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Journal of Neurology

, Volume 267, Issue 1, pp 45–56 | Cite as

European muscle MRI study in limb girdle muscular dystrophy type R1/2A (LGMDR1/LGMD2A)

  • Andrea BarpEmail author
  • Pascal Laforet
  • Luca Bello
  • Giorgio Tasca
  • John Vissing
  • Mauro Monforte
  • Enzo Ricci
  • Ariane Choumert
  • Tanya Stojkovic
  • Edoardo Malfatti
  • Elena Pegoraro
  • Claudio Semplicini
  • Roberto Stramare
  • Olivier Scheidegger
  • Jana Haberlova
  • Volker Straub
  • Chiara Marini-Bettolo
  • Nicoline Løkken
  • Jordi Diaz-Manera
  • Jon A. Urtizberea
  • Eugenio Mercuri
  • Martin Kynčl
  • Maggie C. Walter
  • Robert Y. Carlier
Original Communication
  • 232 Downloads

Abstract

Background

Limb girdle muscular dystrophy type R1/2A (LGMDR1/LGMD2A) is a progressive myopathy caused by deficiency of calpain 3, a calcium-dependent cysteine protease of skeletal muscle, and it represents the most frequent type of LGMD worldwide. In the last few years, muscle magnetic resonance imaging (MRI) has been proposed as a tool for identifying patterns of muscular involvement in genetic disorders and as a biomarker of disease progression in muscle diseases. In this study, 57 molecularly confirmed LGMDR1 patients from a European cohort (age range 7–78 years) underwent muscle MRI and a global evaluation of functional status (Gardner-Medwin and Walton score and ability to raise the arms).

Results

We confirmed a specific pattern of fatty substitution involving predominantly the hip adductors and hamstrings in lower limbs. Spine extensors were more severely affected than spine rotators, in agreement with higher incidence of lordosis than scoliosis in LGMDR1. Hierarchical clustering of lower limb MRI scores showed that involvement of anterior thigh muscles discriminates between classes of disease progression. Severity of muscle fatty substitution was significantly correlated with CAPN3 mutations: in particular, patients with no or one “null” alleles showed a milder involvement, compared to patients with two null alleles (i.e., predicting absence of calpain-3 protein). Expectedly, fat infiltration scores strongly correlated with functional measures. The “pseudocollagen” sign (central areas of sparing in some muscle) was associated with longer and more severe disease course.

Conclusions

We conclude that skeletal muscle MRI represents a useful tool in the diagnostic workup and clinical management of LGMDR1.

Keywords

LGMDR1/LGMD2A Muscle MRI Mercuri score CAPN3 mutations 

Notes

Acknowledgements

We would like to thank all participating patients and their families.

Compliance with ethical standards

Conflicts of interest

The authors have non-competing interests with regard to the present work. The authors declare no financial support for the conduct of the study. Dr. Scheidegger reports other from Sanofy Genzyme, outside the submitted work; Dr. Bello reports personal fees from PTC Therapeutics, grants from Santhera Pharmaceuticals to his Institution, personal fees from Sarepta Therapeutics, personal fees from Reveragen Biopharma, outside the submitted work; Dr. Pegoraro reports non-financial support from Genzyme, grants and non-financial support from Santhera, personal fees from Sarepta, personal fees and non-financial support from PTC Therapeuticals, personal fees and non-financial support from Roche, outside the submitted work; Maggie C. Walter has served on advisory boards for Avexis, Biogen, Novartis, Roche, Santhera, Sarepta, PTC Therapeutics, Ultragenyx, Wave Sciences, received funding for Travel or Speaker Honoraria from Novartis, Biogen, Ultragenyx, Santhera, PTC Therapeutics, and worked as an ad-hoc consultant for AskBio, Audentes Therapeutics, Biogen Pharma GmbH, Fulcrum Therapeutics, GLG Consult, Guidepoint Global, Gruenenthal Pharma, Novartis, Pharnext, PTC Therapeutics, and Roche. The remaining authors have nothing to disclose.

