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

Recruiting

• Conditions: Charcot-Marie-Tooth Disease, Type Ia (Disorder); HMSN

• Registration Number: NCT01193088
• Lead Sponsor: University of Iowa

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.

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 Timeline

• Study Start: 2010-05
• Study First Submitted: 2010-08-09
• Study First Submitted QC: 2010-08-31
• Study First Posted: 2010-09-01
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-09
• Last Update Posted: 2024-05-13
• Primary Completion: 2026-12
• Study Completion: 2026-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1050

Inclusion Criteria

All patients must agree to take part in the study and sign a consent form. A teenager (age 13-17 years) considering enrolling must agree to take part in the study and sign an assent form (depending on local ethics committee requirements).

Additional inclusion criteria are described below.

Inclusion Criteria: CMT1A Gene Modifier Study

Patients must have at least one of the following:

1. Patient has a documented PMP22 duplication. AND/OR
2. 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.

Inclusion Criteria - Patients for CMT Exome Project

a. Patient has demonstrated neuropathy on nerve conduction studies or clinically diagnosed genetic neuropathy, in the opinion of the investigator or genetic counsellor.

Inclusion Criteria - Controls for CMT Exome Project

1. Person is a family member of a CMT patient who is enrolled in the CMT Exome Project.

   AND one of the following:

2. Person does not have a peripheral neuropathy, in the opinion of the investigator or genetic counsellor.

   OR

3. Person is suspected to have a peripheral neuropathy, but has not been examined at an INC site.

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. Patients with 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.

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
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.
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.

Trial Locations

Locations (17)

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Cedars-Sinai Medical Center; 🇺🇸 Los Angeles, California, United States

Children's Hospital of Westmead; 🇦🇺 Sydney, New South Wales, Australia

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Stanford University; 🇺🇸 Palo Alto, California, United States

Nemours Children's Clinic; 🇺🇸 Orlando, Florida, United States

Connecticut Children's Medical Center; 🇺🇸 Hartford, Connecticut, United States

C. Besta Neurological Institute; 🇮🇹 Milan, Italy

University of Miami; 🇺🇸 Miami, Florida, United States

University of Iowa; 🇺🇸 Iowa City, Iowa, United States

Dubowitz Neuromuscular Centre; 🇬🇧 London, United Kingdom

Harvard/Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

National Hospital of Neurology and Neurosurgery; 🇬🇧 London, England, United Kingdom

University of Colorado Hospital; 🇺🇸 Aurora, Colorado, United States

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

University of Rochester; 🇺🇸 Rochester, New York, United States

University of Minnesota; 🇺🇸 Maple Grove, Minnesota, United States