X-linked myotubular myopathy: an untreated treatable disease.

X-linked myotubular myopathy; adeno-associated viral vectors; centronuclear myopathy; congenital myopathy; gene therapy; myotubularin; neuromuscular junction; Humans; Animals; Phenotype; Disease Models, Animal; Myopathies, Structural, Congenital/genetics; Myopathies, Structural, Congenital/therapy; Myopathies, Structural, Congenital/physiopathology; Genetic Therapy; Pharmacology; Drug Discovery; Clinical Biochemistry

Abstract :

[en] [en] INTRODUCTION: X-linked myotubular myopathy (XLMTM) is a life-threatening congenital disorder characterized by severe respiratory and motor impairment. This disease presents significant therapeutic challenges, with various strategies being explored to address its underlying pathology. Among these approaches, gene replacement therapy has demonstrated substantial functional improvements in clinical trials. However, safety issues emerged across different therapeutic approaches, highlighting the need for further research. AREAS COVERED: This review provides a comprehensive analysis of the data gathered from natural history studies, preclinical models and clinical trials, with a particular focus on gene replacement therapy for XLMTM. The different therapeutic strategies are addressed, including their outcomes and associated safety concerns. EXPERT OPINION: Despite the encouraging potential of gene therapy for XLMTM, the occurrence of safety challenges emphasizes the urgent need for a more comprehensive understanding of the disease's complex phenotype. Enhancing preclinical models to more accurately mimic the full spectrum of disease manifestations will be crucial for optimizing therapeutic strategies and reducing risks in future clinical applications.

Disciplines :

Pediatrics

Author, co-author :

Martin, Cristina; Department of Paediatrics, MDUK Oxford Neuromuscular Centre & NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK

Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques ; Department of Paediatrics, MDUK Oxford Neuromuscular Centre & NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK

Language :

English

Title :

X-linked myotubular myopathy: an untreated treatable disease.

Publication date :

April 2025

Journal title :

Expert Opinion on Biological Therapy

ISSN :

1471-2598

eISSN :

1744-7682

Publisher :

Taylor and Francis Ltd., England

Volume :

Issue :

Pages :

379 - 394

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://www.tandfonline.com/doi/pdf/10.1080/14712598.2025.2473430

Available on ORBi :

since 11 April 2025

Statistics

Number of views

72 (1 by ULiège)