Ethical standards

The study has been approved by ethics committees of all the involved institutions. All data were gathered after informed consent was obtained from each participant, in accordance with specific national laws and the ethics standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Supplementary material

415_2019_9539_MOESM1_ESM.pdf (2.4 mb)
Boxplots of Gardner-Medwin & Walton (GMW) score by T1w Mercuri score in 29 lower limb muscles. The boxplots illustrate the correlation between T1w MRI findings in each muscle and functional score (GMW) outcome measures evaluated within ± 12 month before or after performing the MRI. The thirty hand panels correspond to GMW correlations. The muscles are ordered from proximal to distal (hip/abdomen, thigh, leg) starting from the top and left. Red dashed lines indicate correlations, and their thickness is proportional to the strength of the correlation (PDF 2507 kb)
415_2019_9539_MOESM2_ESM.png (180 kb)
Supplementary Material 2 (PNG 181 kb)
415_2019_9539_MOESM3_ESM.pdf (143 kb)
Boxplots illustrating correlations between the presence of a “pseudocollagen sign” and disease duration and severity in our CAPN3 cohort. The presence/absence of “pseudocollagen sign” is indicated on the horizontal axis of the graphs, while disease duration and Gardner-Medwin & Walton score are indicated in the vertical axis (PDF 142 kb)
415_2019_9539_MOESM4_ESM.docx (23 kb)
Supplementary file4 (DOCX 22 kb)

