Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Type (CMT1B), 2A (CMT2A), 4A (CMT4A), 4C (CMT4C), and Others
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 5,000
- 试验地点
- 22
- 主要终点
- Charcot Marie Tooth Neuropathy Score (CMTNS)
研究概览
简要总结
This is an observational longitudinal study to determine the natural history and genotype-phenotype correlations of disease causing mutations in Charcot Marie Tooth disease (CMT) type 1B (CMT1B), 2A (CMT2A), 4A (CMT4A), and 4C (CMT4C).
The investigators will also be determine the capability of the newly developed CMT Pediatric Scale (CMT Peds scale) and the Minimal Dataset to measure impairment and perform longitudinal measurements in patients with multiple forms of CMT over a five year window
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •All patients must be seen in-person at a participating center for the initial visit.
- •Inclusion Criteria - patients with CMT (all subtypes)
- •Patient has documented, pathogenic or likely pathogenic CMT-causing variant(s)
- •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.
- •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.
- •Patients whose clinical presentation is suggestive of CMT, but CMT type and variant are unknown will be characterized by the following categories:
- •Nerve conduction velocities: demyelinating, axonal, intermediate
- •Inheritance: dominant, recessive, X-linked, or unknown
- •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
- •Person does not have a peripheral neuropathy, as determined by the investigator.
- •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
- •Patient has a variant of uncertain significance that cannot be further classified following methods listed in the Inclusion Criteria.
- •Patient does not wish to be a part of the study or has not signed an informed consent form.
- •Patient is deemed inappropriate by the Site PI.
排除标准
- 未提供
结局指标
主要结局
Charcot Marie Tooth Neuropathy Score (CMTNS)
时间窗: 1 year
Charcot Marie Tooth Neuropathy Score (CMTNS) is a composite measure of disability based on a person's symptoms, signs, and electrophysiology. It is based on a 36 point scale, with 9 items each worth up to 4 points. A higher score signifies increased disability.
Minimal dataset
时间窗: 1 year
This includes diagnosis, family history, developmental history, walking ability, hand function, strength, sensation, and neurophysiology.
次要结局
未报告次要终点
研究者
Michael Shy
Professor
University of Iowa