Myotubular Myopathy Genetic Testing Study

NCT01817946 | Completed

• 1 other identifier: CMDIR-001
• Study Type: observational
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

Myotubular myopathy (XLMTM) is an X-linked disorder caused by mutations in the myotubularin gene (MTM1). The clinical spectrum is variable and ranges from individuals who require a wheelchair and full time breathing support to those who are able to walk and breathe on their own. Symptoms of myotubular myopathy include long faces, facial weakness with eye muscle weakness, breathing support with a muscle biopsy demonstrating central nucleated fibers. These symptoms may be caused by mutations or changes in the MTM1, BIN1 (bridging integrator 1), DNM2 (dynamin 2) and RYR1 (ryanodine receptor 1) genes. However, the majority are caused by mutations in the MTM1 gene. Some patients with symptoms consistent with myotubular myopathy who initially have negative testing of the MTM1 gene were later found to have a unique type of change in the MTM1 gene. This unique change, called a deletion or duplication, can be found with a different type of genetic test called a CGH (comparative genomic hybridization) array. Investigators do not know how frequent deletions and duplications are in patients with X-linked myotubular myopathy. Recently, there have been advances in identifying potential treatments for XLMTM. The next step will be to proceed with clinical trials of potential treatments. In order to be ready for clinical trials, it is important that investigators find the specific genetic change that is causing XLMTM in people with this diagnosis. This study will attempt to find changes in the MTM1 gene in individuals who have clinical symptoms consistent with a diagnosis of XLMTM. Participants will be asked to enroll in the CMDIR (Congenital Muscle Disease International Registry), complete a brief clinical survey, provide access to medical records, and provide a saliva or blood sample for genetic testing. Results of genetic testing will be communicated to participants by the physician specified in the consent by the signing person. Study Hypothesis: Not all individuals with a clinical diagnosis of XLMTM have access to genetic testing. Investigators know that deletions and duplications of the MTM1 gene can cause XLMTM. Investigators will find more individuals with XLMTM by performing genetic testing of the MTM1 gene, including CGH array for deletions and duplications.

Conditions

Myotubular Myopathy

Keywords

Congenital Myopathy; Centronuclear Myopathy; Myotubular Myopathy; Myotubularin; MTM1 Gene; Genetic testing; Sequencing; Deletion/Duplication Mutation; CGH array

Outcome Measures

Primary Outcomes (1)

• Description of Mutations in the MTM1 Gene by Complete Genetic Sequencing

  To confirm presence, locations and frequencies of mutations in the MTM1 gene in study participants presenting with symptoms as listed in the Brief Summary and muscle biopsy and/or family history typical for myotubular myopathy or prior confirmation of a mutation in the MTM1 gene by research sequencing.

  1 year

Secondary Outcomes (2)

• Frequency of Deletion/Duplication Mutations in the MTM1 Gene by CGH Array Testing

  1 year

• To Examine the Relation of the Mutation in the MTM1 Gene to the Phenotype

  2 years

Study Arms (1)

Genetic testing

All participants determined eligible for the study will be placed into genetic testing arm.

Other: Genetic Testing

Interventions

Genetic Testing OTHER

Genetic testing services will be provided by the University of Chicago under the guidance of Dr. Soma Das, PhD. Services will be coordinated by Rachel Alvarez, CMDIR Associate Director. Genetic testing will include standard sequencing of the MTM1 gene followed by CGH array for deletion/duplication in cases where no pathologic variant is identified by standard sequencing.

Also known as: Sequencing

Genetic testing

Eligibility Criteria

• Age: 30 Days+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The study will be composed of individuals registered in the CMDIR who have been clinically diagnosed with XLMTM but do not have an XLMTM diagnosis confirmed by genetic testing.

You may qualify if:

• Males and females in the US and Canada who have a known mutation in the MTM1 gene identified in a research lab and never confirmed in a clinical CLIA (Clinical Laboratory Improvement Amendments) -certified laboratory.
• Male and female patients in the US and Canada who meet 2 of 3 of the following criteria: + clinical history, + family history, + centronucleation on muscle biopsy (no signs of nemaline rods or cores). Clinical history includes: post-natal breathing support (not necessarily continued after first month), length above 90% for EGA (estimated gestational age), facial characteristics (narrow facies), facial weakness (ophthalmoplegia, excessive saliva with need for suctioning).
• Males and females in the US and Canada who present with XLMTM symptoms and no genetic mutation in the MTM1 gene found with conventional sequencing, requiring CGH array deletion/duplication testing.
• Age range: One month - no maximum age.
• Individual is registered with the CMDIR.
• Written study consent provided by parent/caregiver (affected individual's age less than 18 years or for those individuals greater than 18 years with learning disabilities or inability to physically access consent) or affected individual (age greater than 18 years)

You may not qualify if:

• \. Carrier testing for asymptomatic mothers.

