Studying Nerve Function and Structure in Charcot-Marie-Tooth Disease, Anti-MAG Neuropathy and CIDP (CMT-NFS)

March 6, 2026 updated by: Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

Axonal Excitability and Ultrasound Patterns in Charcot-Marie-Tooth Disease and Other Demyelinating Disorders

The project aims to perform both conventional nerve-conduction studies and axonal-excitability assessments using the TRONDF protocol in patients with selected forms of Charcot-Marie-Tooth disease, with comparison to individuals affected by dysimmune, acquired neuropathies, specifically chronic inflammatory demyelinating polyneuropathy (CIDP) and anti-MAG-neuropathy. The study further includes the analysis of nerve fibers obtained from skin biopsy in patients with CMT, as well as ultrasound evaluation of nerves (from the wrist to the axilla) and of intrinsic hand muscles. Axonal-excitability techniques involve the delivery of two electrical stimuli to the nerve under investigation; both stimuli vary in intensity, whereas only the first, known as the conditioning stimulus, varies in duration. Changes in response amplitude are then measured as these stimulation parameters are systematically adjusted. Some preliminary studies have already suggested the effectiveness of this method in distinguishing CMT1A from certain forms of acquired demyelinating disease, including acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and CIDP. Despite the promising results, only a limited number of studies have so far been conducted in humans and mice, and no comprehensive and systematic study has yet been carried out describing the changes in axonal excitability in the various CMT subtypes, either in humans or in mouse models.

Study Overview

Status

Recruiting

Conditions

Detailed Description

Charcot-Marie-Tooth neuropathy (CMT) is the most prevalent hereditary neuromuscular disorder, estimated to affect 11.8 to 82.3 individuals per 100,000 in Europe. While genetic assessment is increasingly gaining significance, neurophysiology continues to play a crucial role in classifying CMT into axonal, intermediate or demyelinating forms. Despite its diagnostic importance, standard neurophysiology techniques may prove inadequate to reliably capture disease progression, advocating for the adoption of newer methodologies in the near future. Among these, axonal excitability testing, providing information about the properties of axonal membranes insight into the behaviour of voltage-gated ion channels, pump and exchangers involved in impulse conduction, could have potential additional diagnostic and prognostic value in neuromuscular disorder.

Axonal excitability techniques provide insights into ion channel function, serving as an in vivo surrogate markers of axonal membrane potential in human axons. Recent advancements in this field have standardized procedures, increased execution speed, and minimized patients' discomfort enabling routine clinical application. These advancements include the development of standardized semi-automated recording setups and the publication of international guidelines. It is plausible that progressive ion-channel dysfunction and spontaneous baseline depolarization of nerves maybe associated with disease severity and response to therapy (in patients with acquired polyneuropathies).

Investigators plan to study a series of patients with different types of CMT with this technique and compare results with diseased controls affected by dysimmune neuropathies and corresponding mouse models, by conventional nerve conduction studies, by electrical nerve stimulation to study neuronal excitability as below depicted, and by examining myelinated skin nerves by performing skin biopsy in a subset of patients.

Moreover, literature data demonstrate that nerve ultrasound supports the diagnosis and follow-up of neuromuscular disorders. In the context of neuropathies, nerve ultrasound enables an anatomical and structural evaluation that provides useful data for the differential diagnosis between hereditary and acquired forms. In particular, in Charcot-Marie-Tooth disease, nerve ultrasound allows the identification of pathognomonic patterns that can significantly guide genetic testing (e.g CMT1A).

In severe acquired forms, where the pathological process is so extensive that clear electrophysiological findings are not always present, nerve ultrasound can detect specific alterations that may help guiding the diagnosis. Moreover, nerve ultrasound can identify certain features that may suggest (and correlate with) the severity of the disease.

Muscle ultrasound in neuromuscular disorders is instead a more recent application. The detection of specific patterns of muscle involvement can suggest a possible regional distribution, described in some nosological entities. Furthermore, literature data show that the structural and ultrasound characteristics of the muscle correlate with the degree of strength deficit. Despite the increasing amount of literature in the field, no nerve or muscle ultrasound studies have yet been published on some acquired forms and rare forms of Charcot-Marie-Tooth disease. The collection and analysis of ultrasound data in these cases would allow for a broader understanding of the related pathological processes, potentially identifying patterns that support diagnosis and follow-up.

Collaborators for this project are the following: Inherited Neuropathy Consortium (INC); Prof. Christian Krarup (Dept of Clin. Neurophys., Rigshospitalet, Copenhagen, DK; Dept of Neuroscience, Univ. of Copenhagen, Copenhagen, DK); Prof. Mihai Moldovan (Dept of Neurol., North Zealand Hospital, Hillerød, DK; Dept of Clin. Neurophys., Rigshospitalet, Copenhagen, DK; Dept of Neuroscience, Univ. of Copenhagen, Copenhagen, DK); Prof. Hatice Tankisi (Aarhus University Hospital, Department of Clinical Neurophysiology, Aarhus, Denmark; Aarhus University, Department of Clinical Medicine, Aarhus, Denmark)

Study Type

Observational

Enrollment (Estimated)

39

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

  • A minimum of 30 patients with a genetically confirmed diagnosis of CMT
  • At least 15 patients diagnosed with either Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) or anti-myelin associated glycoprotein (MAG) polyneuropathy as a disease control group.

