The most common inherited neuropathy is Charcot-Marie-Tooth disease type 1A (CMT1A), caused by a duplication of the gene expressing PMP22. CMT1A patients develop symptoms in early childhood with variable progression and there is no established therapy until now. Therapy must start in childhood, before peripheral nerves degenerate. However, the investigators lack easily obtainable biomarkers in early disease stages. In peripheral nerves from young CMT1A rats, the invstigators found changes in gene regulation that predicted the clinical disease severity later in adulthood, and gene expression from blood samples in young CMT1A rats were strong predictors of the future disease course. In blood samples from adult CMT1A patients, changes in gene expression also correlated with disease severity, demonstrating that findings can be "translated" from CMT rats to patients.
Objectives: In CMT-MODs, the investigators will identify disease and prognostic biomarkers in young CMT1A patients.
Strategy/ Methodology: In a translational approach, the investigators will first perform a multi-omic analysis (transcriptomic and proteomic) in sciatic nerves, blood and skin of young CMT1A rats at two timepoints in order to identify novel early markers of disease severity. In parallel, the investigators will assess a large cohort of CMT1A children, adolescents and young adults aged 10-30 years over 12 months applying the novel clinical outcome measures CMT Examination Score/CMT Neuropathy Score Version Version 2 Rasch versions (CMTES-R/CMTNSv2-R), the functional outcome measure CMT-FOM, pCMT-Qol, as well as a nerve conduction study (NCS) and quantitative MRI. Moreover, the following patient-reported outcome measures (PROMs) will also applied: VAS (pain, fatigue, cramps), WALK-12 and PGI-c. Blood (and optional skin) samples will be taken and gene expression of the most promising candidates, which the investigators originally identified in CMT rats, will be measured.
Results: This unprecedented assessment of CMT patients and animal models at early disease stages will allow CMT-MODs to establish biomarkers that may serve as a standard readout for disease severity and predict the disease course.
Impact: These novel diagnostic measures are urgently needed and will make clinical trials in early disease stages (children) possible in order to effectively treat and prevent CMT1A disease. Without effective biomarkers, promising preclinical therapeutic strategies cannot be translated to patients.
collaborative children, adolescents and young adults aged 10-30 years
genetic diagnosis of CMT1A, or clinical diagnosis and genetic diagnosis in affected relatives
able to walk with/ without support.
neuromuscular disorders other than CMT1A
concomitant disease preventing correct patient evaluation and contraindication to qMRI
Outpatients clinics, patient support groups, German CMT registry
Cohort
Prospective
Not listed
Charcot-Marie-Tooth Examination Score Rasch Analysis (CMTES-R)
The Charcot-Marie-Tooth Examination Score Rasch Version (CMTES-R) is a refined version of the Charcot-Marie-Tooth Examination Score (CMTES), which is used to assess disease severity in Charcot-Marie-Tooth disease (CMT). The Rasch version applies Rasch analysis, a statistical method that ensures the scale measures disease severity in a linear and more reliable way. Minimum Score (Best Condition): 0 Indicates no clinical impairment (normal strength, sensation, and reflexes). Maximum Score (Worst Condition): 32 Reflects severe disability, with profound weakness, loss of sensation, and absent reflexes.
Charcot-Marie-Tooth Neuropathy Score Version 2 Rasch Analysis (CMTNSv2-R)
The Charcot-Marie-Tooth Neuropathy Score Version 2 Rasch Version (CMTNSv2-R) is a refined version of the Charcot-Marie-Tooth Neuropathy Score (CMTNSv2), optimized using Rasch analysis for improved measurement of disease severity. Minimum Score (Best Condition): 0 Indicates no clinical impairment (normal strength, sensation, and reflexes). Maximum Score (Worst Condition): 36 Reflects severe disability, with profound weakness, loss of sensation, and absent reflexes.
Charcot-Marie-Tooth Functional Outcome Measeure (CMT-FOM)
The Charcot-Marie-Tooth Functional Outcome Measure (CMT-FOM) is a performance-based assessment designed to evaluate functional abilities in individuals with Charcot-Marie-Tooth disease (CMT). It is primarily used in clinical trials and longitudinal studies to track disease progression and treatment effectiveness. Minimum Score (Best Function): 0 Indicates no functional impairment (optimal performance in all tasks). Maximum Score (Worst Function): 52 Indicates severe functional impairment (significant difficulty or inability to complete tasks).
Short Form-12 (SF-12)
The SF-12 (Short Form-12) Health Survey is a widely used questionnaire designed to measure health-related quality of life (HRQoL). It is a shorter version of the SF-36 Health Survey, maintaining its reliability while reducing respondent burden.The Scoring and Interpretation The SF-12 produces two summary scores: Physical Component Summary (PCS) - Reflects overall physical health. Mental Component Summary (MCS) - Reflects overall mental health. Scores typically range from 0 to 100, with higher scores indicating better health. The scores are standardized based on population norms, where the average is 50 with a standard deviation of 10. SF12 ist used for adults in the study.
pCMT-QoL
The pCMT-QoL (Pediatric Charcot-Marie-Tooth Quality of Life) questionnaire is a disease-specific tool designed to assess the quality of life (QoL) in children and adolescents with Charcot-Marie-Tooth disease (CMT). It was developed to capture the unique physical, emotional, and social challenges faced by young individuals living with CMT. Scoring and Range The pCMT-QoL generates a total score along with subscale scores for different domains. Scores are typically standardized, where a higher score indicates a better quality of life, and a lower score reflects more significant disease burden. The exact numerical range depends on the specific version used, but similar pediatric QoL measures often have a 0-100 scale, where 100 represents the best possible quality of life. The pCMT-QoL ist used for children and adolescents in the study.
Quantitative Mangetic Resonance Imaging (qMRI)
Biomarkers such as fat fraction measured using quantitative MRI (qMRI) in lower limb has been described as largely responsive after 12 months follow-up in CMT1A adults, but was poorly assessed in children and adolescents. In addition, given the length-dependent nature of the disease one can expect that qMRI measurements will be early abnormal in foot muscles. Thus, in all complying young patients (CMT1A and controls) the investigators plan to perform qMRI measurements (1.5T or 3T) in foot and lower leg muscles according to the protocol designed by the Marseille center at T1 and T3.
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University Medical Center Goettingen
Lead sponsor
Assistance Publique Hopitaux De Marseille
Collaborator