Number of downloads

84 (0 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

OpenAlex citations

Bibliography

Laporte J, Blondeau F, Buj-Bello A, et al. The myotubularin family: from genetic disease to phosphoinositide metabolism. Trends Genet. 2001;17(4):221–228. doi: 10.1016/s0168-9525(01)02245-4
Vandersmissen I, Biancalana V, Servais L, et al. An integrated modelling methodology for estimating the prevalence of centronuclear myopathy. Neuromuscul Disord. 2018;28(9):766–777. doi: 10.1016/j.nmd.2018.06.012
Amburgey K, Tsuchiya E, de Chastonay S, et al. A natural history study of X-linked myotubular myopathy. Neurology. 2017;89(13):1355–1364. doi: 10.1212/WNL.0000000000004415
Funayama K, Shimizu H, Tanaka H, et al. An autopsy case of peliosis hepatis with X-linked myotubular myopathy. Leg Med (Tokyo). 2019;38:77–82. doi: 10.1016/j.legalmed.2019.04.005
Graham RJ, Muntoni F, Hughes I, et al. Mortality and respiratory support in X-linked myotubular myopathy: a RECENSUS retrospective analysis. Arch Dis Child. 2020;105(4):332–338. doi: 10.1136/archdischild-2019-317910
Herman GE, Kopacz K, Zhao W, et al. Characterization of mutations in fifty North American patients with X-linked myotubular myopathy. Hum Mutat. 2002;19(2):114–121. doi: 10.1002/humu.10033
McEntagart M, Parsons G, Buj-Bello A, et al. Genotype-phenotype correlations in X-linked myotubular myopathy. Neuromuscul Disord. 2002;12(10):939–946. doi: 10.1016/s0960-8966(02)00153-0
Dowling JJ, Lawlor MW, Das S, et al. X-Linked myotubular myopathy. GeneReviews. Seattle (WA): University of Washington; 2002Feb25.
Annoussamy M, Lilien C, Gidaro T, et al. X-linked myotubular myopathy: a prospective international natural history study. Neurology. 2019;92(16):e1852–e1867. doi: 10.1212/WNL.0000000000007319
D’Amico A, Longo A, Fattori F, et al. Hepatobiliary disease in XLMTM: a common comorbidity with potential impact on treatment strategies [published correction appears in orphanet J rare dis. 2022 Jan 17;17(1): 18. doi: 10.1186/s13023-021-02171-y]. Orphanet J Rare Dis. 2021Oct12;16(1):425. doi: 10.1186/s13023-021-02055-1
Gangfuss A, Schmitt D, Roos A, et al. Diagnosing X-linked myotubular myopathy - a German 20-year follow up experience. J Neuromuscul Dis. 2021;8(1):79–90. doi: 10.3233/JND-200539
Dowling JJ, Müller-Felber W, Smith BK, et al. INCEPTUS natural history, run-in study for gene replacement clinical trial in X-Linked myotubular myopathy. J Neuromuscul Dis. 2022;9(4):503–516. doi: 10.3233/JND-210781
Karolczak S, Deshwar AR, Aristegui E, et al. Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy. J Clin Invest. 2023Sep15;133(18):e166275. doi: 10.1172/JCI166275
Grogan PM, Tanner SM, Ørstavik KH, et al. Myopathy with skeletal asymmetry and hemidiaphragm elevation is caused by myotubularin mutations. Neurology. 2005;64(9):1638–1640. doi: 10.1212/01.WNL.0000160393.99621.D0
Drouet A, Ollagnon-Roman E, Streichenberger N, et al. Expression hémicorporelle d’une myopathie myotubulaire liée à l’X (XLMTM) chez deux des trois femmes conductrices d’une même famille sans cas masculin [Unilateral presentation of X-linked myotubular myopathy (XLMTM) in two out of three female carriers in a family with no affected male]. Rev Neurol (Paris). 2008;164(2):169–176. doi: 10.1016/j.neurol.2007.08.008
Biancalana V, Scheidecker S, Miguet M, et al. Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues. Acta Neuropathol. 2017;134(6):889–904. doi: 10.1007/s00401-017-1748-0
Cocanougher BT, Flynn L, Yun P, et al. Adult MTM1-related myopathy carriers: classification based on deep phenotyping. Neurology. 2019;93(16):e1535–e1542. doi: 10.1212/WNL.0000000000008316
Takeuchi Y, Masuda T, Kimura N, et al. X-linked myotubular myopathy manifesting carrier with central and peripheral nervous system involvement. Intern Med. [cited 2024 Apr16];63(24):3371–3375. doi: 10.2169/internalmedicine.3417-23
Herman GE, Finegold M, Zhao W, et al. Medical complications in long-term survivors with X-linked myotubular myopathy. J Pediatr. 1999;134(2):206–214. doi: 10.1016/s0022-3476(99)70417-8
Biancalana V, Caron O, Gallati S, et al. Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype. Hum Genet. 2003;112(2):135–142. doi: 10.1007/s00439-002-0869-1
Laporte J, Hu LJ, Kretz C, et al. A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet. 1996;13(2):175–182. doi: 10.1038/ng0696-175
Nandurkar HH, Layton M, Laporte J, et al. Identification of myotubularin as the lipid phosphatase catalytic subunit associated with the 3-phosphatase adapter protein, 3-PAP. Proc Natl Acad Sci U S A. 2003;100(15):8660–8665. doi: 10.1073/pnas.1033097100
