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Charcot-Marie-Tooth disease

MedGen UID:
2980
Concept ID:
C0007959
Disease or Syndrome
Synonyms: Charcot-Marie-Tooth hereditary neuropathy; Charcot-Marie-Tooth Neuropathy
 
Genes (locations): CNTNAP1 (17q21.2); DCTN2 (12q13.3); DRP2 (Xq22.1); MCM3AP (21q22.3); MORC2 (22q12.2); SGPL1 (10q22.1); WARS1 (14q32.2)
Related genes: FGD4, SBF2, SH3TC2, INF2, GNB4, TRPV4, PRX, JPH1, GDAP1, HSPB8, KIF1B, NDRG1, MFN2, FIG4, LITAF, AIFM1, MTMR2, YARS1, RAB7A, SBF1, PRPS1, PMP22, NEFL, MPZ, MME, MARS1, IGHMBP2, HSPB1, DNAJB2, HK1, GJB1, GARS1, EGR2, DYNC1H1, AARS1
 
Monarch Initiative: MONDO:0015626
OMIM®: 118200
OMIM® Phenotypic series: PS118220
Orphanet: ORPHA166

Definition

Charcot-Marie-Tooth disease encompasses a group of disorders called hereditary sensory and motor neuropathies that damage the peripheral nerves. Peripheral nerves connect the brain and spinal cord to muscles and to sensory cells that detect sensations such as touch, pain, heat, and sound. Damage to the peripheral nerves that worsens over time can result in alteration or loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.\n\nCharcot-Marie-Tooth disease usually becomes apparent in adolescence or early adulthood, but onset may occur anytime from early childhood through late adulthood. Symptoms of Charcot-Marie-Tooth disease vary in severity and age of onset even among members of the same family. Some people never realize they have the disorder because their symptoms are so mild, but most have a moderate amount of physical disability. A small percentage of people experience severe weakness or other problems which, in very rare cases, can be life-threatening. In most affected individuals, however, Charcot-Marie-Tooth disease does not affect life expectancy.\n\nTypically, the earliest symptoms of Charcot-Marie-Tooth disease result from muscle atrophy in the feet. Affected individuals may have foot abnormalities such as high arches (pes cavus), flat feet (pes planus), or curled toes (hammer toes). They often have difficulty flexing the foot or walking on the heel of the foot. These difficulties may cause a higher than normal step (steppage gait) and increase the risk of ankle injuries and tripping. As the disease worsens, muscles in the lower legs usually weaken, but leg and foot problems rarely require the use of a wheelchair.\n\nAffected individuals may also develop weakness in the hands, causing difficulty with daily activities such as writing, fastening buttons, and turning doorknobs. People with Charcot-Marie-Tooth disease typically experience a decreased sensitivity to touch, heat, and cold in the feet and lower legs, but occasionally feel aching or burning sensations. In rare cases, affected individuals have loss of vision or gradual hearing loss that sometimes leads to deafness.\n\nThere are several types of Charcot-Marie-Tooth disease, which are differentiated by their effects on nerve cells and patterns of inheritance. Type 1 (CMT1) is characterized by abnormalities in myelin, the fatty substance that covers nerve cells, protecting them and helping to transmit nerve impulses. These abnormalities slow the transmission of nerve impulses and can affect the health of the nerve fiber. Type 2 (CMT2) is characterized by abnormalities in the fiber, or axon, that extends from a nerve cell body to muscles or to sense organs. These abnormalities reduce the strength of the nerve impulse. In forms of Charcot-Marie-Tooth disease classified as intermediate type, the nerve impulses are both slowed and reduced in strength, probably due to abnormalities in both myelin and axons. Type 4 (CMT4) is distinguished from the other types by its pattern of inheritance; it can affect either the axons or the myelin. Type X Charcot-Marie-Tooth disease (CMTX) is caused by mutations in genes on the X chromosome, one of the two sex chromosomes. Within the various types of Charcot-Marie-Tooth disease, subtypes (such as CMT1A, CMT1B, CMT2A, CMT4A, and CMTX1) indicate different genetic causes.\n\nSometimes other, historical names are used to refer to particular forms of Charcot-Marie-Tooth disease. For example, Roussy-Levy syndrome is a form of CMT11 with the additional feature of rhythmic shaking (tremors). Dejerine-Sottas syndrome is a term sometimes used to describe a severe, early childhood form of Charcot-Marie-Tooth disease; it is also sometimes called type 3 (CMT3). Depending on the specific gene that is altered, this severe, early-onset form of the disorder may also be classified as CMT1 or CMT4. CMTX5 is also known as Rosenberg-Chutorian syndrome. [from MedlinePlus Genetics]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Charcot-Marie-Tooth disease in Orphanet.

