[en] BACKGROUND: X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death.
OBJECTIVE: We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study.
METHODS: Thirty-four participants < 4 years old with XLMTM and receiving ventilator support enrolled in INCEPTUS, a prospective, multicenter, non-interventional study. Disease-related adverse events, respiratory and motor function, feeding, secretions, and quality of life were assessed.
RESULTS: During median (range) follow-up of 13.0 (0.5, 32.9) months, there were 3 deaths (aspiration pneumonia; cardiopulmonary failure; hepatic hemorrhage with peliosis) and 61 serious disease-related events in 20 (59%) participants, mostly respiratory (52 events, 18 participants). Most participants (80%) required permanent invasive ventilation (>16 hours/day); 20% required non-invasive support (6-16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19-52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort.
CONCLUSIONS: INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.
Disciplines :
Neurology Pediatrics
Author, co-author :
Dowling, James J; Hospital for Sick Children, Toronto, Canada
Müller-Felber, Wolfgang; Dr. v. Haunersches Kinderspital, Klinikum der Universität München, Munich, Germany
Smith, Barbara K; University of Florida, Gainesville, FL, USA
Bönnemann, Carsten G; National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Kuntz, Nancy L; Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA
Muntoni, Francesco; National Institute for Health Research (NIHR) Great Ormond Street (GOS) Hospital Biomedical Research Centre, University College London Institute of Child Health, London, UK
Servais, Laurent ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pédiatrie ; I-Motion, Hôpital Armand Trousseau, Paris, France
Alfano, Lindsay N; Nationwide Children's Hospital, Columbus, OH, USA
Beggs, Alan H; Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Bilder, Deborah A; University of Utah, Salt Lake City, UT, USA
Blaschek, Astrid; Dr. v. Haunersches Kinderspital, Klinikum der Universität München, Munich, Germany
Duong, Tina; Stanford University, Palo Alto, CA, USA
Graham, Robert J; Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Jain, Minal; NIH Hatfield Clinical Research Center, Bethesda, MD, USA
Lawlor, Michael W; Medical College of Wisconsin, Milwaukee, WI, USA
Lee, Jun; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA
Coats, Julie; Astellas Gene Therapies (formerly Audentes Therapeutics), San Francisco, CA, USA
Lilien, Charlotte; I-Motion, Hôpital Armand Trousseau, Paris, France
Lowes, Linda P; Nationwide Children's Hospital, Columbus, OH, USA
MacBean, Victoria; Brunel University London, London, UK and King's College 32 London, London, UK
Neuhaus, Sarah; National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
Noursalehi, Mojtaba; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA
Pitts, Teresa; University of Louisville, Louisville, KY, USA
Finlay, Caroline; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA ; University of Louisville, Louisville, KY, USA
Christensen, Sarah; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA ; University of Louisville, Louisville, KY, USA
Rafferty, Gerrard; King's College London, London, UK
Seferian, Andreea M; I-Motion, Hôpital Armand Trousseau, Paris, France
Tsuchiya, Etsuko; Hospital for Sick Children, Toronto, Canada
James, Emma S; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA ; University of Louisville, Louisville, KY, USA
Miller, Weston; Astellas Gene Therapies (formerly Audentes Therapeutics), San Francisco, CA, USA
Sepulveda, Bryan; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA
Vila, Maria Candida; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA
Prasad, Suyash; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA
Rico, Salvador; Formerly of Astellas Gene Therapies (formerly Audentes Therapeutics) San Francisco, CA, USA
Shieh, Perry B; University of California, Los Angeles, CA, USA
The INCEPTUS and ASPIRO studies are sponsored by Astellas Gene Therapies. The authors thank the children and families with XLMTM who allowed their data to be collected for the INCEPTUS and ASPIRO studies, and the entire XLMTM patient community for their cooperation and participation in the development of the studies, including: the Joshua Frase Foundation, MTM-CNM Family Connection, The Myotubular Trust, Where There’s a Will There’s A Cure Foundation for Myotubular Myopathy, and ZNM – Zusammen Stark! Clinical site management JJD reports research grants from Astellas Gene Therapies,* serving on advisory boards for Dynacure, Kate Therapeutics, and RYR1 Foundation, and serving as an editor of the Journal of Neuromuscular Diseases. BKS reports consulting fees from Astellas Gene Therapies* and Sarepta. CGB is editor-in-chief of the Journal of Neuromuscular Diseases. DAB reports former participation on the Scientific and Clinical Advisory Board for Astellas Gene Therapies* and receiving travel expenses for attending advisory board meetings. AB reports grants or personal fees from Biogene and Sanofi Genzyme; advisory or other board participation at Dynacure and CMD Scientific and Medical. LL reports consulting fees paid to her institution for training of evaluators in the INCEPTUS study. MWL reports research grants paid to his institution from Astellas Gene Therapies,* Solid Biosciences, Kate Therapeutics, Taysha Therapeutics, and Prothelia and consulting fees from Astellas Gene Therapies,* Encoded Therapeutics, Modis Therapeutics, Lacerta Therapeutics, AGADA Biosciences, Dynacure, Affinia, and Biomarin. TD reports personal consulting fees from Astellas Gene Therapies,* Biogen, Avexis, Roche, Novartis, Dynacure, Sarepta, Pfizer, and Genentech. GR reports consulting fees from Astellas Gene Therapies* paid to his institution. VM reports consulting fees from Astellas Gene Therapies* paid both directly to her and her institution. PBS reports grants or personal fees from Astellas Gene Therapies,* Sarepta, AveXis, PTC Therapeutics, Pfizer, Biogen, Argenx, Catalyst, Roche, Ra Pharma, Gri-fols, Alexion, CSL Behring, Fulcrum Therapeutics, Fibrogen, Acceleron, Reveragen, Sanofi, and San-thera. AHB reports sponsored research support from NIH, MDA (USA), AFM Telethon, Alexion Pharmaceuticals Inc., Astellas Gene Therapies,* Dynacure SAS, and Pfizer Inc. He has consulted and received compensation or honoraria from Astellas Gene Therapies,* Biogen, F. Hoffman-La Roche AG, Kate Therapeutics, GLG Inc, Guidepoint Global, and Novartis, holds equity in Kate Therapeutics and Kinea Bio, and is an inventor on a US patent describing a method for gene therapy of XLMTM. LNA reports grants or contracts from Astellas Gene Therapies* for clinical evaluator training and quality control in the INCEPTUS and ASPIRO studies. RJG reports limited consulting fees from Astellas Gene Therapies* for work on the ASPIRO study design and advisory board participation for Astellas Gene Therapies,* Biogen, and Genetech. CL reports consulting fees, payments or honoraria, and/or travel expenses from Roche, Biogen, ATOM, AFEHM, Sysnav, and PeerVoice. LS reports consulting fees from Astel-las Gene Therapies* and Dynacure. NLK reports advisory board participation for Astellas Gene Therapies,* Biogen, Genentech, Novartis and Sarepta. AMS, ET, MJ, FM, SN, TP, and WMF report no conflicts of interest. JC, MN, WS, and BS are employees and/or stockholders of Astellas Gene Therapies.* JL, CF, SC, ES, MCV, SP, and SR are former employees and/or stockholders of Astellas Gene Therapies.* *Formerly Audentes Therapeutics
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