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

NCT07461896 | Recruiting

• 1 other identifier: CMT-NFS
• Study Type: observational
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Charcot-Marie-Tooth; Chronic Inflammatory Demyelinating Polyneuropathy (CIDP); CMT1A; Polyneuropathy Associated With Anti-MAG Antibodies (Anti-MAG Polyneuropathy); Anti-MAG Neuropathy

Keywords

Charcot-Marie-Tooth; Neurophysiology; Axonal excitability; Ultrasound (US); CMT1A; CMT1B; CMTX1; CMT2I/J; CMT4B2; CMT4D; CMT4J; CIDP; anti-MAG

Outcome Measures

Primary Outcomes (4)

• Strength-Duration Time Constant

  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

  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

  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

  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 Outcomes (4)

• Peripheral nerve cross-sectional area by ultrasound

  2 years

• Muscle thickness by ultrasound

  2 years

• Muscle echogenicity by ultrasound (Heckmatt scale)

  2 years

• Correlation of ultrasound parameters with clinical and electrophysiological measures

  2 years

Other Outcomes (5)

• Axonal excitability strength-duration time constant in mouse models

  2 years

• Recovery Cycle of excitability parameters in mouse models

  2 years

• Threshold Electrotonus in mouse models

  2 years

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• The subject is ≥ 18 years old.
• AND:
• A genetically confirmed diagnosis of one of the several CMT subtypes (i.e., CMT1A, CMT1B, CMTX1, CMT2I/J, CMT4B, CMT4D and CMT4J) OR
• A clinical diagnosis of either Chronic Inflammatory Demyelinating Polyneuropathy or anti-MAG polyneuropathy

You may not qualify if:

• Known neuropathy from another cause (e.g., diabetes, chronic renal insufficiency, medications, alcohol), including previous carpal tunnel syndrome surgery.
• 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.
• History of cancer, other than skin cancer, within 5 years prior to enrollment.
• Pregnancy or nursing.
• Known systemic disease that predisposes to neuropathy.
• Other central nervous system diseases.

Sponsors & Collaborators

• Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta: lead

Study Sites (1)

Fondazione IRCCS Istituto Neurologico Carlo Besta

Milan, 20133, Italy

RECRUITING

Related Publications (21)

• Shahrizaila N, Noto Y, Simon NG, Huynh W, Shibuya K, Matamala JM, Dharmadasa T, Devenney E, Kennerson ML, Nicholson GA, Kiernan MC. Quantitative muscle ultrasound as a biomarker in Charcot-Marie-Tooth neuropathy. Clin Neurophysiol. 2017 Jan;128(1):227-232. doi: 10.1016/j.clinph.2016.11.010. Epub 2016 Nov 21.

  PMID: 27940147 BACKGROUND

• Padua L, Granata G, Sabatelli M, Inghilleri M, Lucchetta M, Luigetti M, Coraci D, Martinoli C, Briani C. Heterogeneity of root and nerve ultrasound pattern in CIDP patients. Clin Neurophysiol. 2014 Jan;125(1):160-5. doi: 10.1016/j.clinph.2013.07.023. Epub 2013 Oct 5.

  PMID: 24099922 BACKGROUND

• Noto Y, Shiga K, Tsuji Y, Mizuta I, Higuchi Y, Hashiguchi A, Takashima H, Nakagawa M, Mizuno T. Nerve ultrasound depicts peripheral nerve enlargement in patients with genetically distinct Charcot-Marie-Tooth disease. J Neurol Neurosurg Psychiatry. 2015 Apr;86(4):378-84. doi: 10.1136/jnnp-2014-308211. Epub 2014 Aug 4.

  PMID: 25091364 BACKGROUND

• Schreiber S, Oldag A, Kornblum C, Kollewe K, Kropf S, Schoenfeld A, Feistner H, Jakubiczka S, Kunz WS, Scherlach C, Tempelmann C, Mawrin C, Dengler R, Schreiber F, Goertler M, Vielhaber S. Sonography of the median nerve in CMT1A, CMT2A, CMTX, and HNPP. Muscle Nerve. 2013 Mar;47(3):385-95. doi: 10.1002/mus.23681. Epub 2013 Feb 4.