Recent clinical studies

Etiology

Kitaoji T, Noto YI, Kojima Y, Tsuji Y, Mizuno T, Nakagawa M
Clin Neurophysiol 2021 Oct;132(10):2693-2701. Epub 2021 Jun 29 doi: 10.1016/j.clinph.2021.05.030. PMID: 34294566
Kanwal S, Choi YJ, Lim SO, Choi HJ, Park JH, Nuzhat R, Khan A, Perveen S, Choi BO, Chung KW
BMC Med Genomics 2021 Jun 30;14(1):174. doi: 10.1186/s12920-021-01019-5. PMID: 34193129Free PMC Article
Sivera R, Lupo V, Frasquet M, Argente-Escrig H, Alonso-Pérez J, Díaz-Manera J, Querol L, Del Mar García-Romero M, Ignacio Pascual S, García-Sobrino T, Paradas C, Francisco Vázquez-Costa J, Muelas N, Millet E, Jesús Vílchez J, Espinós C, Sevilla T
Eur J Neurol 2021 Sep;28(9):3001-3011. Epub 2021 Jul 18 doi: 10.1111/ene.15001. PMID: 34189813
Noto YI, Watanabe K, Holobar A, Kitaoji T, Tsuji Y, Kojima Y, Kitani-Morii F, Mizuno T, Nakagawa M
Clin Neurophysiol 2021 Mar;132(3):812-818. Epub 2021 Jan 5 doi: 10.1016/j.clinph.2020.11.040. PMID: 33483296
Kojima Y, Noto YI, Tsuji Y, Kitani-Morii F, Shiga K, Mizuno T, Nakagawa M
Muscle Nerve 2020 Dec;62(6):722-727. Epub 2020 Sep 27 doi: 10.1002/mus.27068. PMID: 32959396

Diagnosis

Xie Y, Lin Z, Liu L, Li X, Huang S, Zhao H, Wang B, Zeng S, Cao W, Li L, Zhu X, Huang S, Yang H, Wang M, Hu Z, Wang J, Guo J, Shen L, Jiang H, Zuchner S, Tang B, Zhang R
Eur J Neurol 2021 Nov;28(11):3774-3783. Epub 2021 Jul 26 doi: 10.1111/ene.15024. PMID: 34255403
Kanwal S, Choi YJ, Lim SO, Choi HJ, Park JH, Nuzhat R, Khan A, Perveen S, Choi BO, Chung KW
BMC Med Genomics 2021 Jun 30;14(1):174. doi: 10.1186/s12920-021-01019-5. PMID: 34193129Free PMC Article
Sivera R, Lupo V, Frasquet M, Argente-Escrig H, Alonso-Pérez J, Díaz-Manera J, Querol L, Del Mar García-Romero M, Ignacio Pascual S, García-Sobrino T, Paradas C, Francisco Vázquez-Costa J, Muelas N, Millet E, Jesús Vílchez J, Espinós C, Sevilla T
Eur J Neurol 2021 Sep;28(9):3001-3011. Epub 2021 Jul 18 doi: 10.1111/ene.15001. PMID: 34189813
Nan H, Hata T, Fukao T, Fukao T, Chen W, Kurita T, Natori T, Takiyama Y
Intern Med 2021 Dec 15;60(24):3969-3974. Epub 2021 Jun 12 doi: 10.2169/internalmedicine.7463-21. PMID: 34121014
Hamada Y, Takahashi K, Kanbayashi T, Hatanaka Y, Kobayashi S, Sonoo M
Intern Med 2021 May 15;60(10):1611-1614. Epub 2020 Dec 22 doi: 10.2169/internalmedicine.6153-20. PMID: 33361678Free PMC Article

