Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others

The Inherited Neuropathies Consortium (INC) is a member of the Rare Disease Clinical Research
Network (RDCRN) that is funded by the National Institutes of Health (NIH) through the Office
of Rare Diseases (ORD) and the NINDS. The University of Iowa is the lead center in INC which
also includes sites from the University of Pennsylvania, Children's Hospital of Philadelphia
(CHOP), the University of Rochester (NY), the National Hospital for Neurology and
Neurosurgery in London England, the Dubowicz Neuromuscular Center, and the University of
Miami (Florida). The North American CMT Network is an additional consortium that is funded by
the Muscular Dystrophy Association (MDA) and the Charcot Marie Tooth Association (CMTA). The
University of Iowa is the lead site for this consortium as well. Additional sites include the
University of Washington (Seattle), Vanderbilt University, Johns Hopkins University, the
University of Sydney, the Besta Neurological Institute in Milan (Italy), Harvard University
and the intramural Neurogenetics division of the NIH. All funding sources have agreed to
allow us to house data from the two consortia together at the NIH funded Data Management
Coordinating Center (DMCC) at the University of South Florida and to group them under the
name of the Inherited Neuropathies Consortium (INC).

The inherited peripheral neuropathies are often called Charcot Marie Tooth Disease (CMT),
named after the three physician scientists who first described them. These are a heterogenous
group of disorders caused by mutations in more than 50 different genes. The diseases cause
weakness and loss of sensation in patients. There are no effective treatments for any forms
of CMT. There is also limited information on the natural history of how any of the different
types of CMT progress and limited outcome measures to measure impairment. The purpose of INC
is to investigate the natural history of the different types of CMT, to identify genes that
modify the severity of individual types of CMT, to develop and test outcome measures for
children with CMT, to develop an interactive website for patients with CMT and to develop the
knowledge needed to perform clinical trials in patients with CMT.

To do this, people who have, are suspected to have, or have a family history of an inherited
neuropathy will take part in a full-day evaluation. These patients are being seen in order to
receive a possible diagnosis of CMT and clinical care, but may also choose to participate in
this research project. Most of the testing being performed would be done as part of the
standard of care for diagnosing and treating a patient with an inherited neuropathy.
Additional testing may be performed on certain subjects if applicable, but the majority of
subjects who volunteer for this study are allowing us to use the clinical information
obtained during their visit as coded data for natural history purposes and to develop outcome
measures.

Because all individuals who attend the CMT clinic would be eligible for participation in this
study, when they arrive for their clinic visit, the initial meeting is to review the consent
form for the research project. Thus, the evaluation will begin with consenting subjects into
the study, if applicable. Then, a variety of tests will take place to measure the presence
and severity of symptoms, along with identifying which type of CMT a patient/subject may
have. Tests included in this study which are also the standard of care for patients with
inherited neuropathies include a neurological evaluation by a trained neurologist, a limited
set of nerve conduction studies, physical therapy assessment, orthotist assessment, genetic
counseling, and possibly genetic testing to determine the form of CMT. Additional clinical
testing which may be used for research includes EMGs or MUNE testing to evaluate possible
muscular dystrophies or muscle involvement in the disease. The results from these tests will
be used for diagnostic purposes and to give each patient a CMT Neuropathy Score (CMTNS) which
is a validated instrument that allows us to assess the severity of disease based on a 36
point scale. If the subject is also involved in the research project, the results will also
be used for research purposes.

Additionally, some subjects may undergo testing which is not a part of regular clinical care,
but is being done for research purposes only. These tests/procedures may include hand
function testing, physical assessment using the CMT Peds Score (an instrument used to
evaluate children with CMT - see substudy 6603), research based genetic testing, quality of
life questionnaires, or a skin biopsy. All of these tests/procedures are optional, subjects
do not have to complete these to be involved in the overall natural history study. Opting out
of any of these procedures does not mean that they would be excluded from the study. Some of
these procedures would only be performed on certain individuals who are eligible based on age
or type of CMT. Skin biopsies are being performed on certain qualified subjects for research
purposes in order to grow fibroblast cells to further study various forms of CMT. These
individuals would be over 18 and have specific forms of CMT.

Additionally, there are sub-studies that are being performed which SOME subjects may be
eligible for. These sub-study options will be discussed with each patient prior to their
participation.

