Myotubular Myopathy Event Study

NCT01840657 | Completed

• 1 other identifier: CMDIR-002
• Study Type: observational
• Target: 33
• Locations: 1 country
• Sites: 1

Brief Summary

X-Linked myotubular myopathy (XLMTM), a form of centronuclear myopathy (CNM) is the result of a mutation in the MTM1 (myotubularin) gene which leads to altered myotubularin. Myotubularin is essential for optimum muscle function. To date, over 100 mutations have been described resulting in a range of disease onset and symptom severity. The early onset form presents with neonatal hypotonia, muscle weakness, respiratory distress and an ongoing requirement for continuous ventilatory support with the inability to maintain a sitting position once placed. Males with both later onset and milder symptoms usually do not require ongoing ventilatory support, achieve a higher maximal motor function with ability to sit when placed and even walk, and have improved survival rates. Males with XLMTM may experience complications (events) at birth and throughout their lifetime. The goal of the study is to identify the number of events over twelve months in males with genetically confirmed XLMTM. Parents or affected individuals over the age of 18 years who are able to access telephone will provide answers to an established event survey to evaluate the frequency and types of events. Emergency department, hospital admissions and mortality will be confirmed by obtaining medical reports. The investigators hypothesize that there will be no association between the frequency of events and markers of clinical severity including the need for ventilatory support at birth, current level of ventilatory support (no support, support less than 12 hours, support more than 12 hours) and current motor function (walking, sitting without support, inability to sit without support).

Conditions

X-linked Myotubular Myopathy

Keywords

CMDIR (Congenital Muscle Disease International Registry); X-linked myotubular myopathy; centronuclear myopathy; myotubularin; MTM1 gene; mutation; survival; adverse event; disease complication; hospital admission; emergency room visit; motor function; respiratory function; natural history study

Outcome Measures

Primary Outcomes (3)

• Survey of a defined set of events

  Changes in care needed, breathing support, motor ability, medications and medical care, nutrition/weight management, communication/vision/learning/behavior, and frequency of outpatient/hospital/ER visits are recorded by a monthly telephone survey.

  12 months

• Frequency of a predefined set of events related to ventilatory status

  To analyze the strength of the association between the frequency of events surveyed and 1) duration of ventilatory support directly after birth and 2) current need for ventilatory support.

  12 months

• Frequency of a predefined set of events related to current motor function

  To analyze the strength of the association between the frequency of events surveyed and current motor function

  12 months

Secondary Outcomes (2)

• Association between event frequency and genotype

  12 months

• Association between event rate and season

  12 months

Eligibility Criteria

• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Participants for the MTM Event study will be recruited from 2 sources: * the Centronculear Myopathy Natural History Study and * the Congenital Muscle Disease International Registry (CMDIR)

You may qualify if:

• males with a confirmed MTM1 mutation OR
• males with a muscle biopsy consistent with myotubular myopathy AND family history consistent with X-linked inheritance AND
• English-speaking parent/guardian of a living male child or a decisionally impaired adult OR English-speaking affected male over 18 years of age who can access telephone
• signed study consent
• enrolled in the Congenital Muscle Disease International Registry (CMDIR)

You may not qualify if:

• males with only a clinical diagnosis of XLMTM but without family history of XLMTM
• an affected male who has a genetically confirmed form of centronuclear myopathy (CNM) that is not caused by a mutation in the MTM1 gene
• females with MTM1 due to the limited number of females affected and the variability of clinical presentation

Sponsors & Collaborators

• Cure CMD: lead
• Congenital Muscle Disease International Registr: collaborator
• University of Michigan: collaborator

Study Sites (1)

CMDIR

Torrance, California, 90502, United States

Location

Related Publications (21)

• Al-Qusairi L, Laporte J. T-tubule biogenesis and triad formation in skeletal muscle and implication in human diseases. Skelet Muscle. 2011 Jul 13;1(1):26. doi: 10.1186/2044-5040-1-26.