References

  1. 1.
    Richard I, Broux O, Allamand V, Fougerousse F, Chiannilkulchai N, Bourg N, Brenguier L, Devaud C, Pasturaud P, Roudaut C et al (1995) Mutations in the proteolytic enzyme calpain 3 cause limb–girdle muscular dystrophy type 2A. Cell 81(1):27–40.  https://doi.org/10.1016/0092-8674(95)90368-2 CrossRefPubMedGoogle Scholar
  2. 2.
    Straub V, Murphy A, Udd B (2018) LGMD workshop study group 229th ENMC international workshop: Limb girdle muscular dystrophies—Nomenclature and reformed classification Naarden, the Netherlands, 17–19 March 2017. Neuromuscul Disord 28(8):702–710.  https://doi.org/10.1016/j.nmd.2018.05.007 CrossRefPubMedGoogle Scholar
  3. 3.
    Fardeau M, Hillaire D, Mignard C, Feingold N, Feingold J, Mignard D, de Ubeda B, Collin H, Tome FM, Richard I, Beckmann J (1996) Juvenile limb–girdle muscular dystrophy Clinical, histopathological and genetic data from a small community living in the Reunion Island. Brain 119(Pt 1):295–308.  https://doi.org/10.1093/brain/119.1.295 CrossRefPubMedGoogle Scholar
  4. 4.
    Mercuri E, Lampe A, Allsop J, Knight R, Pane M, Kinali M, Bonnemann C, Flanigan K, Lapini I, Bushby K, Pepe G, Muntoni F (2005) Muscle MRI in Ullrich congenital muscular dystrophy and Bethlem myopathy. Neuromuscul Disord 15(4):303–310.  https://doi.org/10.1016/j.nmd.2005.01.004 CrossRefPubMedGoogle Scholar
  5. 5.
    Urtasun M, Sáenz A, Roudaut C, Poza JJ, Urtizberea JA, Cobo AM, Richard I, García Bragado F, Leturcq F, Kaplan JC, Martí Massó JF, Beckmann JS, López de Munain A (1998) Limb–girdle muscular dystrophy in Guipúzcoa (Basque Country, Spain). Brain 121(Pt 9):1735–1747.  https://doi.org/10.1093/brain/121.9.1735 CrossRefPubMedGoogle Scholar
  6. 6.
    Gallardo E, Saenz A, Illa I (2011) Limb–girdle muscular dystrophy 2A. Handb Clin Neurol 101:97–110.  https://doi.org/10.1016/B978-0-08-045031-5.00006-2 CrossRefPubMedGoogle Scholar
  7. 7.
    Richard I, Roudaut C, Saenz A, Pogue R, Grimbergen JE, Anderson LV, Beley C, Cobo AM, de Diego C, Eymard B, Gallano P, Ginjaar HB, Lasa A, Pollitt C, Topaloglu H, Urtizberea JA, de Visser M, van der Kooi A, Bushby K, Bakker E, Lopez de Munain A, Fardeau M, Beckmann JS (1999) Calpainopathy—a survey of mutations and polymorphisms. Am J Hum Genet 64(6):1524–1540.  https://doi.org/10.1086/302426 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    De Paula F, Vainzof M, Passos-Bueno MR, de Cássia M, Pavanello R, Matioli SR, Anderson L, Nigro V, Zatz M (2002) Clinical variability in calpainopathy: what makes the difference? Eur J Hum Genet 10(12):825–832.  https://doi.org/10.1038/sj.ejhg.5200888 CrossRefPubMedGoogle Scholar
  9. 9.
    Sáenz A, Leturcq F, Cobo AM, Poza JJ, Ferrer X, Otaegui D, Camaño P, Urtasun M, Vílchez J, Gutiérrez-Rivas E, Emparanza J, Merlini L, Paisán C, Goicoechea M, Blázquez L, Eymard B, Lochmuller H, Walter M, Bonnemann C, Figarella-Branger D, Kaplan JC, Urtizberea JA, Martí-Massó JF, López de Munain A (2005) LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene. Brain 128(Pt 4):732–742.  https://doi.org/10.1093/brain/awh408 CrossRefPubMedGoogle Scholar
  10. 10.
    Krahn M, Bernard R, Pecheux C, el Hammouda H, Eymard B, Lopez de Munain A, Cobo AM, Romero N, Urtizberea A, Leturcq F, Levy N (2006) Calpain Study Group of the French LGMD Network Screening of the CAPN3 gene in patients with possible LGMD2A. Clin Genet 69(5):444–449.  https://doi.org/10.1111/j.1399-0004.2006.00603.x CrossRefPubMedGoogle Scholar
  11. 11.
    Nascimbeni AC, Fanin M, Tasca E, Angelini C (2010) Transcriptional and translational effects of intronic CAPN3 gene mutations. Hum Mutat 9:1658–1669.  https://doi.org/10.1002/humu.21320 CrossRefGoogle Scholar
  12. 12.