Tronchère H, Laporte J, Pendaries C, et al. Production of phosphatidylinositol 5-phosphate by the phosphoinositide 3-phosphatase myotubularin in mammalian cells. J Biol Chem. 2004;279(8):7304–7312. doi: 10.1074/jbc.M311071200
Buj-Bello A, Fougerousse F, Schwab Y, et al. Aav-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis. Hum Mol Genet. 2008;17(14):2132–2143. doi: 10.1093/hmg/ddn112
Hnia K, Tronchère H, Tomczak KK, et al. Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeletal muscle. J Clin Invest. 2011;121(1):70–85. doi: 10.1172/JCI44021
Ribeiro I, Yuan L, Tanentzapf G, et al. Phosphoinositide regulation of integrin trafficking required for muscle attachment and maintenance. PloS Genet. 2011 [cited 2011 Feb10];7(2):e1001295. doi: 10.1371/journal.pgen.1001295
Gavriilidis C, Laredj L, Solinhac R, et al. The MTM1-UBQLN2-HSP complex mediates degradation of misfolded intermediate filaments in skeletal muscle. Nat Cell Biol. 2018;20(2):198–210. doi: 10.1038/s41556-017-0024-9
Al-Qusairi L, Weiss N, Toussaint A, et al. T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase. Proc Natl Acad Sci U S A. 2009;106(44):18763–18768. doi: 10.1073/pnas.0900705106
Dowling JJ, Vreede AP, Low SE, et al. Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy. PloS Genet. 2009;5(2):e1000372. doi: 10.1371/journal.pgen.1000372
Toussaint A, Cowling BS, Hnia K, et al. Defects in amphiphysin 2 (BIN1) and triads in several forms of centronuclear myopathies. Acta Neuropathol. 2011;121(2):253–266. doi: 10.1007/s00401-010-0754-2
Dowling JJ, Joubert R, Low SE, et al. Myotubular myopathy and the neuromuscular junction: a novel therapeutic approach from mouse models. Dis Model Mech. 2012;5(6):852–859. doi: 10.1242/dmm.009746
Jungbluth H, Treves S, Zorzato F, et al. Congenital myopathies: disorders of excitation-contraction coupling and muscle contraction. Nat Rev Neurol. 2018;14(3):151–167. doi: 10.1038/nrneurol.2017.191
Razidlo GL, Katafiasz D, Taylor GS., Myotubularin regulates Akt-dependent survival signaling via phosphatidylinositol 3-phosphate. J Biol Chem. 2011;286(22):20005–20019. doi: 10.1074/jbc.M110.197749
Al-Qusairi L, Prokic I, Amoasii L, et al. Lack of myotubularin (MTM1) leads to muscle hypotrophy through unbalanced regulation of the autophagy and ubiquitin-proteasome pathways. FASEB J. 2013;27(8):3384–3394. doi: 10.1096/fj.12-220947
Joubert R, Vignaud A, Le M, et al. Site-specific Mtm1 mutagenesis by an AAV-Cre vector reveals that myotubularin is essential in adult muscle. Hum Mol Genet. 2013;22(9):1856–1866. doi: 10.1093/hmg/ddt038
Fetalvero KM, Yu Y, Goetschkes M, et al. Defective autophagy and mTORC1 signaling in myotubularin null mice. Mol Cell Biol. 2013;33(1):98–110. doi: 10.1128/MCB.01075-12
Robb SA, Sewry CA, Dowling JJ, et al. Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies. Neuromuscul Disord. 2011;21(6):379–386. doi: 10.1016/j.nmd.2011.02.012
Beeson D. Congenital myasthenic syndromes: recent advances. Curr Opin Neurol. 2016;29(5):565–571. doi: 10.1097/WCO.0000000000000370
Vanhaesebrouck AE, Webster R, Maxwell S, et al. β2-adrenergic receptor agonists ameliorate the adverse effect of long-term pyridostigmine on neuromuscular junction structure. Brain. 2019;142(12):3713–3727. doi: 10.1093/brain/awz322
Nigro E, Amburgey K, Djordjevic D, et al. P66 salbutamol therapy in a neuromuscular cohort. Neuromuscul Disord. 2023;33(1):S75. doi: 10.1016/j.nmd.2023.07.047
Shieh PB, Kuntz N, Smith B, et al. ASPIRO gene therapy trial in X-Linked myotubular myopathy (XLMTM): update on preliminary safety and efficacy findings up to 72 weeks post-treatment (1053). Neurology. 2020;94(15):1053. doi: 10.1212/WNL.94.15_supplement.1053
Shieh PB, Kuntz NL, Dowling JJ, et al. Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial. Lancet Neurol. 2023;22(12):1125–1139. doi: 10.1016/S1474-4422(23)00313-7
myotubulartrust.org [Internet] Dynacure; [cited 2024 Oct23]. Available from:https://myotubulartrust.org/wp-content/uploads/PatientCommunicationsFinalJuly.pdf
clinicaltrials.gov [Internet]. [cited 2024 Oct23]. Available from:https://clinicaltrials.gov/study/NCT04915846?cond=NCT04915846&rank=1
Beggs AH, Byrne BJ, De Chastonay S, et al. A multicenter, retrospective medical record review of X-linked myotubular myopathy: the recensus study. Muscle Nerve. 2018;57(4):550–560. doi: 10.1002/mus.26018
Buj-Bello A, Laugel V, Messaddeq N, et al. The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice. Proc Natl Acad Sci U S A. 2002;99(23):15060–15065. doi: 10.1073/pnas.212498399
Pierson CR, Dulin-Smith AN, Durban AN, et al. Modeling the human MTM1 p.R69C mutation in murine Mtm1 results in exon 4 skipping and a less severe myotubular myopathy phenotype. Hum Mol Genet. 2012;21(4):811–825. doi: 10.1093/hmg/ddr512