  PMID: 23381770 BACKGROUND

• Manganelli F, Nolano M, Pisciotta C, Provitera V, Fabrizi GM, Cavallaro T, Stancanelli A, Caporaso G, Shy ME, Santoro L. Charcot-Marie-Tooth disease: New insights from skin biopsy. Neurology. 2015 Oct 6;85(14):1202-8. doi: 10.1212/WNL.0000000000001993. Epub 2015 Sep 11.

  PMID: 26362287 BACKGROUND

• Nobbio L, Visigalli D, Radice D, Fiorina E, Solari A, Lauria G, Reilly MM, Santoro L, Schenone A, Pareyson D; CMT-TRIAAL Group. PMP22 messenger RNA levels in skin biopsies: testing the effectiveness of a Charcot-Marie-Tooth 1A biomarker. Brain. 2014 Jun;137(Pt 6):1614-20. doi: 10.1093/brain/awu071. Epub 2014 May 8.

  PMID: 24812204 BACKGROUND

• Burke D, Kiernan MC, Bostock H. Excitability of human axons. Clin Neurophysiol. 2001 Sep;112(9):1575-85. doi: 10.1016/s1388-2457(01)00595-8.

  PMID: 11514239 BACKGROUND

• Kiernan MC, Burke D, Andersen KV, Bostock H. Multiple measures of axonal excitability: a new approach in clinical testing. Muscle Nerve. 2000 Mar;23(3):399-409. doi: 10.1002/(sici)1097-4598(200003)23:33.0.co;2-g.

  PMID: 10679717 BACKGROUND

• Bostock H, Cikurel K, Burke D. Threshold tracking techniques in the study of human peripheral nerve. Muscle Nerve. 1998 Feb;21(2):137-58. doi: 10.1002/(sici)1097-4598(199802)21:23.0.co;2-c.

  PMID: 9466589 BACKGROUND

• Moldovan M, Alvarez S, Pinchenko V, Klein D, Nielsen FC, Wood JN, Martini R, Krarup C. Na(v)1.8 channelopathy in mutant mice deficient for myelin protein zero is detrimental to motor axons. Brain. 2011 Feb;134(Pt 2):585-601. doi: 10.1093/brain/awq336. Epub 2010 Dec 17.

  PMID: 21169333 BACKGROUND

• Rosberg MR, Alvarez S, Klein D, Nielsen FC, Martini R, Levinson SR, Krarup C, Moldovan M. Progression of motor axon dysfunction and ectopic Nav1.8 expression in a mouse model of Charcot-Marie-Tooth disease 1B. Neurobiol Dis. 2016 Sep;93:201-14. doi: 10.1016/j.nbd.2016.05.014. Epub 2016 May 20.

  PMID: 27215377 BACKGROUND

• Nasu S, Misawa S, Nakaseko C, Shibuya K, Isose S, Sekiguchi Y, Mitsuma S, Ohmori S, Iwai Y, Beppu M, Shimizu N, Ohwada C, Takeda Y, Fujimaki Y, Kuwabara S. Bortezomib-induced neuropathy: axonal membrane depolarization precedes development of neuropathy. Clin Neurophysiol. 2014 Feb;125(2):381-7. doi: 10.1016/j.clinph.2013.07.014. Epub 2013 Aug 21.

  PMID: 23973385 BACKGROUND

• Lin CS, Krishnan AV, Park SB, Kiernan MC. Modulatory effects on axonal function after intravenous immunoglobulin therapy in chronic inflammatory demyelinating polyneuropathy. Arch Neurol. 2011 Jul;68(7):862-9. doi: 10.1001/archneurol.2011.137.

