X-linked myotubular myopathy (XLMTM) is a rare neuromuscular condition that presents with neonatal hypotonia and weakness and is associated with severe morbidities (including wheelchair, feeding tube, and ventilator dependence) and early death.1 It is defined by muscle biopsy features, including central nuclei, abnormal oxidative stain distribution, and type I fiber hypotrophy.2 Mutations in myotubularin (MTM1) account for all genetically solved cases of XLMTM, but have not been discovered in all individuals with characteristic clinical and biopsy features.3 Of note, there are some forms of autosomal centronuclear myopathy that can resemble XLMTM, such as those associated with mutations in BIN1, DNM2, RYR1, and SPEG, although rarely are such cases a complete phenocopy of XLMTM.4 In this study, we present a case that illustrates the importance of considering noncoding mutations as a cause of XLMTM and illustrate the utility of RNA analysis in individuals with a phenotype suggestive of a particular genetic diagnosis.
Acknowledgments
Acknowledgment: The authors thank Etsuko Tsuchiya for assistance for REB and Valerion Therapeutics for support of longitudinal natural history study.
Footnotes
Author contributions: Dr. Al-Hashim: study concept and design, data acquisition, and writing of manuscript. Dr. Gonorazky and Ms. Amburgey: data acquisition and interpretation and critical revision of manuscript. Dr. Das: data interpretation and critical revision of manuscript for intellectual content. Dr. Dowling: study concept and design, study supervision, acquisition and interpretation of data, and writing and critical revision of manuscript for intellectual content.
Study funding: Study funded by the Department of Paediatrics Start-up Fund at the Hospital for Sick Children. Study participant seen as part of an ongoing longitudinal natural history study funded by Valerion Therapeutics.
Disclosure: A. Al-Hashim, H. Gonorazky, K. Amburgey, and S. Das report no disclosures. J.J. Dowling serves on the scientific advisory boards of the RYR1 Foundation, the MTM/CNM patient registry, and the World Muscle Society; has received donations to SickKids Foundation, Where There's a Will Foundation, and Joshua Frase Foundation; has received travel funding from Audentes; has served on the editorial boards of Muscle & Nerve, PLoS Currents: Muscular Dystrophy, Journal of Neuromuscular Diseases, Neuromuscular Disorders, and Disease Models & Mechanisms; has been a consultant for Guidepoint Global Advisors and GLG Group; and has received research funding from Valerion Therapeutics, CIHR, NIH, NSERC, Genome Canada, Hospital for Sick Children, Cure CMD, Joshua Frase Foundation, Team Joseph, Myotubular Trust, and Muscular Dystrophy Association. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was funded by Genome Canada.
- Received May 11, 2017.
- Accepted in final form July 11, 2017.
- Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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