Abstracts/NeuromuscularDisorders30(2020)S46–S150 S103 P.191
Preliminary datafor the cost-effectiveness assessmentof the newborn screeningforSMAinBelgium
T.Dangouloff1,L.Servais2,M.Hiligsmann3
1Universityof Liege,Liege, Belgium; 2Universityof Oxford, Oxford, UK; 3MaastrichtUniversity,Maastricht,Netherlands
Neonatal screening is becoming increasingly important in the spinal muscularatrophy(SMA)landscape.Yetthereisagrowingsetofevidences that earlypre-symptomatic management ismuchmore efficientthan post-symptomatic treatment, there is however no information available on the cost-effectivenessofSMAnewbornscreening(NBS).Suchhealtheconomic analysisisneverthelessveryimportanttoconvincepolicymakerstoallocate fundsforNBS.Wewillpresentthehealth-economicdataofpre-symptomatic and post-symptomatictreatedpatients inBelgiumthatwillfurtherbeused toassessthecost-effectivenessofNBS.BetweenMarch2018andFebruary 2020, screening was conducted among71,000 newborns, among which 9 weredetectedwithSMA.Allbutoneidentifiedpatientsweretreatedbefore the onset of symptoms: 5 with nusinersen (one was mildly symptomatic at the time of treatment), 2 with Zolgensma, 1 with Risdiplam and the last one to be determined. Survival, costs and quality of life of these 9 patients(agedbetween10daysand 18months) arecurrentlyprospectively collected. In addition, data from 3 additional asymptomatic patients who were siblings of affected children arealso collected. Survival,health care resources consumption and quality of life data have also been collected on symptomatic treatedand untreated patients. For untreated patients, we collectedprospectivelythedataduringtwoyearsin81patients(53patients with SMA Type 2, 9 non-ambulant with SMA Type 3 and 19 ambulant withSMAType3).Wearealsocollecting similardataprospectivelyin30 symptomaticpatientstreatedwithnusinersenand2untreated patients,aged between4months and60 years(9patients withSMA1,14 patientswith SMA2, and9patients withSMA3).Two-thirds ofthesepatientsalready have atleast2 years offollow-up.Using thesethreesetsof data,we are currently developing a model to assess the cost-effectiveness of newborn screeningforSMA.Wewillpresentthepreliminaryresultsissuedfromthis model.
http://dx.doi.org/10.1016/j.nmd.2020.08.193
CONGENITALMUSCULARDYSTROPHIES
P.192
Gene therapy approach for LAMA2-related muscular dystrophy usinglinkerproteins
J.Reinhard1,S.Lin1,K.McKee2,P.Yurchenco2,M.Ruegg1
1Universityof Basel,Basel,Switzerland; 2Rutgers University, Piscataway, USA
LAMA2-related muscular dystrophy (LAMA2 MD or MDC1A) is the most frequent form of congenital muscular dystrophies. It is caused by mutations in LAMA2, the geneencoding laminin-α2, the long armof the heterotrimeric(α2, β1,γ 1)basementmembrane proteinlaminin-211 (Lm-211).Patientswiththeearly-onsetform lackLm-211due tobiallelic loss-of-function mutations in LAMA2. The large size of the cDNA encoding laminin-α2and theheterotrimericstructureofLm-211presentachallenge forgenereplacement orgeneeditingstrategies.Toovercomethis,wehave designed tworather smalllinkerproteinsthat qualifyforadeno-associated virus (AAV)-mediated gene delivery.This strategytakes advantage of the compensatory expression of laminin-α4, giving rise to Lm-411 (α4, β1, γ 1), present in LAMA2 MD biopsies and laminin-α2-deficient mice. Lm-411only formsalabilemusclebasement membraneand thusisunableto functionallycompensateforthelossofLm-211.Toovercomethefunctional deficit of Lm-411, one linker protein, called mini-agrin (mag), mediates bindingofLm-411tothesarcolemmalLm-211receptorα-dystroglycan.The secondlinker, calledαLNNd,consistingoftheN-terminalpartof
laminin-α1 and the laminin-binding site of nidogen-1, allows polymerization of Lm-411.Whenaddedtogether, Lm-411and thelinkers form a functional muscle basement membrane in vitro and upon transgenic expression in dyW/dyWmice,amousemodelforLAMA2MD.Consequently,themuscular dystrophy in dyW/dyW mice is largely improved, overall body weight is increasedandmediansurvivalisdrasticallyextendedfrom15weeksto81 weeks(Reinhardetal.,ScienceTransl. Med.,2017).Wewillpresentdata fromourongoing effortstoevaluate thetherapeuticpotentialofthelinker proteinsbytargetingdifferenttissuesatdifferenttimepointsandbytesting thepossibility to use AAV9-mediated deliveryof thelinkers to dyW/dyW mice.