  PMID: 21747028 BACKGROUND

• Park SB, Lin CS, Krishnan AV, Goldstein D, Friedlander ML, Kiernan MC. Oxaliplatin-induced neurotoxicity: changes in axonal excitability precede development of neuropathy. Brain. 2009 Oct;132(Pt 10):2712-23. doi: 10.1093/brain/awp219. Epub 2009 Sep 10.

  PMID: 19745023 BACKGROUND

• Sung JY, Kuwabara S, Kaji R, Ogawara K, Mori M, Kanai K, Nodera H, Hattori T, Bostock H. Threshold electrotonus in chronic inflammatory demyelinating polyneuropathy: correlation with clinical profiles. Muscle Nerve. 2004 Jan;29(1):28-37. doi: 10.1002/mus.10516.

  PMID: 14694495 BACKGROUND

• Moldovan M, Pisciotta C, Pareyson D, Krarup C. Myelin protein zero gene dose dependent axonal ion-channel dysfunction in a family with Charcot-Marie-Tooth disease. Clin Neurophysiol. 2020 Oct;131(10):2440-2451. doi: 10.1016/j.clinph.2020.06.034. Epub 2020 Aug 6.

  PMID: 32829291 BACKGROUND

• Vanhees L, Aubert A, Fagard R, Hespel P, Amery A. Influence of beta 1- versus beta 2-adrenoceptor blockade on left ventricular function in humans. J Cardiovasc Pharmacol. 1986 Sep-Oct;8(5):1086-91. doi: 10.1097/00005344-198609000-00030.

  PMID: 2429084 BACKGROUND

• Nodera H, Bostock H, Kuwabara S, Sakamoto T, Asanuma K, Jia-Ying S, Ogawara K, Hattori N, Hirayama M, Sobue G, Kaji R. Nerve excitability properties in Charcot-Marie-Tooth disease type 1A. Brain. 2004 Jan;127(Pt 1):203-11. doi: 10.1093/brain/awh020. Epub 2003 Nov 7.

  PMID: 14607794 BACKGROUND

• Kiernan MC, Bostock H, Park SB, Kaji R, Krarup C, Krishnan AV, Kuwabara S, Lin CS, Misawa S, Moldovan M, Sung J, Vucic S, Wainger BJ, Waxman S, Burke D. Measurement of axonal excitability: Consensus guidelines. Clin Neurophysiol. 2020 Jan;131(1):308-323. doi: 10.1016/j.clinph.2019.07.023. Epub 2019 Aug 2.

  PMID: 31471200 BACKGROUND

• Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009 Jul;8(7):654-67. doi: 10.1016/S1474-4422(09)70110-3.

  PMID: 19539237 BACKGROUND

• Laura M, Pipis M, Rossor AM, Reilly MM. Charcot-Marie-Tooth disease and related disorders: an evolving landscape. Curr Opin Neurol. 2019 Oct;32(5):641-650. doi: 10.1097/WCO.0000000000000735.

  PMID: 31343428 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Skin biopsy for research purpose

MeSH Terms

Conditions

Charcot-Marie-Tooth Disease; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Charcot-Marie-Tooth disease, X-linked, 1; Charcot-Marie-Tooth disease, Type 4B2; Neuropathy, hereditary motor and sensory, LOM type

Condition Hierarchy (Ancestors)

Hereditary Sensory and Motor Neuropathy; Nervous System Malformations; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Polyneuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Polyradiculoneuropathy; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Davide Pareyson, MD

  Fondazione IRCCS Istituto Neurologico Carlo Besta

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Davide Pareyson, MD

CONTACT

+ 39 02.2394; davide.pareyson@istituto-besta.it

Amedeo De Grado, M.D.

CONTACT

02.2394; amedeo.degrado@istituto-besta.it

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2026
• First Posted: March 10, 2026
• Study Start: March 3, 2025
• Primary Completion: May 1, 2026
• Study Completion: May 1, 2026
• Last Updated: March 10, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)