  PMID: 21797990 BACKGROUND

• Al-Qusairi L, Weiss N, Toussaint A, Berbey C, Messaddeq N, Kretz C, Sanoudou D, Beggs AH, Allard B, Mandel JL, Laporte J, Jacquemond V, Buj-Bello A. T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18763-8. doi: 10.1073/pnas.0900705106. Epub 2009 Oct 21.

  PMID: 19846786 BACKGROUND

• Beggs AH, Bohm J, Snead E, Kozlowski M, Maurer M, Minor K, Childers MK, Taylor SM, Hitte C, Mickelson JR, Guo LT, Mizisin AP, Buj-Bello A, Tiret L, Laporte J, Shelton GD. MTM1 mutation associated with X-linked myotubular myopathy in Labrador Retrievers. Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14697-702. doi: 10.1073/pnas.1003677107. Epub 2010 Aug 3.

  PMID: 20682747 BACKGROUND

• Biancalana V, Caron O, Gallati S, Baas F, Kress W, Novelli G, D'Apice MR, Lagier-Tourenne C, Buj-Bello A, Romero NB, Mandel JL. Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype. Hum Genet. 2003 Feb;112(2):135-42. doi: 10.1007/s00439-002-0869-1. Epub 2002 Nov 28.

  PMID: 12522554 BACKGROUND

• Buj-Bello A, Biancalana V, Moutou C, Laporte J, Mandel JL. Identification of novel mutations in the MTM1 gene causing severe and mild forms of X-linked myotubular myopathy. Hum Mutat. 1999;14(4):320-5. doi: 10.1002/(SICI)1098-1004(199910)14:43.0.CO;2-O.

  PMID: 10502779 BACKGROUND

• Buj-Bello A, Fougerousse F, Schwab Y, Messaddeq N, Spehner D, Pierson CR, Durand M, Kretz C, Danos O, Douar AM, Beggs AH, Schultz P, Montus M, Denefle P, Mandel JL. 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 Jul 15;17(14):2132-43. doi: 10.1093/hmg/ddn112. Epub 2008 Apr 22.

  PMID: 18434328 BACKGROUND

• Cao C, Backer JM, Laporte J, Bedrick EJ, Wandinger-Ness A. Sequential actions of myotubularin lipid phosphatases regulate endosomal PI(3)P and growth factor receptor trafficking. Mol Biol Cell. 2008 Aug;19(8):3334-46. doi: 10.1091/mbc.e08-04-0367. Epub 2008 Jun 4.

  PMID: 18524850 BACKGROUND

• Dowling JJ, Lawlor MW, Das S. X-Linked Myotubular Myopathy. 2002 Feb 25 [updated 2018 Aug 23]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1432/

  PMID: 20301605 BACKGROUND

• de Gouyon BM, Zhao W, Laporte J, Mandel JL, Metzenberg A, Herman GE. Characterization of mutations in the myotubularin gene in twenty six patients with X-linked myotubular myopathy. Hum Mol Genet. 1997 Sep;6(9):1499-504. doi: 10.1093/hmg/6.9.1499.

  PMID: 9285787 BACKGROUND

• Dowling JJ, Gibbs EM, Feldman EL. Membrane traffic and muscle: lessons from human disease. Traffic. 2008 Jul;9(7):1035-43. doi: 10.1111/j.1600-0854.2008.00716.x. Epub 2008 Feb 4.

  PMID: 18266915 BACKGROUND

• Dowling JJ, Vreede AP, Low SE, Gibbs EM, Kuwada JY, Bonnemann CG, Feldman EL. Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy. PLoS Genet. 2009 Feb;5(2):e1000372. doi: 10.1371/journal.pgen.1000372. Epub 2009 Feb 6.

  PMID: 19197364 BACKGROUND

• Herman GE, Finegold M, Zhao W, de Gouyon B, Metzenberg A. Medical complications in long-term survivors with X-linked myotubular myopathy. J Pediatr. 1999 Feb;134(2):206-14. doi: 10.1016/s0022-3476(99)70417-8.