Sub-study #6601 - Test-retest protocol addendum for pCMT-QOL. Substudy for a small group of
subjects in order to assess the test-retest reliability indicates reproducibility of the
pCMT-QOL. In order to calculate test-retest reliability, at a single site of the Inherited
Neuropathy Consortium (University of Iowa), 25 subjects aged 8-18 and their parents will be
given the appropriate version of pCMT-QOL, as well as the parents of 10 subjects aged 7 and
under. These parents will in addition be given a pre-stamped envelope containing the same
version of the pCMT-QOL that they took, to be completed by their child and/or parent in 4
weeks and return by mail (in CMT, the disease should not fluctuate in a 4 week interval).
Parents will be given one reminder phone call in 6-8 weeks, and the pCMT-QOL forms will be
mailed to them again if they are reported missing. Test-retest reliability will be estimated
by intraclass correlation coefficients (two-way random effects model) to show correlations
between any given individual's scores in two QOL assessments taken 4 weeks apart.

Sub-study #6602 - 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 type 2 (CMT2). 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.

Sub-study #6603 - This project is to develop a new CMT Pediatric Scale (CMT Peds) for
Children with CMT. Although there is a validated score (the CMTNS) which measures disease
severity for CMT, it is not always applicable to children due to their limited ability to
relay information about their symptoms. The CMT Peds scale is being developed and validated
in order to measure disease severity in children and have outcome measures available for
future clinical trials. Children (defined as 21 and under) being evaluated will be asked to
perform functional tasks such as using stairs, walking in a hallway, and performing hand
function tests. This information will be used to validate the CMT Peds score. Subjects will
be informed that this study is optional.

These tests will be performed in one day during the clinic visit. Patients who attend the
clinic are given the option of returning for annual visits to help with disease management.
If a patient decides to follow up in the clinic, they will once again be asked to participate
in the research. They do not need to participate in the research in order to be seen in the
clinic, and they can opt out at any time. If a subject does not follow up by making an
appointment in the clinic, they will not be contacted by us to schedule a return visit. All
return visits are initiated by the patient/subject. An individual can decide not to
participate in the research, but will still be able to be seen in the clinic and receive
medical recommendations, treatment, and care by the clinical team who specializes in
inherited neuropathies.

Inclusion Criteria:

All patients MUST be seen in person at a participating clinical site to be enrolled in the
study.

Inclusion Criteria - Charcot Marie Tooth disease type 1B (CMT1B) and type 2A (CMT2A)

1. Patient has documented, disease causing mutation in the MPZ gene (for CMT1B) or in
MFN2 (for CMT2A) OR

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

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

- 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:

- Variant is listed as disease causing at
http://www.molgen.ua.ac.be/CMTMutations/Mutations/Default.cfm.

- 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).

4. Patient has understood and signed an IRB approved consent form for the study.
Teenagers (age 13 - 17 years) must sign an assent form. See Appendix A for a sample
consent form with HIPAA. See Appendix B for a sample assent form.

Inclusion Criteria - Charcot Marie Tooth disease type 4A (CMT4A) and 4C (CMT4C)

1. Patient has two documented, disease causing mutations in the GDAP1 gene (for CMT4A) or
two mutations in the SH3TC2 gene (for CMT4C) OR

2. Patients who have variants of uncertain significance, as determined by the laboratory
performing the testing, may still be included if one of the following circumstances
applies:

- Patient has one known disease causing mutation and one variant that is listed as
disease causing at http://www.molgen.ua.ac.be/CMTMutations/Mutations/Default.cfm.

OR

- Patient has two variants listed as disease causing mutations at the above
website.

OR

- Patient is homozygous for a variant with or without consanguineous parents. OR

- The principal investigator and the site investigator agree that the variant(s) is
(are) most likely disease causing.

3. Patient has understood and signed an IRB approved consent form for the study.
Teenagers (age 13 - 17 years) must sign an assent form.

ADDITIONAL PARTICIPANTS

For patients with other forms of CMT than listed above, we will perform all assessments to
prepare for further studies into the disease and the disease process. These patients will
be characterized based on their type of CMT, if known, or by the following categories:

- Nerve conduction velocities: demyelinating , axonal, intermediate

- Inheritance: dominant, recessive, X-linked, or unknown

Exclusion Criteria:

1. Patient does not have a documented mutation in MPZ (for CMT1B) or MFN2 (for CMT2A),
nor does a first or second degree family member. Patient does not have two documented
mutations in GDAP1 (for CMT4A) or SH3TC2 (CMT4C).

2. Patient has a variant of uncertain significance that cannot be further classified
following methods listed in the Inclusion Criteria.

3. Patient does not wish to be a part of the study or has not signed an informed consent
form.

4. Patient is deemed inappropriate by the Site PI.