductionattheGMPlevelisnowon going.ThesedatawillbeincludedinanINDforAAV-mediatedtransferof FKRPinpatients.

http://dx.doi.org/10.1016/j.nmd.2018.06.126

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Limb-girdle muscular dystrophy 2Z in a Bulgarian family

T. Chamova1,A.Taneva1,M.Gospodinova2, D.Zlatareva1, K.Johnson3, A.Töpf3_,V.Straub3_,I.Tournev1

1_{MedicalUniversity-Sofia,Sofia,Bulgaria;}2_{MedicalInstituteofMIA,Sofia,}

Bulgaria;3_{InstituteofGeneticMedicine,NewcastleuponTyne,UK}

Mutations in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involvedinNotchposttranslationalmodificationand functionhavebeen re-centlyidentified ascausinganewtypeoflimb-girdle musculardystrophy, knownasLGMD2Z.Theclinicalfeaturesoftheidentifiedpatients encom-passedvariableclinicalonsetfrom1stto5thdecade,muscleweakness pre-dominantly in theproximal lower limbs,followed byupper limb involve-mentand wheelchairconfinement.WereportaBulgarianfamilywiththree affected sisters,homozygous for R98W mutationin POGLUT1. They un-derwentneurological examination,electromyography, measurementof cre-atine kinase,ventilatoryassessment, electrocardiography, echocardiography and muscle muscle magnetic resonance imaging (MRI). The initial com-plaintsintwoofthemwerenoticedattheageof24-25years,whileinthe third-attheageof44years.Theleadingsymptomsatonset weremuscle weaknessintheproximallegmuscleswithdifficultiesinclimbingstairsand gettingupfromsquattingposition.Theinvolvementoftheupperlimbswas noticedbetween6and23yearsafterthelowerlimbweakness.CKwaswithin normalrangeinallthreeaffected.Thecardiacfunctionseamedspared,mild restrictiverespiratoryinvolvementwas observedin onlyone ofthesisters. MRIofthelegsrevealedearlyfattyreplacementofinternalregionsofthigh musclesandsparing oftheexternal areas.InconclusionPOGLUT1 muta-tionsareassociatedwithlateonsetARLGMDwithspecificMRIpatternof inside-to-outsidemodeoffattydegenerationinthelowerlimbs.

http://dx.doi.org/10.1016/j.nmd.2018.06.127

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BVES loss-of-function mutations in limb-girdle muscular dystrophy 2X with cardiac conduction disorders

I. Nelson1_{, W. De Ridder}2_{, B. Asselbergh}2_{, B. De Paepe}3_{, M. Beuvin}4_,

R.BenYaou4_,A.Boland5_,J.Deleuze5_,T.Maisonobe6_,B.Eymard6_,J.De

Bleecker3_,S.Symoens3_,R.Schindler7_{,T. Brand}7_,A.Töpf8_,K.Johnson8_,

V.Straub8_,P.DeJonghe2_,J.Baets2_,G.Bonne1

1_{Sorbonne Universités INSERM, Paris, France;} 2_{University of Antwerp,}

Antwerp,Belgium;3_{GhentUniversityHospital,Ghent,Belgium;}4_Sorbonne

UniversitésINSERM,Paris,France;5_{CEA,Inst.deBiologieFJacob,Evry,}

France; 6APHP, G.H. Pitié-Salpêtrière, Paris, France; 7Imperial College London,London,UK;8NewcastleUniversity,NewcastleuponTyne,UK

BVESencodesfor a 360 aminoacid protein also known asPOPDC1, which is part of the Popeye domain containing (POPDC) family of pro-teins.POPDC1,POPDC2 and POPDC3 arecAMP-bindingtransmembrane proteinsthat are abundantly expressed in striated muscle. A homozygous