Chen X, Gao YQ, Zheng YY, et al. The intragenic microRNA miR199A1 in the dynamin 2 gene contributes to the pathology of X-linked centronuclear myopathy. J Biol Chem. 2020;295(26):8656–8667. doi: 10.1074/jbc.RA119.010839
Gupta VA, Hnia K, Smith LL, et al. Loss of catalytically inactive lipid phosphatase myotubularin-related protein 12 impairs myotubularin stability and promotes centronuclear myopathy in zebrafish. PloS Genet. 2013;9(6):e1003583. doi: 10.1371/journal.pgen.1003583
Dowling JJ, Low SE, Busta AS, et al. Zebrafish MTMR14 is required for excitation-contraction coupling, developmental motor function and the regulation of autophagy. Hum Mol Genet. 2010;19(13):2668–2681. doi: 10.1093/hmg/ddq153
Sabha N, Volpatti JR, Gonorazky H, et al. PIK3C2B inhibition improves function and prolongs survival in myotubular myopathy animal models. J Clin Invest. 2016;126(9):3613–3625. doi: 10.1172/JCI86841
Beggs AH, Böhm J, Snead E, et al. MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers. Proc Natl Acad Sci U S A. 2010;107(33):14697–14702. doi: 10.1073/pnas.1003677107
Shelton GD, Rider BE, Child G, et al. X-linked myotubular myopathy in Rottweiler dogs is caused by a missense mutation in exon 11 of the MTM1 gene. Skelet Muscle. 2015 [cited 2015 Jan27];5(1):1. doi: 10.1186/s13395-014-0025-3
Grange RW, Doering J, Mitchell E, et al. Muscle function in a canine model of X-linked myotubular myopathy. Muscle Nerve. 2012;46(4):588–591. doi: 10.1002/mus.23463
Goddard MA, Mack DL, Czerniecki SM, et al. Muscle pathology, limb strength, walking gait, respiratory function and neurological impairment establish disease progression in the p.N155K canine model of X-linked myotubular myopathy [published correction appears in ann transl med. 2016 Jan;4(1): 23. doi: 10.3978/j.Issn.2305–5839.2015.12.44]. Ann Transl Med. 2015;3(18):262. doi: 10.3978/j.issn.2305-5839.2015.10.31
Lawlor MW, Beggs AH, Buj-Bello A, et al. Skeletal muscle pathology in X-Linked myotubular myopathy: review with cross-species comparisons [published correction appears in J neuropathol exp neurol. 2016 May;75(5): 479. doi: 10.1093/jnen/nlw029]. J Neuropathol Exp Neurol. 2016;75(2):102–110. doi: 10.1093/jnen/nlv020
Laporte J, Biancalana V, Tanner SM, et al. MTM1 mutations in X-linked myotubular myopathy. Hum Mutat. 2000;15(5):393–409. doi: 10.1002/(SICI)1098-1004(200005)15:5<393:AID-HUMU1>3.0.CO;2-R
Bertini E, Biancalana V, Bolino A, et al. 118th ENMC International workshop on advances in Myotubular myopathy. 26–28 September 2003, Naarden, the Netherlands. (5th workshop of the International consortium on Myotubular myopathy). Neuromuscul Disord. 2004;14(6):387–396. doi: 10.1016/j.nmd.2004.04.002
Tsai TC, Horinouchi H, Noguchi S, et al. Characterization of MTM1 mutations in 31 Japanese families with myotubular myopathy, including a patient carrying 240 kb deletion in Xq28 without male hypogenitalism. Neuromuscul Disord. 2005;15(3):245–252. doi: 10.1016/j.nmd.2004.12.005
Childers MK, Joubert R, Poulard K, et al. Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy. Sci Transl Med. 2014;6(220):220ra10. doi: 10.1126/scitranslmed.3007523
Mack DL, Poulard K, Goddard MA, et al. Systemic AAV8-mediated gene therapy drives whole-body correction of myotubular myopathy in dogs. Mol Ther. 2017;25(4):839–854. doi: 10.1016/j.ymthe.2017.02.004
Dupont JB, Guo J, Renaud-Gabardos E, et al. AAV-Mediated gene transfer restores a normal muscle transcriptome in a canine Model of X-Linked myotubular myopathy. Mol Ther. 2020;28(2):382–393. doi: 10.1016/j.ymthe.2019.10.018
Ross JA, Tasfaout H, Levy Y, et al. rAAV-related therapy fully rescues myonuclear and myofilament function in X-linked myotubular myopathy. Acta Neuropathol Commun. 2020 [cited 2020 Oct19];8(1):167. doi: 10.1186/s40478-020-01048-8
Lawlor MW, Armstrong D, Viola MG, et al. Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy. Hum Mol Genet. 2013;22(8):1525–1538. doi: 10.1093/hmg/ddt003
Zou J, Zhang C, Marjanovic J, et al. Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8. Proc Natl Acad Sci U S A. 2012;109(24):9539–9544. doi: 10.1073/pnas.1207021109
Quattrone A, Gambardella A, Bono F, et al. Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths: clinical, electrophysiologic, and genetic aspects of a large family. Neurology. 1996;46(5):1318–1318. doi: 10.1212/wnl.46.5.1318
Szigeti K, Lupski JR. Charcot-Marie-Tooth disease. Eur J Hum Genet. 2009;17(6):703–710. doi: 10.1038/ejhg.2009.31
Laporte J, Liaubet L, Blondeau F, et al. Functional redundancy in the myotubularin family. Biochem Biophys Res Commun. 2002;291(2):305–312. doi: 10.1006/bbrc.2002.6445
Kim SA, Taylor GS, Torgersen KM, et al. Myotubularin and MTMR2, phosphatidylinositol 3-phosphatases mutated in myotubular myopathy and type 4B Charcot-Marie-Tooth disease. J Biol Chem. 2002;277(6):4526–4531. doi: 10.1074/jbc.M111087200