    Richard I, Roudaut C, Marchand S, Baghdiguian S, Herasse M, Stockholm D, Ono Y, Suel L, Bourg N, Sorimachi H, Lefranc G, Fardeau M, Sébille A, Beckmann JS (2000) Loss of calpain 3 proteolytic activity leads to muscular dystrophy and to apoptosis-associated IkappaBalpha/nuclear factor kappaB pathway perturbation in mice. J Cell Biol 151(7):1583–1590.  https://doi.org/10.1083/jcb.151.7.1583 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Richard I, Hogrel JY, Stockholm D, Payan CA, Fougerousse F; Calpainopathy Study Group, Eymard B, Mignard C, de Munain AL, Fardeau M, Urtizberea JA (2016) Natural history of LGMD2A for delineating outcome measures in clinical trials. Ann Clin Transl Neurol 3(4):248–265.  https://doi.org/10.1002/acn3.287 CrossRefGoogle Scholar
  14. 14.
    Vissing J, Barresi R, Witting N, Van Ghelue M, Gammelgaard L, Bindoff LA, Straub V, Lochmüller H, Hudson J, Wahl CM, Arnardottir S, Dahlbom K, Jonsrud C, Duno M (2016) A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy. Brain 139(Pt 8):2154–2163.  https://doi.org/10.1093/brain/aww133 CrossRefPubMedGoogle Scholar
  15. 15.
    Mercuri E, Pichiecchio A, Allsop J, Messina S, Pane M, Muntoni F (2007) Muscle MRI in inherited neuromuscular disorders: past, present, and future. J Magn Reson Imaging 25(2):433–440.  https://doi.org/10.1002/jmri.20804 CrossRefPubMedGoogle Scholar
  16. 16.
    Tasca G, Iannaccone E, Monforte M, Masciullo M, Bianco F, Laschena F, Ottaviani P, Pelliccioni M, Pane M, Mercuri E, Ricci E (2012) Muscle MRI in Becker muscular dystrophy. Neuromuscul Disord 1(22 Suppl 2):S100–S106.  https://doi.org/10.1016/j.nmd.2012.05.015 CrossRefGoogle Scholar
  17. 17.
    Quijano-Roy S, Avila-Smirnow D, Carlier RY, WB-MRI muscle study group (2012) Whole body muscle MRI protocol: pattern recognition in early onset NM disorders. Neuromuscul Disord 1(22 Suppl 2):S68–84.  https://doi.org/10.1016/j.nmd.2012.08.003 CrossRefGoogle Scholar
  18. 18.
    Barp A, Bello L, Caumo L, Campadello P, Semplicini C, Lazzarotto A, Sorarù G, Calore C, Rampado A, Motta R, Stramare R, Pegoraro E (2017) Muscle MRI and functional outcome measures in Becker muscular dystrophy. Sci Rep 7(1):16060.  https://doi.org/10.1038/s41598-017-16170-2 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tasca G, Monforte M, Díaz-Manera J, Brisca G, Semplicini C, D'Amico A, Fattori F, Pichiecchio A, Berardinelli A, Maggi L, Maccagnano E, Løkken N, Marini-Bettolo C, Munell F, Sanchez A, Alshaikh N, Voermans NC, Dastgir J, Vlodavets D, Haberlová J, Magnano G, Walter MC, Quijano-Roy S, Carlier RY, van Engelen BGM, Vissing J, Straub V, Bönnemann CG, Mercuri E, Muntoni F, Pegoraro E, Bertini E, Udd B, Ricci E, Bruno C (2018) MRI in sarcoglycanopathies: a large international cohort study. J Neurol Neurosurg Psychiatry 89(1):72–77.  https://doi.org/10.1136/jnnp-2017-316736 CrossRefPubMedGoogle Scholar
  20. 20.
    Feng X, Luo S, Li J, Yue D, Xi J, Zhu W, Gao X, Guan X, Lu J, Liang Z, Zhao C (2018) Fatty infiltration evaluation and selective pattern characterization of lower limbs in limb–girdle muscular dystrophy type 2A by muscle magnetic resonance imaging. Muscle Nerve 58(4):536–541.  https://doi.org/10.1002/mus.26169 CrossRefPubMedGoogle Scholar
  21. 21.
    Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C (2009) Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 37(9):e67.  https://doi.org/10.1093/nar/gkp215 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Carlier RY, Laforet P, Wary C, Mompoint D, Laloui K, Pellegrini N, Annane D, Carlier PG, Orlikowski D (2011) Whole-body muscle MRI in 20 patients suffering from late onset Pompe disease: Involvement patterns. Neuromuscul Disord 21(11):791–799.  https://doi.org/10.1016/j.nmd.2011.06.748 CrossRefPubMedGoogle Scholar
  23. 23.
    Pogoda TV, Krakhmaleva IN, Lipatova NA, Shakhovskaya NI, Shishkin SS, Limborska SA (2000) High incidence of 550delA mutation of CAPN3 in LGMD2 patients from Russia. Hum Mutat 15(3):295.  https://doi.org/10.1002/(SICI)1098-1004(200003)15:3%3c295:AID-HUMU15%3e3.0.CO;2-8 CrossRefPubMedGoogle Scholar
