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Original research
Mortality and respiratory support in X-linked myotubular myopathy: a RECENSUS retrospective analysis
  1. Robert J Graham1,
  2. Francesco Muntoni2,
  3. Imelda Hughes3,
  4. Sabrina W Yum4,
  5. Nancy L Kuntz5,
  6. Michele L Yang6,
  7. Barry J Byrne7,
  8. Suyash Prasad8,
  9. Rachel Alvarez9,
  10. Casie A Genetti10,
  11. Tmirah Haselkorn11,
  12. Emma S James8,
  13. Laurie B LaRusso12,
  14. Mojtaba Noursalehi8,
  15. Salvador Rico8,
  16. Alan H Beggs10
  1. 1 Department of Anesthesiology, Critical Care and Pain Medicine, Division of Critical Care Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  2. 2 The Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health and NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK
  3. 3 Royal Manchester Children's Hospital, Manchester, UK
  4. 4 Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  5. 5 Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
  6. 6 Children's Hospital Colorado, Aurora, Colorado, USA
  7. 7 Children’s Research Institute, University of Florida, Gainesville, Florida, USA
  8. 8 Audentes Therapeutics, San Francisco, California, USA
  9. 9 Cure CMD, Torrance, California, USA
  10. 10 Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  11. 11 EpiMetrix, Los Altos, California, USA
  12. 12 Chestnut Medical Communications, Walpole, Massachusetts, USA
  1. Correspondence to Professor Alan H Beggs, Division of Genetics & Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; beggs{at}enders.tch.harvard.edu; Dr. Robert J Graham, Division of Critical Care Medicine, Dept. of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, MA, 02115, USA; robert.graham{at}childrens.harvard.edu

Abstract

Purpose Individuals with X-linked myotubular myopathy (XLMTM) who survive infancy require extensive supportive care, including ventilator assistance, wheelchairs and feeding tubes. Half die before 18 months of age. We explored respiratory support and associated mortality risk in RECENSUS, particularly among patients ≤5 years old who received respiratory support at birth; this subgroup closely matches patients in the ASPIRO trial of gene therapy for XLMTM.

Design RECENSUS is an international, retrospective study of patients with XLMTM. Descriptive and time-to-event analyses examined survival on the basis of age, respiratory support, tracheostomy use, predicted mutational effects and life-sustaining care.

Results Outcomes for 145 patients were evaluated. Among 126 patients with respiratory support at birth, mortality was 47% overall and 59% among those ≤5 years old. Median survival time was shorter for patients ≤5 years old than for those >5 years old (2.2 years (IQR 0.7–5.6) vs 30.2 years (IQR 19.4–30.2)). The most common cause of death was respiratory failure (66.7%). Median survival time was longer for patients with a tracheostomy than for those without (22.8 years (IQR 8.7–30.2) vs 1.8 years (IQR 0.2–not estimable)). The proportion of patients living without a tracheostomy was 50% at age 6 months and 28% at age 2 years. Median survival time was longer with provision of life-sustaining care than without (19.4 years (IQR 3.1–not estimable) vs 0.2 years (IQR 0.1–2.1)).

Conclusions High mortality, principally due to respiratory failure, among patients with XLMTM ≤5 years old despite respiratory support underscores the need for early diagnosis, informed decision-making and disease-modifying therapies.

Trial registration number NCT02231697

  • X-linked myotubular myopathy
  • centronuclear myopathy
  • congenital myopathy
  • retrospective chart review
  • mortality
  • respiratory support
  • tracheostomy
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/archdischild-2019-317910

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    Footnotes

    • Contributors SP conceptualised the study. AHB, CAG, RA, NLK, MLY and SWY collected data and contributed to the interpretation of data. MN conducted the statistical analyses. AHB, LBL, RJG, ESJ, SR and TH wrote the manuscript.

    • Funding The RECENSUS study was funded by Audentes Therapeutics. Support for subject ascertainment, enrolment and data acquisition was provided by the National Institutes of Health (grant R01 AR044345) and Muscular Dystrophy Association (USA) (grant MDA602235). Data aggregation was also achieved through neuromuscular clinics supported by the Muscular Dystrophy Association (USA).

    • Competing interests RJG, IH, MLY, NLK and SWY report no conflicts of interest with respect to this study. RJG is an unpaid member of Audentes Therapeutics Board of Scientific and Clinical Advisors. RA is a volunteer for Cure CMD and has no financial interest in Audentes or related to this study. LBL received financial compensation for medical writing, and TH is a consultant to Audentes Therapeutics. ESJ, MN, SR and SP are employees and shareholders of Audentes Therapeutics. AHB is a member of the Audentes Therapeutics Board of Scientific and Clinical Advisors and has received support from a sponsored research agreement with Audentes Therapeutics to cover running costs for this study.

    • Patient consent for publication Not required.

    • Ethics approval The study protocol was reviewed and approved by the Western Institutional Review Board (IRB) (Pr No 20141715) and the local IRBs at participating institutions. Informed consent was obtained from the parent(s) or legal guardian(s) of each patient and/or assent by the patient (when applicable) before initiating medical record review.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement Data are available upon reasonable request.

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