Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A, New Causes of CMT2 (INC-6602)

Study Description

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

This project includes two projects. One is looking for new genes that cause Charcot Marie Tooth disease (CMT). The other is looking for genes that do not cause CMT, but may modify the symptoms a person has.

Condition or disease
Charcot-Marie-Tooth Disease, Type Ia (Disorder); HMSN

Detailed Description:

This project is to understand modifier genes and how they influence the severity of disease expression, along with identifying new forms of CMT which have not been genetically determined. Subjects who are eligible will either have CMT type 1A (CMT1A) or an unknown form of CMT. Blood will be drawn and sent to the University of Miami where they receive the coded sample and process it through exome sequencing. Subjects will be told that this is optional.

Study Design

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Study Type :	Observational
Estimated Enrollment :	1050 participants
Observational Model:	Cohort
Time Perspective:	Prospective
Official Title:	Genetics of Charcot Marie Tooth Disease (CMT) - Modifiers of CMT1A, New Causes of CMT
Actual Study Start Date :	April 2010
Estimated Primary Completion Date :	December 2019
Estimated Study Completion Date :	December 2019

Groups and Cohorts

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Group/Cohort
CMT1A
Genetically undefined CMT; Families/people with genetically undefined CMT with common causes ruled out.

Outcome Measures

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Primary Outcome Measures :

1. Charcot Marie Tooth disease type 1A (CMT1A) gene modifiers [ Time Frame: once ]
   While the same genetic change - an extra copy of PMP22 - causes CMT1A by definition, it is unclear why some people have more severe symptoms and some have less severe. We are looking for genetic modifiers - changes in the DNA that may be causing the differences in symptoms.
2. New genetic causes of CMT [ Time Frame: Once ]
   At least 33% of people with CMT have an unknown or genetically un-found form of the condition. We are looking for additional genes that cause CMT when mutated.

Biospecimen Retention:   Samples With DNA

DNA extracted from whole blood. Filter cards with blood spots.

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Senior
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes
Sampling Method:	Non-Probability Sample

Study Population

Patients participating in Inherited Neuropathies Consortium (INC)-6601 and meeting eligibility criteria for this study will be recruited.

Criteria

Inclusion Criteria:

Patient MUST be seen in person at one of the clinical sites involved in this study.

Charcot Marie Tooth disease type 1A (CMT1A) modifier gene study

• Patient has a documented PMP22 duplication OR

• Patient has a first or second degree relative (parent, child, sibling, half-sibling, aunt, uncle, grandparent, grandchild, niece, or nephew) with a documented PMP22 duplication AND a clear link between that family member and the affected patient AND a phenotype consistent with CMT1A.

  i. A clear link is necessary for a second-degree relative. For example, if a grandparent is affected and has a PMP22 duplication, and the parent does not have any signs, symptoms, or electrophysiology consistent with CMT1A, there is no clear link.

ii. In cases where clear links are not available, genetic testing is required for the patient or the first degree family member who is not clearly affected.

AND

• Patient has agreed to take part in the study and has signed a consent form.
• A teenager (ages 13-17) considering enrolling must agree to take part in the study and sign an assent form

Inclusion Criteria - CMT Exome Project

1. Patient has demonstrated neuropathy on nerve conduction studies or a clinically diagnosed genetic neuropathy.
2. Patient or first or second degree family member with a clear link as described in the CMT1A Inclusion Criteria part b has had negative MFN2 genetic testing, if has an axonal form of CMT (nerve conductions greater than 38 m/s) or negative testing for PMP22 duplication, deletion, sequencing, MPZ, and GJB1 if a demyelinating form of CMT is present (<38 m/s).
3. More than one family member is willing eligible to participate.

i. Sample pedigrees showing optimal degrees of relationship are shown below. ii. Participation includes being able to complete all aspects of the study, including the giving informed consent, having a brief physical examination, and providing a DNA sample.

d. Patient has agreed to take part in the study and has signed a consent form. e. A teenager (ages 13-17) considering enrolling must agree to take part in the study and sign an assent form.

Inclusion Criteria - Controls

1. Person does not have a peripheral neuropathy, as determined by the investigator.
2. Person has understood the study and signed an IRB approved consent form. Teenagers (age 13-17 years) must sign an assent form.

Exclusion Criteria:

1. Patient does not wish to participate or does not sign a consent form.
2. For CMT Exome Project, patient has a genetically confirmed form of CMT (i.e. mutation in MFN2 causing CMT2A, mutation in GARS causing CMT2D, etc.).
3. Known neuropathy from a non-genetic source, such as chemotherapies (i.e. Vincristine, Taxol, Cisplatin), diabetes, alcoholism will be evaluated independently so that genetic contributions to their effects on CMT1A phenotypes can also be analyzed.

Contacts and Locations

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Shawna Feely, MS, CGC	319-384-6362	UICMTClinic@uiowa.edu
Contact: Tiffany Grider, MS, CGC	319-384-6362	UICMTClinic@uiowa.edu

  Show 22 Study Locations

Sponsors and Collaborators

University of Iowa

National Institute of Neurological Disorders and Stroke (NINDS)

Muscular Dystrophy Association

University of Rochester

University of Pennsylvania

King's College Hospital NHS Trust

Sydney Children's Hospitals Network

Children's Hospital of Philadelphia

University of Miami

Johns Hopkins University

University of Washington

Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

Cedars-Sinai Medical Center

Nemours Children's Clinic

Stanford University

University of Michigan

Vanderbilt University Medical Center

Investigators

Principal Investigator:	Michael E Shy, MD	University of Iowa

More Information

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Inherited Neuropathies Consortium Website 

Publications of Results:

Montenegro G, Powell E, Huang J, Speziani F, Edwards YJ, Beecham G, Hulme W, Siskind C, Vance J, Shy M, Züchner S. Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family. Ann Neurol. 2011 Mar;69(3):464-70. doi: 10.1002/ana.22235. Epub 2011 Jan 20.

Responsible Party:	Michael Shy, Professor, University of Iowa
ClinicalTrials.gov Identifier:	NCT01193088 History of Changes
Other Study ID Numbers:	INC-6602; 1U54NS065712-01 ( U.S. NIH Grant/Contract )
First Posted:	September 1, 2010
Last Update Posted:	September 13, 2017
Last Verified:	September 2017

Keywords provided by Michael Shy, University of Iowa:

CMT; CMT1A

Additional relevant MeSH terms:

Tooth Diseases; Charcot-Marie-Tooth Disease; Nerve Compression Syndromes; Hereditary Sensory and Motor Neuropathy; Stomatognathic Diseases; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies	Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; 4-des-dimethylaminotetracycline; Matrix Metalloproteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action