Description

Inclusion Criteria:

  1. The subject is ≥ 18 years old.

    AND:

  2. A genetically confirmed diagnosis of one of the several CMT subtypes (i.e., CMT1A, CMT1B, CMTX1, CMT2I/J, CMT4B, CMT4D and CMT4J) OR
  3. A clinical diagnosis of either Chronic Inflammatory Demyelinating Polyneuropathy or anti-MAG polyneuropathy

Exclusion Criteria:

  1. Known neuropathy from another cause (e.g., diabetes, chronic renal insufficiency, medications, alcohol), including previous carpal tunnel syndrome surgery.
  2. History of exposure to chemotherapeutic agents (e.g., bortezomib, vincristine, cisplatin, taxol, vedotin/auromycin-conjugated antibodies), or other medications (e.g., disulfuram, thalidomide, voriconizole, chronic colchicine use) that can cause neuropathy, active alcohol abuse.
  3. History of cancer, other than skin cancer, within 5 years prior to enrollment.
  4. Pregnancy or nursing.
  5. Known systemic disease that predisposes to neuropathy.
  6. Other central nervous system diseases.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Strength-Duration Time Constant
Time Frame: 2 years
Strength-duration time constant (SDTC, ms) measured using threshold tracking nerve excitability testing in participants with genetically defined Charcot-Marie-Tooth disease subtypes and acquired immune-mediated neuropathies (CIDP and anti-MAG neuropathy).
2 years
Recovery Cycle of Nerve Excitability Parameters
Time Frame: 2 years
Recovery cycle of nerve excitability parameters measured using threshold tracking nerve excitability testing in participants with genetically defined Charcot-Marie-Tooth disease subtypes and acquired immune-mediated neuropathies (CIDP and anti-MAG neuropathy), including superexcitability and late subexcitability (% threshold change)
2 years
Threshold Electrotonus
Time Frame: 2 years
Threshold Electrotonus (TE, % threshold change at specified time intervals) measured using threshold tracking nerve excitability testing in participants with genetically defined Charcot-Marie-Tooth disease subtypes and acquired immune-mediated neuropathies (CIDP and anti-MAG neuropathy).
2 years
Current-Threshold (I/V) Relationship
Time Frame: 2 years
Current-threshold (I/V) relationship parameters (e.g., slope of threshold change versus polarizing current) measured using threshold tracking nerve excitability testing in participants with genetically defined Charcot-Marie-Tooth disease subtypes and acquired immune-mediated neuropathies (CIDP and anti-MAG neuropathy).
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Peripheral nerve cross-sectional area by ultrasound
Time Frame: 2 years
Cross-sectional area (CSA, mm²) of the median and ulnar nerves measured by ultrasound from the wrist to the axilla in participants with Charcot-Marie-Tooth disease, CIDP, and anti-MAG neuropathy.
2 years
Muscle thickness by ultrasound
Time Frame: 2 years
Muscle thickness (mm) of the abductor pollicis brevis, abductor digiti minimi, and first dorsal interosseous muscles measured by ultrasound in participants with Charcot-Marie-Tooth disease, CIDP, and anti-MAG neuropathy.
2 years
Muscle echogenicity by ultrasound (Heckmatt scale)
Time Frame: 2 years

Muscle echogenicity graded using the Heckmatt scale (grades 1-4) in the abductor pollicis brevis, abductor digiti minimi, and first dorsal interosseous muscles.

Heckmatt scale grading:

Grade 1: normal Grade 2: increased muscle echogenicity with preserved architecture and normal bone reflection Grade 3: increased echogenicity with partial loss of architecture and reduced bone reflection Grade 4: markedly increased echogenicity with complete loss of architecture and absent bone reflection
2 years
Correlation of ultrasound parameters with clinical and electrophysiological measures
Time Frame: 2 years
Correlation between ultrasound parameters (nerve CSA, muscle thickness, and Heckmatt grade) and clinical severity measured by CMTNS/CMTES and axonal excitability parameters.
2 years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Axonal excitability strength-duration time constant in mouse models
Time Frame: 2 years
Strength-duration time constant (SDTC, ms) measured using threshold tracking nerve excitability testing in TM/TM mice carrying the MPZ T124M mutation, C3-PMP22 transgenic mice, and wild-type control mice.
2 years
Recovery Cycle of excitability parameters in mouse models
Time Frame: 2 years
Recovery Cycle of excitability parameters, including relative refractory period (ms), superexcitability (% threshold change), and late subexcitability (% threshold change), measured in TM/TM mice, C3-PMP22 transgenic mice, and wild-type control mice.
2 years
Threshold Electrotonus in mouse models
Time Frame: 2 years
Threshold Electrotonus (TE, % threshold change at specified time intervals) measured in TM/TM mice, C3-PMP22 transgenic mice, and wild-type control mice.
2 years
Current-threshold (I/V) relationship in mouse models
Time Frame: 2 years
Current-threshold (I/V) relationship parameters (e.g., slope of threshold change versus polarizing current) measured in TM/TM mice, C3-PMP22 transgenic mice, and wild-type control mice.
2 years
Cross-species comparison of axonal excitability parameters
Time Frame: 2 years
Comparison of axonal excitability parameters (SDTC, Recovery Cycle, TE, and I/V relationship) between mouse models and homologous human disease cohorts.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

Investigators

  • Principal Investigator: Davide Pareyson, MD, Fondazione IRCCS Istituto Neurologico Carlo Besta

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 3, 2025

Primary Completion (Estimated)

May 1, 2026

Study Completion (Estimated)

May 1, 2026

Study Registration Dates

First Submitted

January 29, 2026

First Submitted That Met QC Criteria

March 6, 2026

First Posted (Actual)

March 10, 2026

Study Record Updates

Last Update Posted (Actual)

March 10, 2026

Last Update Submitted That Met QC Criteria

March 6, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CMT-NFS

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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