Myotubular Myopathy Genetic Testing Study

Brief Title

Myotubular Myopathy Genetic Testing Study

Official Title

Myotubular Myopathy Genetic Testing Study

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.
    

Detailed Description

      -  Prospective participants will complete registration in the CMDIR.

        -  The CMDIR genetic curator will review CMDIR data for study eligibility.

        -  If eligible, participant will be called and consented to participate in the study.

        -  Sequencing can be done with a saliva sample. However, if this method does not detect a
           mutation or change in the MTM1 gene, a further test, called CGH Array, has to be
           performed. For the CGH Array test, a saliva sample may deliver a clear result in terms
           of a deletion/duplication mutation. In the event, CGH Array with the saliva sample does
           not provide a result, a the blood sample is necessary to repeat CGH Array.

        -  The study participant will receive a kit and instructions for saliva specimen collection
           for genetic testing from the CMDIR in the mail.

        -  If a mutation or change in the MTM1 gene could not be found by genetic testing and CGH
           Array with a saliva sample, the study participant will receive a second kit in the mail
           from the CMDIR with instructions for a blood draw to be used for CGH Array.

        -  The family will coordinate collection of the saliva specimen or a local blood draw, if
           necessary, and will be responsible for mailing the specimen in a pre-paid parcel to the
           University of Chicago. There will be a $40 reimbursement for the cost of the blood draw.
           Mailing the specimen to the testing site is at no cost for the participant. A two-week
           turn-around from receipt of the kit to sending it to the testing laboratory is
           requested.

        -  Genetic testing will start with standard sequencing of the MTM1 gene, isolated from the
           saliva specimen, followed by CGH Array if sequencing of the MTM1 gene isolated from the
           saliva sample or further from a blood sample if a variant consistent with the symptoms
           could not be detected using the saliva sample.

        -  Test results will be 1) reported to a physician specified by the study participant and
           2) uploaded into the study participant's profile in the CMDIR and 3) if concurrently
           enrolled in the Beggs Laboratory or other IRB-approved clinical study, test results will
           also be made available to that study provided appropriate informed consent has been
           given.
    


Study Type

Observational


Primary Outcome

Description of Mutations in the MTM1 Gene by Complete Genetic Sequencing

Secondary Outcome

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

Condition

Myotubular Myopathy

Intervention

Genetic Testing

Study Arms / Comparison Groups

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Other

Estimated Enrollment

23

Start Date

March 2013

Completion Date

March 2017

Primary Completion Date

March 2017

Eligibility Criteria

        Inclusion Criteria: Patient eligibility will be determined by the CMDIR genetic curator
        using the following prioritization protocol.

          1. 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.

          2. 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).

          3. 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.

          4. Age range: One month - no maximum age.

          5. Individual is registered with the CMDIR.

          6. 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)

        Exclusion Criteria:

        1. Carrier testing for asymptomatic mothers.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

Sabine de Chastonay, PhD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01817946

Organization ID

CMDIR-001


Responsible Party

Sponsor

Study Sponsor

Cure CMD

Collaborators

 Valerion Therapeutics, LLC

Study Sponsor

Sabine de Chastonay, PhD, Principal Investigator, CMDIR


Verification Date

March 2018