  24. 24.
    Milic A, Canki-Klain N (2005) Calpainopathy (LGMD2A) in Croatia: molecular and haplotype analysis. Croat Med J 46(4):657–663PubMedGoogle Scholar
  25. 25.
    Dorobek M, Ryniewicz B, Kabzińska D, Fidziańska A, Styczyńska M, Hausmanowa-Petrusewicz I (2015) The frequency of c.550delA mutation of the CANP3 gene in the Polish LGMD2A population. Genet Test Mol Biomark 19(11):637–640.  https://doi.org/10.1089/gtmb.2015.0131 CrossRefGoogle Scholar
  26. 26.
    Matsubara E, Tsuchiya A, Minami N, Nishino I, Pappolla MA, Shoji M, Abe K (2007) A unique case of limb–girdle muscular dystrophy type 2A carrying novel compound heterozygous mutations in the human CAPN3 gene. Eur J Neurol 14(7):819–822.  https://doi.org/10.1111/j.1468-1331.2007.01808.x CrossRefPubMedGoogle Scholar
  27. 27.
    Fanin M, Nascimbeni AC, Angelini C (2014) Gender difference in limb–girdle muscular dystrophy: a muscle fiber morphometric study in 101 patients. Clin Neuropathol 33(3):179–185.  https://doi.org/10.5414/NP300728 CrossRefPubMedGoogle Scholar
  28. 28.
    Fanin M, Nascimbeni AC, Fulizio L, Angelini C (2005) The frequency of limb girdle muscular dystrophy 2A in northeastern Italy. Neuromuscul Disord 15(3):218–224.  https://doi.org/10.1016/j.nmd.2004.11.003 CrossRefPubMedGoogle Scholar
  29. 29.
    Richard I, Brenguier L, Dinçer P, Roudaut C, Bady B, Burgunder JM, Chemaly R, Garcia CA, Halaby G, Jackson CE, Kurnit DM, Lefranc G, Legum C, Loiselet J, Merlini L, Nivelon-Chevallier A, Ollagnon-Roman E, Restagno G, Topaloglu H, Beckmann JS (1997) Multiple independent molecular etiology for limb–girdle muscular dystrophy type 2A patients from various geographical origins. Am J Hum Genet 60(5):1128–1138PubMedPubMedCentralGoogle Scholar
  30. 30.
    Dinçer P, Leturcq F, Richard I, Piccolo F, Yalnizoglu D, de Toma C, Akçören Z, Broux O, Deburgrave N, Brenguier L, Roudaut C, Urtizberea JA, Jung D, Tan E, Jeanpierre M, Campbell KP, Kaplan JC, Beckmann JS, Topaloglu H (1997) A biochemical, genetic, and clinical survey of autosomal recessive limb girdle muscular dystrophies in Turkey. Ann Neurol 42(2):222–229.  https://doi.org/10.1002/ana.410420214 CrossRefPubMedGoogle Scholar
  31. 31.
    Canki-Klain N, Milic A, Kovac B, Trlaja A, Grgicevic D, Zurak N, Fardeau M, Leturcq F, Kaplan JC, Urtizberea JA, Politano L, Piluso G, Feingold J (2004) Prevalence of the 550delA mutation in calpainopathy (LGMD 2A) in Croatia. Am J Med Genet A 125A(2):152–156.  https://doi.org/10.1002/ajmg.a.20408 CrossRefPubMedGoogle Scholar
  32. 32.
    Gerevini S, Scarlato M, Maggi L, Cava M, Caliendo G, Pasanisi B, Falini A, Previtali SC, Morandi L (2016) Muscle MRI findings in facioscapulohumeral muscular dystrophy. Eur Radiol 26(3):693–705.  https://doi.org/10.1007/s00330-015-3890-1 CrossRefPubMedGoogle Scholar
  33. 33.
    Diaz-Manera J, Fernandez-Torron R, LLauger J, James MK, Mayhew A, Smith FE, Moore UR, Blamire AM, Carlier PG, Rufibach L, Mittal P, Eagle M, Jacobs M, Hodgson T, Wallace D, Ward L, Smith M, Stramare R, Rampado A, Sato N, Tamaru T, Harwick B, Rico Gala S, Turk S, Coppenrath EM, Foster G, Bendahan D, Le Fur Y, Fricke ST, Otero H, Foster SL, Peduto A, Sawyer AM, Hilsden H, Lochmuller H, Grieben U, Spuler S, Tesi Rocha C, Day JW, Jones KJ, Bharucha-Goebel DX, Salort-Campana E, Harms M, Pestronk A, Krause S, Schreiber-Katz O, Walter MC, Paradas C, Hogrel JY, Stojkovic T, Takeda S, Mori-Yoshimura M, Bravver E, Sparks S, Bello L, Semplicini C, Pegoraro E, Mendell JR, Bushby K, Straub V; Jain COS Consortium (2018) Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials. J Neurol Neurosurg Psychiatry 89(10):1071–1081.  https://doi.org/10.1136/jnnp-2017-317488 CrossRefPubMedGoogle Scholar
