Evaluating the natural history of Charcot Marie Tooth Disease

Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Type (CMT1B), 2A (CMT2A), 4A (CMT4A), 4C (CMT4C), and Others

This study is trying to learn more about how different types of Charcot Marie Tooth Disease affect people over time and how their genetics play a role.

Quick facts

• Study type: Observational
• Enrollment: 5000 (estimated)
• Sex: All
• Sponsor: University of Iowa (other)
• Locations: 22 sites (Los Angeles, California and 21 other locations)
• Trial ID: NCT01193075 on ClinicalTrials.gov

What this trial studies

This observational study aims to assess the natural history and genotype-phenotype correlations of various types of Charcot Marie Tooth Disease (CMT), including CMT1B, CMT2A, CMT4A, and CMT4C. The study will utilize the newly developed CMT Pediatric Scale and Minimal Dataset to measure impairment and track longitudinal changes in patients over a five-year period. Conducted by the Inherited Neuropathies Consortium, it involves multiple prestigious institutions across North America and Europe, focusing on gathering comprehensive data on CMT. The study will include patients with documented pathogenic variants or those with a family history of CMT.

Who should consider this trial

Good fit: Ideal candidates include patients with documented pathogenic CMT-causing variants or those with a family member who has such variants.

Not a fit: Patients without a confirmed diagnosis of CMT or those who do not meet the familial linkage criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could enhance understanding of CMT, leading to improved diagnosis and management strategies for patients.

How similar studies have performed: Other studies focusing on the natural history of genetic neuropathies have shown promise, indicating that this approach could yield valuable insights.

Eligibility criteria

Inclusion Criteria:

All patients must be seen in-person at a participating center for the initial visit.

Inclusion Criteria - patients with CMT (all subtypes)

1. Patient has documented, pathogenic or likely pathogenic CMT-causing variant(s)

   OR
2. Patient has a first- or second-degree family member (parent, child, sibling, half-sibling, aunt, uncle, grandparent, or grandchild) with a documented pathogenic or likely pathogenic CMT-causing variant AND a clear link between that family member and the affected patient AND a phenotype consistent with the diagnosis

   i. A clear link is necessary for a second-degree relative. For example, if a grandparent is affected and has a pathogenic or likely pathogenic variant, and the parent does not have any signs, symptoms, or electrophysiology consistent with the diagnosis, there is no clear link unless the parent has also been found to have the pathogenic or likely pathogenic variant such as in cases with reduced penetrance

   ii. In cases where clear links are not available, genetic testing is required for the patient or the family member who is not clearly affected.
3. Patients who have a variant of uncertain significance, as determined by the laboratory performing the testing may still be included if one of the following circumstances applies:

   i. Variant is categorized as pathogenic or likely pathogenic per the ACMG variant interpretation guidelines. \[80, 81\]

   ii. Variant has been found in multiple affected people in a family and has not been found in unaffected family members. (Note - both affected and unaffected family members must be tested in this situation to be included).

   iii. The principal investigator and the site investigator agree that the variant(s) is (are) most likely pathogenic.
4. Patients whose clinical presentation is suggestive of CMT, but CMT type and variant are unknown will be characterized by the following categories:

   1. Nerve conduction velocities: demyelinating, axonal, intermediate
   2. Inheritance: dominant, recessive, X-linked, or unknown
5. Patient or patient's legally authorized representative has understood and signed an IRB approved consent form for the study. Teenagers (age 13 - 17 years) and cognitively impaired adults who are able to read and write must sign an assent form (depending on local ethics committee requirements).

Inclusion Criteria - Controls

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

EXCLUSION CRITERIA

1. Patient has a variant of uncertain significance that cannot be further classified following methods listed in the Inclusion Criteria.
2. Patient does not wish to be a part of the study or has not signed an informed consent form.
3. Patient is deemed inappropriate by the Site PI.

Where this trial is running

Los Angeles, California and 21 other locations

• Cedars-Sinai Medical Center — Los Angeles, California, United States (RECRUITING)
• Stanford University — Palo Alto, California, United States (RECRUITING)
• University of Colorado Hospital — Aurora, Colorado, United States (RECRUITING)
• University of Connecticut/Connecticut Children's Medical Center — Hartford, Connecticut, United States (RECRUITING)
• Children's National Hospital — Washington D.C., District of Columbia, United States (RECRUITING)
• University of Miami — Miami, Florida, United States (RECRUITING)
• Nemours Children's Health — Orlando, Florida, United States (RECRUITING)
• Nemours Children's Hospital — Orlando, Florida, United States (RECRUITING)
• University of Iowa — Iowa City, Iowa, United States (RECRUITING)
• Johns Hopkins University — Baltimore, Maryland, United States (RECRUITING)
• Harvard/Massachusetts General Hospital — Boston, Massachusetts, United States (RECRUITING)
• University of Michigan — Ann Arbor, Michigan, United States (NOT_YET_RECRUITING)
• University of Minnesota — Minneapolis, Minnesota, United States (RECRUITING)
• University of Rochester — Rochester, New York, United States (RECRUITING)
• Children's Hospital of Philadelphia — Philadelphia, Pennsylvania, United States (RECRUITING)
• University of Pennsylvania — Philadelphia, Pennsylvania, United States (RECRUITING)
• St. Jude Children's Research Hospital — Memphis, Tennessee, United States (RECRUITING)
• Seattle Children's Hospital — Seattle, Washington, United States (NOT_YET_RECRUITING)
• University of Westmead — Sydney, New South Wales, Australia (RECRUITING)
• The Hospital for Sick Children — Toronto, Ontario, Canada (RECRUITING)
• C. Besta Neurological Institute — Milan, Milan, Italy (RECRUITING)
• National Hospital of Neurology and Neurosurgery — London, England, United Kingdom (RECRUITING)

Study contacts

• Principal investigator: Michael E Shy, MD — University of Iowa
• Study coordinator: Nicole M Kressin, MSN, RN

Conditions: Charcot Marie Tooth Disease, Charcot Marie Tooth disease, CMT, HMSN, HMN, HSN, CMT1, CMT2