http://dx.doi.org/10.1016/j.nmd.2020.08.194
P.193
Collagen VI-related myopathy. Clinical and genetic findings in a largeChileancohort
B.Suarez,J.Jofre,M.Martinez-Jalilie,M.Diemer,X.Ortega,T.Vial,S.Lillo, M.Haro,G.Calcagno,M.Palomino,C.Hervias,C.Castiglioni
ClinicaLasCondes,Santiago,Chile
Collagen VI related myopathy is one of the more prevalent inherited neuromuscularmyopathies.Determiningthegeneticandclinicalfeaturesin ourpopulationisrelevantto improvepatientscareand developa platform forcollaborativestudiesandfutureclinicaltrials.Wedescribethephenotype, genotypeandmuscleMRI(WBMRI)inaseries ofpatientswith Collagen VI-RelatedMyopathy(COLVI-RM).Aretrospective studyofpatientswith a geneticdiagnosis of Collagen-VI-RM, IRB-approved. Demographic data andpatients’ characteristics were obtainedfrom medicalrecords. Eighteen patients(9families)withCOL6mutationfromtwenty-onepatientssuspected ofCOLVI-RM.12/6(female/male),agerange1-54yearsand (average:25 years).AllpatientspresentanautosomaldominantCOL6-relatedcondition; 4/9 were de novo mutations. 5/9 families carrya COL6A1 mutation,3/9 families a COL6A3 and one family a COL6A2 mutation.Ageof disease onset was before the age of two in 9/18. (motor delay, frequent falls, hip dislocation), followed by neonatal onset (5/18) (hypotonia, congenital torticollis, hip dislocation). A one-year-old patient was diagnosed at pre-symptomaticstate.MostpatientspresentedtypicalCOLVI-RMskinlesions (16/18)and distalhyperlaxity.Mostshoweda slightelevationof totalCK (261-500). Muscle biopsies from 9 patients showed a dystrophic pattern in 5, nonspecific myopathic pattern in 4 patients. Seven patients had a WBMRIprevioustogeneticdiagnose;allofthemshowedthecharacteristic involvementofmusclesdescribedinCOLVI-RM.16/18 patientsdeveloped a Bethlem phenotype, maintaining ambulation. Two patients presented an Ullrichdystrophy phenotypeand ventilatoryfailure. COLVI-RMdominant conditions and Bethlemmyopathy phenotype are prevalent in our cohort. WBMRIisausefultoolthatguidesthediagnosticprocess.TheuseofNGS helpstoshortenthediagnosticodysseyandperformabetterclinical follow-upandgeneticcounselling.
http://dx.doi.org/10.1016/j.nmd.2020.08.195
P.194
Diet, motor activity & daily activity limitations in individuals with
SELENON(SEPN1)relatedmyopathy
J. Prystupa1, R. Alvarez2, C. Genetti1, E. Weller1, S. Liu1, B.Moghadaszadeh1,E.Troiano1,A.Beggs1
1BostonChildren’sHospital,Boston,USA;2CureCMD,Lakewood,USA
SELENON (SEPN1) relatedmyopathies (SELENON-RM) are a group ofrarecongenitalmyopathiescausedbymutationsin theSELENONgene. SELENON-RMpatientstypicallypresentwithaxialweakness,spinalrigidity, scoliosis,decreased stamina,lowbody mass,and respiratoryinsufficiency; however, there is a wide range of symptom severity in these patients,