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

Sponsor

University of Iowa (Other)

Overall Status

Recruiting

CT.gov ID

NCT01193088

Collaborator

National Institute of Neurological Disorders and Stroke (NINDS) (NIH), Muscular Dystrophy Association (Other), University of Rochester (Other), University of Pennsylvania (Other), King's College Hospital NHS Trust (Other), Sydney Children's Hospitals Network (Other), Children's Hospital of Philadelphia (Other), University of Miami (Other), Johns Hopkins University (Other), Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta (Other), Cedars-Sinai Medical Center (Other), Nemours Children's Clinic (Other), Stanford University (Other), University of Minnesota (Other), Harvard University Massachusetts General Hospital (Other), University of Colorado, Denver (Other), Wayne State University (Other)

1,050

Enrollment

Locations

151

Anticipated Duration (Months)

55.3

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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	Intervention/Treatment	Phase
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

Study Type:

Observational

Anticipated 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 :

May 1, 2010

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
CMT1A Families/people with genetically defined CMT1A
Genetically undefined CMT Families/people with genetically undefined CMT with common causes ruled out.

Outcome Measures

Primary Outcome Measures

Charcot Marie Tooth disease type 1A (CMT1A) gene modifiers [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.
New genetic causes of CMT [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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.

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.

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

Patient has demonstrated neuropathy on nerve conduction studies or a clinically diagnosed genetic neuropathy.
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).
More than one family member is willing eligible to participate.

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.
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

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

Exclusion Criteria:

Patient does not wish to participate or does not sign a consent form.
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.).
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

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
2	Stanford University	Palo Alto	California	United States	94304
3	University of Colorado Hospital	Aurora	Colorado	United States	80045
4	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
5	University of Miami	Miami	Florida	United States	33136
6	Nemours Children's Clinic	Orlando	Florida	United States	32827
7	University of Iowa	Iowa City	Iowa	United States	52242
8	Johns Hopkins University	Baltimore	Maryland	United States	21205
9	Harvard/Massachusetts General Hospital	Boston	Massachusetts	United States	02114
10	Wayne State University/Detroit Medical Center	Detroit	Michigan	United States	48201
11	University of Minnesota	Maple Grove	Minnesota	United States	55369
12	University of Rochester	Rochester	New York	United States	14642
13	Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43210
14	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
15	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
16	Children's Hospital of Westmead	Sydney	New South Wales	Australia	2145
17	C. Besta Neurological Institute	Milan		Italy
18	National Hospital of Neurology and Neurosurgery	London	England	United Kingdom	WC1N 3BG
19	Dubowitz Neuromuscular Centre	London		United Kingdom