Therapy

Õunpuu S, Garibay E, Acsadi G, Brimacombe M, Pierz K
Gait Posture 2021 Mar;85:198-204. Epub 2021 Feb 12 doi: 10.1016/j.gaitpost.2021.02.005. PMID: 33610823
Zuccarino R, Anderson KM, Shy ME, Wilken JM
Muscle Nerve 2021 Jan;63(1):40-45. Epub 2020 Aug 26 doi: 10.1002/mus.27027. PMID: 32696510Free PMC Article
Pipis M, Feely SME, Polke JM, Skorupinska M, Perez L, Shy RR, Laura M, Morrow JM, Moroni I, Pisciotta C, Taroni F, Vujovic D, Lloyd TE, Acsadi G, Yum SW, Lewis RA, Finkel RS, Herrmann DN, Day JW, Li J, Saporta M, Sadjadi R, Walk D, Burns J, Muntoni F, Ramchandren S, Horvath R, Johnson NE, Züchner S, Pareyson D, Scherer SS, Rossor AM, Shy ME, Reilly MM; Inherited Neuropathies Consortium - Rare Disease Clinical Research Network (INC-RDCRN).
Brain 2020 Dec 1;143(12):3589-3602. doi: 10.1093/brain/awaa323. PMID: 33415332Free PMC Article
Le-Rademacher JG, Lopez CL, Kanwar R, Major-Elechi B, Abyzov A, Banck MS, Therneau TM, Sloan JA, Loprinzi CL, Beutler AS
J Neurol Sci 2020 Apr 15;411:116687. Epub 2020 Jan 14 doi: 10.1016/j.jns.2020.116687. PMID: 32018185Free PMC Article
Rossor AM, Shy ME, Reilly MM
Brain Res 2020 Feb 15;1729:146625. Epub 2019 Dec 30 doi: 10.1016/j.brainres.2019.146625. PMID: 31899213Free PMC Article

Prognosis

Pipis M, Cortese A, Polke JM, Poh R, Vandrovcova J, Laura M, Skorupinska M, Jacquier A, Juntas-Morales R, Latour P, Petiot P, Sole G, Fromes Y, Shah S, Blake J, Choi BO, Chung KW, Stojkovic T, Rossor AM, Reilly MM
J Neurol Neurosurg Psychiatry 2022 Jan;93(1):48-56. Epub 2021 Sep 13 doi: 10.1136/jnnp-2021-327186. PMID: 34518334Free PMC Article
Rebelo AP, Cortese A, Abraham A, Eshed-Eisenbach Y, Shner G, Vainshtein A, Buglo E, Camarena V, Gaidosh G, Shiekhattar R, Abreu L, Courel S, Burns DK, Bai Y, Bacon C, Feely SME, Castro D, Peles E, Reilly MM, Shy ME, Zuchner S
Brain 2021 May 7;144(4):1197-1213. doi: 10.1093/brain/awab019. PMID: 33889941Free PMC Article
Pipis M, Feely SME, Polke JM, Skorupinska M, Perez L, Shy RR, Laura M, Morrow JM, Moroni I, Pisciotta C, Taroni F, Vujovic D, Lloyd TE, Acsadi G, Yum SW, Lewis RA, Finkel RS, Herrmann DN, Day JW, Li J, Saporta M, Sadjadi R, Walk D, Burns J, Muntoni F, Ramchandren S, Horvath R, Johnson NE, Züchner S, Pareyson D, Scherer SS, Rossor AM, Shy ME, Reilly MM; Inherited Neuropathies Consortium - Rare Disease Clinical Research Network (INC-RDCRN).
Brain 2020 Dec 1;143(12):3589-3602. doi: 10.1093/brain/awaa323. PMID: 33415332Free PMC Article
Park HJ, Choi YC, Oh JW, Yi SW
Neuroepidemiology 2020;54(4):313-319. Epub 2020 Jan 29 doi: 10.1159/000505815. PMID: 31995800
Deng S, Feely SME, Shi Y, Zhai H, Zhan L, Siddique T, Deng HX, Shy ME
Neuromolecular Med 2020 Mar;22(1):68-72. Epub 2019 Aug 29 doi: 10.1007/s12017-019-08564-4. PMID: 31468327