Raess MA, Cowling BS, Bertazzi DL, et al. Expression of the neuropathy-associated MTMR2 gene rescues MTM1-associated myopathy. Hum Mol Genet. 2017;26(19):3736–3748. doi: 10.1093/hmg/ddx258
Danièle N, Moal C, Julien L, et al. Intravenous administration of a MTMR2-encoding AAV vector ameliorates the phenotype of myotubular myopathy in mice. J Neuropathol Exp Neurol. 2018;77(4):282–295. doi: 10.1093/jnen/nly002
Bitoun M, Durieux AC, Prudhon B, et al. Dynamin 2 mutations associated with human diseases impair clathrin-mediated receptor endocytosis. Hum Mutat. 2009;30(10):1419–1427. doi: 10.1002/humu.21086
Mooren OL, Kotova TI, Moore AJ, et al. Dynamin2 GTPase and cortactin remodel actin filaments. J Biol Chem. 2009;284(36):23995–24005. doi: 10.1074/jbc.M109.024398
Søreng K, Munson MJ, Lamb CA, et al. SNX18 regulates ATG9A trafficking from recycling endosomes by recruiting dynamin-2. EMBO Rep. 2018;19(4):e44837. doi: 10.15252/embr.201744837
Puri C, Manni MM, Vicinanza M, et al. A DNM2 centronuclear myopathy mutation reveals a link between recycling endosome scission and autophagy. Dev Cell. 2020;53(2):154–168.e6. doi: 10.1016/j.devcel.2020.03.018
Bitoun M, Maugenre S, Jeannet PY, et al. Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet. 2005;37(11):1207–1209. doi: 10.1038/ng1657
Cowling BS, Chevremont T, Prokic I, et al. Reducing dynamin 2 expression rescues X-linked centronuclear myopathy. J Clin Invest. 2014;124(3):1350–1363. doi: 10.1172/JCI71206
Giraud Q, Spiegelhalter C, Messaddeq N, et al. MTM1 overexpression prevents and reverts BIN1-related centronuclear myopathy. Brain. 2023;146(10):4158–4173. doi: 10.1093/brain/awad251
McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new tgf-beta superfamily member. Nature. 1997;387(6628):83–90. doi: 10.1038/387083a0
Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci U S A. 2001;98(16):9306–9311. doi: 10.1073/pnas.151270098
Mariot V, Joubert R, Hourdé C, et al. Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches. Nat Commun. 2017 [cited 2017 Nov30];8(1):1859. doi: 10.1038/s41467-017-01486-4
Koch C, Buono S, Menuet A, et al. Myostatin: a circulating Biomarker correlating with disease in myotubular myopathy mice and patients. Mol ther methods Clin Dev. 2020 [cited 2020 May4];17:1178–1189. doi: 10.1016/j.omtm.2020.04.022
Bom A, Hope F, Rutherford S, et al. Preclinical pharmacology of sugammadex. J Crit Care. 2009;24(1):29–35. doi: 10.1016/j.jcrc.2008.10.010
Caldwell JE. Clinical limitations of acetylcholinesterase antagonists. J Crit Care. 2009;24(1):21–28. doi: 10.1016/j.jcrc.2008.08.003
Lorenzoni PJ, Scola RH, Kay CS, et al. Salbutamol therapy in congenital myasthenic syndrome due to DOK7 mutation. J Neurol Sci. 2013;331(1–2):155–157. doi: 10.1016/j.jns.2013.05.017
Webster RG, Vanhaesebrouck AE, Maxwell SE, et al. Effect of salbutamol on neuromuscular junction function and structure in a mouse model of DOK7 congenital myasthenia. Hum Mol Genet. 2020;29(14):2325–2336. doi: 10.1093/hmg/ddaa116
McMacken G, Whittaker RG, Wake R, et al. Neuromuscular junction involvement in inherited motor neuropathies: genetic heterogeneity and effect of oral salbutamol treatment. J Neurol. 2023;270(6):3112–3119. doi: 10.1007/s00415-023-11643-z
Rossi L, Mota BI, Valadão PAC, et al. Influence of β2-adrenergic selective agonist formoterol on the motor unit of a mouse model of a congenital myasthenic syndrome with complete VAChT deletion. Neuropharmacology. 2024;260:110116. doi: 10.1016/j.neuropharm.2024.110116
Jean S, Kiger AA. Classes of phosphoinositide 3-kinases at a glance. J Cell Sci. 2014;127(5):923–928. doi: 10.1242/jcs.093773
Zoncu R, Perera RM, Balkin DM, et al. A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes. Cell. 2009;136(6):1110–1121. doi: 10.1016/j.cell.2009.01.032
Marat AL, Wallroth A, Lo WT, et al. mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate. Science. 2017;356(6341):968–972. doi: 10.1126/science.aaf8310
Kutchukian C, Szentesi P, Allard B, et al. Ca2±induced sarcoplasmic reticulum Ca2+ release in myotubularin-deficient muscle fibers. Cell Calcium. 2019;80:91–100. doi: 10.1016/j.ceca.2019.04.004
Yang XJ, Seto E. HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene. 2007;26(37):5310–5318. doi: 10.1038/sj.onc.1210599
Shahbazian MD, Grunstein M. Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem. 2007;76(1):75–100. doi: 10.1146/annurev.biochem.76.052705.162114
Bachmann C, Jungbluth H, Muntoni F, et al. Cellular, biochemical and molecular changes in muscles from patients with X-linked myotubular myopathy due to MTM1 mutations. Hum Mol Genet. 2017;26(2):320–332. doi: 10.1093/hmg/ddw388