  34. 34.
    Willis TA, Hollingsworth KG, Coombs A, Sveen ML, Andersen S, Stojkovic T, Eagle M, Mayhew A, de Sousa PL, Dewar L, Morrow JM, Sinclair CD, Thornton JS, Bushby K, Lochmuller H, Hanna MG, Hogrel JY, Carlier PG, Vissing J, Straub V (2014) Quantitative magnetic resonance imaging in limb–girdle muscular dystrophy 2I: a multinational cross-sectional study. PLoS ONE 9(2):e90377.  https://doi.org/10.1371/journal.pone.0090377 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Regnery C, Kornblum C, Hanisch F, Vielhaber S, Strigl-Pill N, Grunert B, Müller-Felber W, Glocker FX, Spranger M, Deschauer M, Mengel E, Schoser B (2012) 36 months observational clinical study of 38 adult Pompe disease patients under alglucosidase alfa enzyme replacement therapy. J Inherit Metab Dis 35(5):837–845.  https://doi.org/10.1007/s10545-012-9451-8 CrossRefPubMedGoogle Scholar
  36. 36.
    Carlier PG, Marty B, Scheidegger O, Loureiro de Sousa P, Baudin PY, Snezhko E, Vlodavets D (2016) Skeletal muscle quantitative nuclear magnetic resonance imaging and spectroscopy as an outcome measure for clinical trials. J Neuromuscul Dis 3(1):1–28.  https://doi.org/10.3233/JND-160145 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Andrea Barp
    • 1
    • 6
    Email author
  • Pascal Laforet
    • 2
  • Luca Bello
    • 1
  • Giorgio Tasca
    • 3
  • John Vissing
    • 4
  • Mauro Monforte
    • 3
  • Enzo Ricci
    • 3
  • Ariane Choumert
    • 5
  • Tanya Stojkovic
    • 6
  • Edoardo Malfatti
    • 2
  • Elena Pegoraro
    • 1
  • Claudio Semplicini
    • 1
  • Roberto Stramare
    • 7
  • Olivier Scheidegger
    • 8
  • Jana Haberlova
    • 9
  • Volker Straub
    • 10
  • Chiara Marini-Bettolo
    • 10
  • Nicoline Løkken
    • 4
  • Jordi Diaz-Manera
    • 11
  • Jon A. Urtizberea
    • 12
  • Eugenio Mercuri
    • 13
  • Martin Kynčl
    • 14
  • Maggie C. Walter
    • 15
  • Robert Y. Carlier
    • 16
  1. 1.Department of Neurosciences DNS, Neuromuscular CentreUniversity of PadovaPaduaItaly
  2. 2.Neurology Department, Raymond-Poincaré Teaching HospitalCentre de Référence Des Maladies Neuromusculaires Nord/Est/Ile-de-France, AP-HPGarchesFrance
  3. 3.Unità Operativa Complessa Di Neurologia, Dipartimento Di Scienze Dell’Invecchiamento, Neurologiche, Ortopediche E Della Testa-Colo, Fondazione Policlinico Universitario A. Gemelli IRCCSRomeItaly
  4. 4.Copenhagen Neuromuscular Center, Rigshospitalet, University of CopenhagenCopenhaghenDenmark
  5. 5.Centre de Référence des Maladies Neuromusculaires PACA-Réunion-Rhônes-Alpes CHULa RéunionFrance
  6. 6.APHP, G-H Pitié-Salpêtrière, Institut de Myologie, Centre de Référence des Maladies Neuromusculaires Paris EstParisFrance
  7. 7.Department of Medicine (DIMED), Institute of RadiologyUniversity of PadovaPaduaItaly
  8. 8.Department of Neurology, Institute for Diagnostic and Interventional Neuroradiology, Inselspital, Bern University HospitalUniversity of BernBernSwitzerland
  9. 9.Department of Paediatric NeurologyCharles University in PraguePragueCzech Republic
  10. 10.John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic MedicineNewcastle Upon TyneUK
  11. 11.Unitat de Malalties Neuromusculars, Servei de Neurologia, Hospital de La Santa Creu I Sant PauBarcelonaSpain
  12. 12.Centre de Compétence Neuromusculaire Filnemus/APHP, Hôpital MarinHendayeFrance
  13. 13.Pediatric Neurology and Nemo Clinical CentreUniversità Cattolica Sacro Cuore, Fondazione Policlinico Universitario, A. GemelliRomeItaly
  14. 14.Radiology DepartmentFaculty Hospital MotolPragueCzech Republic
  15. 15.Friedrich-Baur InstitutLudwig-Maximilians University MunichMunichGermany
  16. 16.APHP, Department of RadiologyGarches Neuromuscular Center (GNMH), Raymond Poincaré University Hospital (UVSQ, U 1179)GarchesFrance

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