Clinical prediction guides

Kitaoji T, Noto YI, Kojima Y, Tsuji Y, Mizuno T, Nakagawa M
Clin Neurophysiol 2021 Oct;132(10):2693-2701. Epub 2021 Jun 29 doi: 10.1016/j.clinph.2021.05.030. PMID: 34294566
Xie Y, Lin Z, Liu L, Li X, Huang S, Zhao H, Wang B, Zeng S, Cao W, Li L, Zhu X, Huang S, Yang H, Wang M, Hu Z, Wang J, Guo J, Shen L, Jiang H, Zuchner S, Tang B, Zhang R
Eur J Neurol 2021 Nov;28(11):3774-3783. Epub 2021 Jul 26 doi: 10.1111/ene.15024. PMID: 34255403
Rebelo AP, Cortese A, Abraham A, Eshed-Eisenbach Y, Shner G, Vainshtein A, Buglo E, Camarena V, Gaidosh G, Shiekhattar R, Abreu L, Courel S, Burns DK, Bai Y, Bacon C, Feely SME, Castro D, Peles E, Reilly MM, Shy ME, Zuchner S
Brain 2021 May 7;144(4):1197-1213. doi: 10.1093/brain/awab019. PMID: 33889941Free PMC Article
Noto YI, Watanabe K, Holobar A, Kitaoji T, Tsuji Y, Kojima Y, Kitani-Morii F, Mizuno T, Nakagawa M
Clin Neurophysiol 2021 Mar;132(3):812-818. Epub 2021 Jan 5 doi: 10.1016/j.clinph.2020.11.040. PMID: 33483296
Kojima Y, Noto YI, Tsuji Y, Kitani-Morii F, Shiga K, Mizuno T, Nakagawa M
Muscle Nerve 2020 Dec;62(6):722-727. Epub 2020 Sep 27 doi: 10.1002/mus.27068. PMID: 32959396

Recent systematic reviews

Mandarakas MR, Rose KJ, Sanmaneechai O, Menezes MP, Refshauge KM, Burns J
J Peripher Nerv Syst 2018 Jun;23(2):99-107. Epub 2018 Mar 23 doi: 10.1111/jns.12258. PMID: 29521025
Berciano J, García A, Gallardo E, Peeters K, Pelayo-Negro AL, Álvarez-Paradelo S, Gazulla J, Martínez-Tames M, Infante J, Jordanova A
J Neurol 2017 Aug;264(8):1655-1677. Epub 2017 Mar 31 doi: 10.1007/s00415-017-8474-3. PMID: 28364294
Barreto LC, Oliveira FS, Nunes PS, de França Costa IM, Garcez CA, Goes GM, Neves EL, de Souza Siqueira Quintans J, de Souza Araújo AA
Neuroepidemiology 2016;46(3):157-65. Epub 2016 Feb 6 doi: 10.1159/000443706. PMID: 26849231
Gess B, Baets J, De Jonghe P, Reilly MM, Pareyson D, Young P
Cochrane Database Syst Rev 2015 Dec 11;(12):CD011952. doi: 10.1002/14651858.CD011952. PMID: 26662471Free PMC Article
Sman AD, Hackett D, Fiatarone Singh M, Fornusek C, Menezes MP, Burns J
J Peripher Nerv Syst 2015 Dec;20(4):347-62. doi: 10.1111/jns.12116. PMID: 26010435

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