Lee E, Marcucci M, Daniell L, et al. Amphiphysin 2 (Bin1) and T-tubule biogenesis in muscle. Science. 2002;297(5584):1193–1196. doi: 10.1126/science.1071362
Peter BJ, Kent HM, Mills IG, et al. BAR domains as sensors of membrane curvature: the amphiphysin BAR structure. Science. 2004;303(5657):495–499. doi: 10.1126/science.1092586
Daumke O, Roux A, Haucke V. BAR domain scaffolds in dynamin-mediated membrane fission. Cell. 2014;156(5):882–892. doi: 10.1016/j.cell.2014.02.017
D’Alessandro M, Hnia K, Gache V, et al. Amphiphysin 2 orchestrates nucleus positioning and shape by linking the nuclear envelope to the actin and Microtubule Cytoskeleton. Dev Cell. 2015;35(2):186–198. doi: 10.1016/j.devcel.2015.09.018
Nicot AS, Toussaint A, Tosch V, et al. Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. Nat Genet. 2007;39(9):1134–1139. doi: 10.1038/ng2086
Royer B, Hnia K, Gavriilidis C, et al. The myotubularin–amphiphysin 2 complex in membrane tubulation and centronuclear myopathies. EMBO Rep. 2013;14(10):907–915. doi: 10.1038/embor.2013.119
Perdreau-Dahl H, Lipsett DB, Frisk M, et al. BIN1, Myotubularin, and Dynamin-2 coordinate T-Tubule growth in Cardiomyocytes. Circ Res. 2023;132(11):e188–e205. doi: 10.1161/CIRCRESAHA.122.321732
Lionello VM, Nicot AS, Sartori M, et al. Amphiphysin 2 modulation rescues myotubular myopathy and prevents focal adhesion defects in mice. Sci Transl Med. 2019;11(484):eaav1866. doi: 10.1126/scitranslmed.aav1866
Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease [published correction appears in cell 2017 Apr 6;169(2): 361–371. doi: 10.1016/j.Cell.2017.03.035]. Cell. 2017;168(6):960–976. doi: 10.1016/j.cell.2017.02.004
Elverman M, Goddard MA, Mack D, et al. Long-term effects of systemic gene therapy in a canine model of myotubular myopathy. Muscle Nerve. 2017;56(5):943–953. doi: 10.1002/mus.25658
Andreoletti G, Romano O, Chou HJ, et al. High-throughput transcriptome analyses from ASPIRO, a phase 1/2/3 study of gene replacement therapy for X-linked myotubular myopathy. Am J Hum Genet. 2023;110(10):1648–1660. doi: 10.1016/j.ajhg.2023.08.008
Lawlor MW, Schoser B, Margeta M, et al. Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial. EBioMedicine. 2024;99:104894. doi: 10.1016/j.ebiom.2023.104894
George LA, Sullivan SK, Giermasz A, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017;377(23):2215–2227. doi: 10.1056/NEJMoa1708538
Miesbach W, Meijer K, Coppens M, et al. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood. 2018;131(9):1022–1031. doi: 10.1182/blood-2017-09-804419
Chand D, Mohr F, McMillan H, et al. Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J Hepatol. 2021;74(3):560–566. doi: 10.1016/j.jhep.2020.11.001
George LA, Monahan PE, Eyster ME, et al. Multiyear factor VIII expression after AAV gene transfer for hemophilia a. N Engl J Med. 2021;385(21):1961–1973. doi: 10.1056/NEJMoa2104205
Konkle BA, Walsh CE, Escobar MA, et al. BAX 335 hemophilia B gene therapy clinical trial results: potential impact of CpG sequences on gene expression. Blood. 2021;137(6):763–774. doi: 10.1182/blood.2019004625
Giermasz A, Visweshwar N, Harrington TJ, et al. Updated results of the Alta study, a phase 1/2 study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) gene therapy in adults with severe hemophilia Α. Blood. 2022;140(1):7776–7777. doi: 10.1182/blood-2022-159421
Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxaparvovec gene therapy for hemophilia a. N Engl J Med. 2022;386(11):1013–1025. doi: 10.1056/NEJMoa2113708
Xue F, Li H, Wu X, et al. Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial. Lancet Haematol. 2022;9(7):e504–e513. doi: 10.1016/S2352-3026(22)00113-2
Nathwani AC, Reiss U, Tuddenham E, et al. Adeno-associated mediated gene transfer for hemophilia B: 8 year follow up and impact of removing “empty viral particles” on safety and efficacy of gene transfer. Blood. 2018;132(1):491. doi: 10.1182/blood-2018-99-118334
Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear follow-up of AAV5-hFVIII-sq gene therapy for hemophilia a. N Engl J Med. 2020;382(1):29–40. doi: 10.1056/NEJMoa1908490
Fong S, Yates B, Sihn CR, et al. Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia a. Nat Med. 2022;28(4):789–797. doi: 10.1038/s41591-022-01751-0
George LA, Ragni MV, Rasko JEJ, et al. Long-term follow-up of the first in human intravascular delivery of AAV for gene transfer: AAV2-hFIX16 for severe hemophilia B. Mol Ther. 2020;28(9):2073–2082. doi: 10.1016/j.ymthe.2020.06.001
Friese J, Geitmann S, Holzwarth D, et al. Safety monitoring of gene therapy for spinal muscular atrophy with onasemnogene abeparvovec -A single centre experience. J Neuromuscul Dis. 2021;8(2):209–216. doi: 10.3233/JND-200593
