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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
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Source: Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
 
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.

Charcot-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.

Typically, 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.

Affected 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.

There 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. People with CMT2 may develop amyotrophic lateral sclerosis (ALS), a condition characterized by progressive muscle weakness, a loss of muscle mass, and an inability to control movement.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.

Sometimes 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.

Professional guidelines

PubMed

Yiu EM, Bray P, Baets J, Baker SK, Barisic N, de Valle K, Estilow T, Farrar MA, Finkel RS, Haberlová J, Kennedy RA, Moroni I, Nicholson GA, Ramchandren S, Reilly MM, Rose K, Shy ME, Siskind CE, Yum SW, Menezes MP, Ryan MM, Burns J
J Neurol Neurosurg Psychiatry 2022 May;93(5):530-538. Epub 2022 Feb 9 doi: 10.1136/jnnp-2021-328483. PMID: 35140138
Mary P, Servais L, Vialle R
Orthop Traumatol Surg Res 2018 Feb;104(1S):S89-S95. Epub 2017 Nov 28 doi: 10.1016/j.otsr.2017.04.019. PMID: 29196274
Pareyson D, Marchesi C
Lancet Neurol 2009 Jul;8(7):654-67. doi: 10.1016/S1474-4422(09)70110-3. PMID: 19539237

Recent clinical studies

Etiology

Beloribi-Djefaflia S, Attarian S
Rev Neurol (Paris) 2023 Jan-Feb;179(1-2):35-48. Epub 2022 Dec 30 doi: 10.1016/j.neurol.2022.11.006. PMID: 36588067
McCray BA, Scherer SS
Neurotherapeutics 2021 Oct;18(4):2269-2285. Epub 2021 Oct 4 doi: 10.1007/s13311-021-01099-2. PMID: 34606075Free PMC Article
Volodarsky M, Kerkhof J, Stuart A, Levy M, Brady LI, Tarnopolsky M, Lin H, Ainsworth P, Sadikovic B
J Med Genet 2021 Apr;58(4):284-288. Epub 2020 May 6 doi: 10.1136/jmedgenet-2019-106641. PMID: 32376792
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
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

Diagnosis

Beloribi-Djefaflia S, Attarian S
Rev Neurol (Paris) 2023 Jan-Feb;179(1-2):35-48. Epub 2022 Dec 30 doi: 10.1016/j.neurol.2022.11.006. PMID: 36588067
Kramarz C, Rossor AM
J Neurol 2022 Sep;269(9):5187-5191. Epub 2022 May 21 doi: 10.1007/s00415-022-11164-1. PMID: 35596796Free PMC Article
Klein CJ
Continuum (Minneap Minn) 2020 Oct;26(5):1224-1256. doi: 10.1212/CON.0000000000000927. PMID: 33003000
Morena J, Gupta A, Hoyle JC
Int J Mol Sci 2019 Jul 12;20(14) doi: 10.3390/ijms20143419. PMID: 31336816Free PMC Article
Pareyson D, Marchesi C
Lancet Neurol 2009 Jul;8(7):654-67. doi: 10.1016/S1474-4422(09)70110-3. PMID: 19539237

Therapy

Stino AM, Naddaf E, Dyck PJ, Dyck PJB
Muscle Nerve 2021 Feb;63(2):157-169. Epub 2020 Sep 11 doi: 10.1002/mus.27046. PMID: 32914902
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
Morena J, Gupta A, Hoyle JC
Int J Mol Sci 2019 Jul 12;20(14) doi: 10.3390/ijms20143419. PMID: 31336816Free PMC Article
Corrado B, Ciardi G, Bargigli C
Medicine (Baltimore) 2016 Apr;95(17):e3278. doi: 10.1097/MD.0000000000003278. PMID: 27124017Free PMC Article
Pareyson D, Marchesi C
Lancet Neurol 2009 Jul;8(7):654-67. doi: 10.1016/S1474-4422(09)70110-3. PMID: 19539237

Prognosis

Rossor AM, Reilly MM
Acta Neurol Scand 2022 Oct;146(4):325-331. Epub 2022 May 25 doi: 10.1111/ane.13650. PMID: 35611606Free 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
Klein CJ
Continuum (Minneap Minn) 2020 Oct;26(5):1224-1256. doi: 10.1212/CON.0000000000000927. PMID: 33003000
Mary P, Servais L, Vialle R
Orthop Traumatol Surg Res 2018 Feb;104(1S):S89-S95. Epub 2017 Nov 28 doi: 10.1016/j.otsr.2017.04.019. PMID: 29196274
Pareyson D, Marchesi C
Lancet Neurol 2009 Jul;8(7):654-67. doi: 10.1016/S1474-4422(09)70110-3. PMID: 19539237

Clinical prediction guides

Cavaletti G, Forsey K, Alberti P
J Peripher Nerv Syst 2023 Sep;28(3):295-307. Epub 2023 Jun 5 doi: 10.1111/jns.12566. PMID: 37249082
Pisciotta C, Bertini A, Tramacere I, Manganelli F, Fabrizi GM, Schenone A, Tozza S, Cavallaro T, Taioli F, Ferrarini M, Grandis M, Bellone E, Mandich P, Previtali SC, Falzone Y, Allegri I, Padua L, Pazzaglia C, Quattrone A, Valentino P, Gentile L, Russo M, Calabrese D, Moroni I, Pagliano E, Saveri P, Magri S, Baratta S, Taroni F, Mazzeo A, Santoro L, Vita G, Pareyson D; Italian CMT Network
Eur J Neurol 2023 Aug;30(8):2461-2470. Epub 2023 May 26 doi: 10.1111/ene.15860. PMID: 37170966
Jennings MJ, Kagiava A, Vendredy L, Spaulding EL, Stavrou M, Hathazi D, Grüneboom A, De Winter V, Gess B, Schara U, Pogoryelova O, Lochmüller H, Borchers CH, Roos A, Burgess RW, Timmerman V, Kleopa KA, Horvath R
Brain 2022 Nov 21;145(11):3999-4015. doi: 10.1093/brain/awac055. PMID: 35148379Free 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
Klein CJ
Continuum (Minneap Minn) 2020 Oct;26(5):1224-1256. doi: 10.1212/CON.0000000000000927. PMID: 33003000

Recent systematic reviews

Cavaletti G, Forsey K, Alberti P
J Peripher Nerv Syst 2023 Sep;28(3):295-307. Epub 2023 Jun 5 doi: 10.1111/jns.12566. PMID: 37249082
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
Corrado B, Ciardi G, Bargigli C
Medicine (Baltimore) 2016 Apr;95(17):e3278. doi: 10.1097/MD.0000000000003278. PMID: 27124017Free PMC Article
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
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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