INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy

James J. Dowling*, Wolfgang Müller-Felber, Barbara K. Smith, Carsten G. Bönnemann, Nancy L. Kuntz, Francesco Muntoni, Laurent Servais, Lindsay N. Alfano, Alan H. Beggs, Deborah A. Bilder, Astrid Blaschek, Tina Duong, Robert J. Graham, Minal Jain, Michael W. Lawlor, Jun Lee, Julie Coats, Charlotte Lilien, Linda P. Lowes, Victoria MacBeanSarah Neuhaus, Mojtaba Noursalehi, Teresa Pitts, Caroline Finlay, Sarah Christensen, Gerrard Rafferty, Andreea M. Seferian, Etsuko Tsuchiya, Emma S. James, Weston Miller, Bryan Sepulveda, Maria Candida Vila, Suyash Prasad, Salvador Rico, Perry B. Shieh

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)503-516
Number of pages14
JournalJournal of Neuromuscular Diseases
Volume9
Issue number4
DOIs
Publication statusPublished - 2022

Keywords

  • centronuclear myopathy
  • mechanical
  • motor disorders
  • neuromuscular diseases
  • respiratory failure
  • ventilators
  • X-linked myotubular myopathy

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