Day JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021;20(4):284–293. doi: 10.1016/S1474-4422(21)00001-6
Horton RH, Saade D, Markati T, et al. A systematic review of adeno-associated virus gene therapies in neurology: the need for consistent safety monitoring of a promising treatment. J Neurol Neurosurg Psychiatry. 2022;93(12):1276–1288. doi: 10.1136/jnnp-2022-329431
Guillou J, de Pellegars A, Porcheret F, et al. Fatal thrombotic microangiopathy case following adeno-associated viral SMN gene therapy. Blood Adv. 2022;6(14):4266–4270. doi: 10.1182/bloodadvances.2021006419
Deng J, Zhang J, Shi K, et al. Drug development progress in Duchenne muscular dystrophy. Front Pharmacol. 2022Jul22;13:950651. doi: 10.3389/fphar.2022.950651
Lek A, Wong B, Keeler A, et al. Death after high-dose rAAV9 gene therapy in a patient with Duchenne’s muscular dystrophy. N Engl J Med. 2023;389(13):1203–1210. doi: 10.1056/NEJMoa2307798
Neese JM, Yum S, Matesanz S, et al. Intracranial hemorrhage secondary to vitamin K deficiency in X-linked myotubular myopathy. Neuromuscul Disord. 2021;31(7):651–655. doi: 10.1016/j.nmd.2021.04.009
Molera C, Sarishvili T, Nascimento A, et al. Intrahepatic Cholestasis is a clinically significant feature associated with natural history of X-Linked myotubular myopathy (XLMTM): a case series and biopsy report. J Neuromuscul Dis. 2022;9(1):73–82. doi: 10.3233/JND-210712
Imamura M, Mochizuki Y, Engvall E, et al. Epsilon-sarcoglycan compensates for lack of alpha-sarcoglycan in a mouse model of limb-girdle muscular dystrophy. Hum Mol Genet. 2005;14(6):775–783. doi: 10.1093/hmg/ddi072
Guiraud S, Aartsma-Rus A, Vieira NM, et al. The pathogenesis and therapy of muscular dystrophies. Annu Rev Genom Hum Genet. 2015;16(1):281–308. doi: 10.1146/annurev-genom-090314-025003
Ricotti V, Spinty S, Roper H, et al. Safety, tolerability, and pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin modulator, following single- and multiple-dose administration to pediatric patients with Duchenne muscular dystrophy. PLoS One. 2016Apr7;11(4):e0152840. doi: 10.1371/journal.pone.0152840
Trochet D, Prudhon B, Beuvin M, et al. Allele-specific silencing therapy for dynamin 2-related dominant centronuclear myopathy. EMBO Mol Med. 2018;10(2):239–253. doi: 10.15252/emmm.201707988
Tasfaout H, Buono S, Guo S, et al. Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice. Nat Commun. 2017Jun7;8:15661. doi: 10.1038/ncomms15661
clinicaltrials.gov [Internet]. [cited2024Oct23]. Available from:https://clinicaltrials.gov/study/NCT04743557?cond=NCT04743557&rank=1
Wagner KR, Fleckenstein JL, Amato AA, et al. A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol. 2008;63(5):561–571. doi: 10.1002/ana.21338
Wagner KR, Abdel-Hamid HZ, Mah JK, et al. Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy [published correction appears in Neuromuscul Disord. 2021 Feb;31(2): 167–168. doi: 10.1016/j.Nmd.2021.01.001]. Neuromuscul Disord. 2020;30(6):492–502. doi: 10.1016/j.nmd.2020.05.002
Sivakumar K, Cochrane TI, Sloth B, et al. Long-term safety and tolerability of bimagrumab (BYM338) in sporadic inclusion body myositis. Neurology. 2020;95(14):e1971–e1978. doi: 10.1212/WNL.0000000000010417
Statland JM, Campbell C, Desai U, et al. Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2022;66(1):50–62. doi: 10.1002/mus.27558
Muntoni F, Byrne BJ, McMillan HJ, et al. The clinical development of Taldefgrobep Alfa: an Anti-Myostatin Adnectin for the treatment of Duchenne muscular dystrophy. Neurol Ther. 2024;13(1):183–219. doi: 10.1007/s40120-023-00570-w
Crawford TO, Darras BT, Day JW, et al. Safety and efficacy of apitegromab in patients with spinal muscular atrophy types 2 and 3: the phase 2 TOPAZ study [published correction appears in neurology. 2024 Jul 9;103(1): e209519. doi: 10.1212/WNL.0000000000209519]. Neurology. 2024;102(5):e209151. doi: 10.1212/WNL.0000000000209151
Lawlor MW, Read BP, Edelstein R, et al. Inhibition of activin receptor type IIB increases strength and lifespan in myotubularin-deficient mice [published correction appears in Am J Pathol. 2011 Mar;178(3): 1406]. Am J Pathol. 2011;178(2):784–793. doi: 10.1016/j.ajpath.2010.10.035
Lawlor MW, Viola MG, Meng H, et al. Differential muscle hypertrophy is associated with satellite cell numbers and Akt pathway activation following activin type IIB receptor inhibition in Mtm1 p.R69C mice. Am J Pathol. 2014;184(6):1831–1842. doi: 10.1016/j.ajpath.2014.03.003
Messina S, Hartley L, Main M, et al. Pilot trial of salbutamol in central core and multi-minicore diseases. Neuropediatrics. 2004;35(5):262–266. doi: 10.1055/s-2004-821173
