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

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

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.

Study Overview

• Status: Recruiting
• Conditions: CMT - Charcot-Marie-Tooth Disease; CMT1A; CMT (Charcot Marie Tooth Disease); CMT 1A; CMT

• Study Type: Observational
• Enrollment (Estimated): 70

Contacts and Locations

• Study Contact: Name: Michael W Sereda, Prof. of Neurology; Phone Number: +49 551 3964162; Email: sereda@mpinat.mpg.de
• Study Contact Backup: Name: Beschan Ahmad; Email: beschan.ahmad@med.uni-goettingen.de

Study Locations

• Germany
  • Göttingen, Germany, 37075
    • Recruiting
    • University Medical Centre
    • Contact: Lisa Reinecke; Phone Number: +49 551 3964162; Email: neurologie.cmt-studien@med.uni-goettingen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Outpatients clinics, patient support groups, German CMT registry

Description

Inclusion criteria:

• 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.

Exclusion Criteria:

• neuromuscular disorders other than CMT1A
• concomitant disease preventing correct patient evaluation and contraindication to qMRI

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
CMT1A patients; 70
Controls; 40

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 months
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.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	12 months
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.	12 months
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.	12 months
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.	12 months
Visual Analogue Scale (VAS) for Pain, Fatigue, Cramps	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").	12 months
Walking Impact Scale-12 (WALK12)	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.	12 months
Patient Global Impression of Change (PGI-c)	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: = Very much improved; = Much improved; = Minimally improved; = No change; = Minimally worse; = Much worse; = Very much worse	12 months
Blood biomarkers	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.	12 months
Skin biomarkers	If patients agree the investigators will take skin biopsies for biomarker validation.	12 months
Fibroblasts	If patients agree, the investigators will take fibroblasts cultures from patients that are mildly and severly affected for future experiments.	The biopsies are taken at baseline visit and will then be cultivated for future experiments

Collaborators and Investigators

• Sponsor: University Medical Center Goettingen
• Collaborators: Assistance Publique Hopitaux De Marseille
• Investigators: Principal Investigator: Michael W Sereda, University Medical Centre Göttingen

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2025
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: February 23, 2025
• First Submitted That Met QC Criteria: March 11, 2026
• First Posted (Actual): March 17, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 9, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: transcriptomics; animal model; CMT1A children; blood-derived prognostic biomarkers; MRI biomarkers; disease modifier
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Peripheral Nervous System Diseases; Neurodegenerative Diseases; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Polyneuropathies; Hereditary Sensory and Motor Neuropathy; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Animal Diseases; Charcot-Marie-Tooth Disease; Disease Models, Animal
• Other Study ID Numbers: 2024-03110

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No