A Multi-omic Approach to the Identification of Novel Biomarkers in Early Charcot-Marie-Tooth 1A Disease (CMT1A)

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).

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.

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.

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.

The Visual Analogue Scale (VAS) is a widely used tool for assessing subjective symptoms such as pain, fatigue, and cramps. It provides a simple and effective way for individuals to self-report the intensity of their symptoms.

Structure and Usage The VAS is typically a straight horizontal or vertical line, 10 cm (100 mm) long.

One end represents no symptoms (e.g., "No pain"), and the other represents the worst possible intensity (e.g., "Worst pain imaginable").

The Walk-12 is a questionnaire designed to assess the impact of walking difficulties on daily life. It is often used for people with neuromuscular, neurological, or musculoskeletal conditions, such as Charcot-Marie-Tooth disease (CMT), multiple sclerosis (MS), or stroke survivors.

Scoring and Range Each question is scored on a 5-point Likert scale (e.g., 0 = no difficulty, 4 = extreme difficulty).

The total score ranges from 0 to 48. 0 = No walking difficulties Higher scores = Greater walking impairment The scores may be converted to a 0-100 scale for easier interpretation, where higher values indicate worse walking limitations.

The PGI-c is a single-item, patient-reported measure used to capture an individual's overall perception of improvement or deterioration in their condition over time. It provides a global assessment of change from the patient's perspective following an intervention or treatment.

Common Scale Range:

Most often, the scale ranges from 1 to 7, where:

1. = Very much improved
2. = Much improved
3. = Minimally improved
4. = No change
5. = Minimally worse
6. = Much worse
7. = Very much worse

In all patients, blood samples for transcriptome and proteome profiling will be analyzed to identify and provide clinically applicable transcriptional biomarkers. The investigators will subject 8 patients (severely affected, mildly affected and age-matched controls) to RNA-seq at T1 (visit 1, baseline). Then the data will be compared with the investigator's already available RNA-seq data sets from CMT1A rats and adult patients. The investigators will cross-validate the resulting candidates with the rat (nerve and blood) data and the existing data from adult patients and derive an integrated list of gene candidates. Next, the investigators will perform a qRT-PCR to validate the gene candidates. As substantial variability in gene expression levels among individuals is expected in RNA-Seq data, longitudinally repeated measurements will be performed to study global gene expression in CMT1A blood samples. Data will be collected and integrated for disease prediction.

If patients agree the investigators will take skin biopsies for biomarker validation.

If patients agree, the investigators will take fibroblasts cultures from patients that are mildly and severly affected for future experiments.