  PMID: 9931531 BACKGROUND

• Herman GE, Kopacz K, Zhao W, Mills PL, Metzenberg A, Das S. Characterization of mutations in fifty North American patients with X-linked myotubular myopathy. Hum Mutat. 2002 Feb;19(2):114-21. doi: 10.1002/humu.10033.

  PMID: 11793470 BACKGROUND

• Hoffjan S, Thiels C, Vorgerd M, Neuen-Jacob E, Epplen JT, Kress W. Extreme phenotypic variability in a German family with X-linked myotubular myopathy associated with E404K mutation in MTM1. Neuromuscul Disord. 2006 Nov;16(11):749-53. doi: 10.1016/j.nmd.2006.07.020. Epub 2006 Sep 26.

  PMID: 17005396 BACKGROUND

• Joseph M, Pai GS, Holden KR, Herman G. X-linked myotubular myopathy: clinical observations in ten additional cases. Am J Med Genet. 1995 Nov 6;59(2):168-73. doi: 10.1002/ajmg.1320590211.

  PMID: 8588581 BACKGROUND

• Jungbluth H, Wallgren-Pettersson C, Laporte J. Centronuclear (myotubular) myopathy. Orphanet J Rare Dis. 2008 Sep 25;3:26. doi: 10.1186/1750-1172-3-26.

  PMID: 18817572 BACKGROUND

• Laporte J, Biancalana V, Tanner SM, Kress W, Schneider V, Wallgren-Pettersson C, Herger F, Buj-Bello A, Blondeau F, Liechti-Gallati S, Mandel JL. MTM1 mutations in X-linked myotubular myopathy. Hum Mutat. 2000;15(5):393-409. doi: 10.1002/(SICI)1098-1004(200005)15:53.0.CO;2-R.

  PMID: 10790201 BACKGROUND

• Lee IC, Su PH, Chen JY, Hu JM, Lu JJ, Ng YY. Congenital myotubular myopathy with a novel MTM1 gene mutation in a premature infant presenting with ventilator dependency and intrahepatic cholestasis. J Child Neurol. 2012 Jan;27(1):99-104. doi: 10.1177/0883073811414419. Epub 2011 Aug 31.

  PMID: 21881007 BACKGROUND

• Penisson-Besnier I, Biancalana V, Reynier P, Cossee M, Dubas F. Diagnosis of myotubular myopathy in the oldest known manifesting female carrier: a clinical and genetic study. Neuromuscul Disord. 2007 Feb;17(2):180-5. doi: 10.1016/j.nmd.2006.10.008. Epub 2007 Jan 23.

  PMID: 17251023 BACKGROUND

• Romero NB, Bitoun M. Centronuclear myopathies. Semin Pediatr Neurol. 2011 Dec;18(4):250-6. doi: 10.1016/j.spen.2011.10.006. No abstract available.

  PMID: 22172420 BACKGROUND

• Robinson FL, Dixon JE. Myotubularin phosphatases: policing 3-phosphoinositides. Trends Cell Biol. 2006 Aug;16(8):403-12. doi: 10.1016/j.tcb.2006.06.001. Epub 2006 Jul 7.

  PMID: 16828287 BACKGROUND

MeSH Terms

Conditions

Myopathies, Structural, Congenital; Respiratory Aspiration

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Respiration Disorders; Respiratory Tract Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Joseph Hornyak, MD, PhD

  University of Michigan

  PRINCIPAL INVESTIGATOR

• Anne Rutkowski, MD

  Cure CMD

  PRINCIPAL INVESTIGATOR

• James Dowling, MD, PhD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 18, 2013
• First Posted: April 26, 2013
• Study Start: April 1, 2013
• Primary Completion: October 1, 2015
• Study Completion: October 1, 2015
• Last Updated: March 7, 2018

Record last verified: 2017-01

Locations

US (1)