Sanders DB, Juel VC, Harati Y, et al. 3,4-diaminopyridine base effectively treats the weakness of Lambert-Eaton myasthenia. Muscle Nerve. 2018;57(4):561–568. doi: 10.1002/mus.26052
Bonanno S, Pasanisi MB, Frangiamore R, et al. Amifampridine phosphate in the treatment of muscle-specific kinase myasthenia gravis: a phase IIb, randomized, double-blind, placebo-controlled, double crossover study. SAGE Open Med. 2018Dec17;6:2050312118819013. doi: 10.1177/2050312118819013
Massana-Muñoz X, Goret M, Nattarayan V, et al. Inactivating the lipid kinase activity of PI3KC2β is sufficient to rescue myotubular myopathy in mice. JCI Insight. 2023May8;8(9):e151933. doi: 10.1172/jci.insight.151933
Goret M, Laporte J. Une cible thérapeutique contre la myopathie myotubulaire - La kinase PI3KC2β [The PI3KC2β kinase as a therapeutic target for myotubular myopathy]. Med Sci (Paris). 2024;40(2):133–136. doi: 10.1051/medsci/2023208
Kutchukian C, Lo Scrudato M, Tourneur Y, et al. Phosphatidylinositol 3-kinase inhibition restores Ca2+ release defects and prolongs survival in myotubularin-deficient mice. Proc Natl Acad Sci U S A. 2016;113(50):14432–14437. doi: 10.1073/pnas.1604099113
Volpatti JR, Ghahramani-Seno MM, Mansat M, et al. X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition. Acta Neuropathol. 2022;144(3):537–563. doi: 10.1007/s00401-022-02468-7
Mannick JB, Lamming DW. Targeting the biology of aging with mTOR inhibitors. Nat Aging. 2023;3(6):642–660. doi: 10.1038/s43587-023-00416-y
Gayi E, Neff LA, Massana Muñoz X, et al. Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy. Nat Commun. 2018 [cited 2018 Nov19];9(1):4848. doi: 10.1038/s41467-018-07058-4
Maani N, Sabha N, Rezai K, et al. Tamoxifen therapy in a murine model of myotubular myopathy. Nat Commun. 2018 [cited 2018 Nov19];9(1):4849. doi: 10.1038/s41467-018-07057-5
Etori S, Nakano R, Kamada H, et al. Tamoxifen-induced lung injury. Intern Med. 2017;56(21):2903–2906. doi: 10.2169/internalmedicine.8649-16
Lim HJ, Joo S, Oh SH, et al. Syngeneic myoblast transplantation improves muscle function in a murine Model of X-Linked myotubular myopathy. Cell Transplant. 2015;24(9):1887–1900. doi: 10.3727/096368914X683494
Mercuri E, Vilchez JJ, Boespflug-Tanguy O, et al. Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in lancet neurol. 2024 Jun;23(6): e10. doi: 10.1016/S1474–4422(24)00172–8] [published correction appears in lancet neurol. 2024 Aug;23(8): e12. doi: 10.1016/S1474–4422(24)00257–6]. Lancet Neurol. 2024;23(4):393–403. doi: 10.1016/S1474-4422(24)00036-X
Henzi BC, Schmidt S, Nagy S, et al. Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2023;22(10):890–899. doi: 10.1016/S1474-4422(23)00285-5
Skuk D, Tremblay JP. Intramuscular cell transplantation as a potential treatment of myopathies: clinical and preclinical relevant data. Expert Opin Biol Ther. 2011;11(3):359–374. doi: 10.1517/14712598.2011.548800
Servais L, Horton R, Saade D, et al. Management of safety issues arising following AAV gene therapy. 261st ENMC international Workshop; 2022 Jun 17–19, Hoofddorp, the Netherlands. Neuromuscul Disord. 2023;33(11):884–896. doi: 10.1016/j.nmd.2023.09.008
Wang CH, Dowling JJ, North K, et al. Consensus statement on standard of care for congenital myopathies. J Child Neurol. 2012;27(3):363–382. doi: 10.1177/0883073812436605
Sacks NC, Healey BE, Cyr PL, et al. Costs and health resource use in patients with X-linked myotubular myopathy: insights from US commercial claims. J Manag Care Spec Pharm. 2021;27(8):1019–1026. doi: 10.18553/jmcp.2021.20501
Kirk EP, Delatycki MB, Archibald AD, et al. Nationwide, couple-based genetic carrier screening. N Engl J Med. 2024;391(20):1877–1889. doi: 10.1056/NEJMoa2314768
Boemer F, Hovhannesyan K, Piazzon F, et al. Population-based, first-tier genomic newborn screening in the maternity ward. Nat Med. 2025Jan28. doi: 10.1038/s41591-024-03465-x
Dangouloff T, Thokala P, Stevenson MD, et al. Cost-effectiveness of spinal muscular atrophy newborn screening based on real-world data in Belgium. Neuromuscul Disord. 2024;34:61–67. doi: 10.1016/j.nmd.2023.11.013
Dangouloff T, Hiligsmann M, Deconinck N, et al. Financial cost and quality of life of patients with spinal muscular atrophy identified by symptoms or newborn screening. Develop Med Child Neuro. 2023;65(1):67–77. doi: 10.1111/dmcn.15286
Dangouloff T, Hovhannesyan K, Mashhadizadeh D, et al. Feasibility and acceptability of a newborn screening program using targeted next-generation sequencing in One Maternity Hospital in Southern Belgium. Children. 2024;11:926. doi: 10.3390/children11080926
Fouarge E, Monseur A, Boulanger B, et al. Hierarchical Bayesian modelling of disease progression to inform clinical trial design in centronuclear myopathy. Orphanet J Rare Dis. 2021;16(1):3. doi: 10.1186/s13023-020-01663-7