Sponsors & Collaborators

• Cure CMD: lead
• Valerion Therapeutics, LLC: collaborator
• Congenital Muscle Disease International Registr: collaborator
• University of Chicago: collaborator
• Boston Children's Hospital: collaborator

Study Sites (1)

Congenital Muscle Disease International Registry

Torrance, California, 90502, United States

Location

Related Publications (7)

• Trump N, Cullup T, Verheij JB, Manzur A, Muntoni F, Abbs S, Jungbluth H. X-linked myotubular myopathy due to a complex rearrangement involving a duplication of MTM1 exon 10. Neuromuscul Disord. 2012 May;22(5):384-8. doi: 10.1016/j.nmd.2011.11.004. Epub 2011 Dec 9.

  PMID: 22153990 BACKGROUND

• Oliveira J, Oliveira ME, Kress W, Taipa R, Pires MM, Hilbert P, Baxter P, Santos M, Buermans H, den Dunnen JT, Santos R. Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database. Eur J Hum Genet. 2013 May;21(5):540-9. doi: 10.1038/ejhg.2012.201. Epub 2012 Sep 12.

  PMID: 22968136 BACKGROUND

• Bevilacqua JA, Bitoun M, Biancalana V, Oldfors A, Stoltenburg G, Claeys KG, Lacene E, Brochier G, Manere L, Laforet P, Eymard B, Guicheney P, Fardeau M, Romero NB. "Necklace" fibers, a new histological marker of late-onset MTM1-related centronuclear myopathy. Acta Neuropathol. 2009 Mar;117(3):283-91. doi: 10.1007/s00401-008-0472-1. Epub 2008 Dec 16.

  PMID: 19084976 BACKGROUND

• Gurgel-Giannetti J, Zanoteli E, de Castro Concentino EL, Abath Neto O, Pesquero JB, Reed UC, Vainzof M. Necklace fibers as histopathological marker in a patient with severe form of X-linked myotubular myopathy. Neuromuscul Disord. 2012 Jun;22(6):541-5. doi: 10.1016/j.nmd.2011.12.005. Epub 2012 Jan 20.

  PMID: 22264517 BACKGROUND

• North KN. Clinical approach to the diagnosis of congenital myopathies. Semin Pediatr Neurol. 2011 Dec;18(4):216-20. doi: 10.1016/j.spen.2011.10.002.

  PMID: 22172416 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

• Tosch V, Vasli N, Kretz C, Nicot AS, Gasnier C, Dondaine N, Oriot D, Barth M, Puissant H, Romero NB, Bonnemann CG, Heller B, Duval G, Biancalana V, Laporte J. Novel molecular diagnostic approaches for X-linked centronuclear (myotubular) myopathy reveal intronic mutations. Neuromuscul Disord. 2010 Jun;20(6):375-81. doi: 10.1016/j.nmd.2010.03.015.

  PMID: 20434914 RESULT

Related Links

• Congenital Muscle Disease International Registry

Biospecimen

Retention: SAMPLES WITH DNA

saliva, whole blood, or other source

MeSH Terms

Conditions

Myopathies, Structural, Congenital; Myotonia Congenita

Interventions

Genetic Testing; Base Sequence

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Myotonic Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services; Molecular Structure; Biochemical Phenomena; Chemical Phenomena; Genetic Structures; Genetic Phenomena

Study Officials

• Sabine de Chastonay, PhD

  CMDIR

  PRINCIPAL INVESTIGATOR

• Elizabeth DeChene, MS, GCG

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

• Soma Das, PhD

  University of Chicago Genetic Testing Services Laboratory

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: March 19, 2013
• First Posted: March 26, 2013
• Study Start: March 1, 2013
• Primary Completion: March 1, 2017
• Study Completion: March 1, 2017
• Last Updated: March 7, 2018

Record last verified: 2018-03

Locations

US (1)