Charcot–Marie–Tooth disease classifications

Classifications of Charcot–Marie–Tooth disease refers to the types and subtypes of Charcot–Marie–Tooth disease (CMT), a genetically and clinically heterogeneous group of inherited disorders of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. CMT is a result of genetic mutations in a number of genes.[1]

Clinical categories

Type Name Incidence Notes
CMT1 Demyelinating type Affects approximately 30% of CMT patients Causes severe demyelination, thereby impairing nerve conduction velocity.
CMT2 Axonal type Affects approximately 20–40% of CMT patients Mainly affects axons. Tends to affect lower extremities more than upper extremities. Clinical symptoms are often less severe than in CMT1. As it is an axonopathy, average nerve conduction velocity is usually not affected (sometimes slightly below normal but mostly above 38 m/s).
CMT3 Dejerine–Sottas disease Very rare Severely impaired nerve conduction velocity.
CMT4 Spinal type
CMT5 Pyramidal type
CMT6 With optic atrophy
CMTDI Dominant intermediate type
CMTRI Recessive intermediate type
CMTX X-linked type Affects approximately 10–20% of CMT patients This type encompasses all CMT forms that are inherited in an X-linked manner. Average NCV: 25–40 m/s.

Genetic subtypes

Type Subtype OMIM Gene Locus Inheritance Notes
CMT1CMT1A[2] 118220PMP2217p11.2Autosomal dominantThe most common form of the disease, 70–80% of Type 1 patients. Average NCV: 20–25 m/s. Allelic with subtype CMT1E. When associated with subtype CMT1B (causing essential tremor and ataxia), it is called Roussy–Lévy syndrome.
CMT1B 118200MPZ1q23.3Autosomal dominantResponsible for 5–10% of Type 1 patients. Average NCV: < 15 m/s
CMT1C 601098LITAF16p13.13Autosomal dominantUsually shows up in infancy. Average NCV: 26–42 m/s. Symptoms are identical to CMT1A.
CMT1D 607678EGR210q21.3Autosomal dominantAverage NCV: 15–20 m/s
CMT1E 118300PMP2217p11.2Autosomal dominantCharacterised by demyelination and loss of hearing; allelic with subtype CMT1A
CMT1F 607734NEFL8p21.2Autosomal dominant
CMT1G 618279PMP28q21.13Autosomal dominant
CMT2CMT2A1 118210KIF1B1p36.22Autosomal dominant
CMT2A2A 609260MFN21p36.22Autosomal dominant
CMT2A2B 617087MFN21p36.22Autosomal recessive
CMT2B 600882RAB7A
RAB7B
3q21.3Autosomal dominant
CMT2B1 605588LMNA1q22Autosomal recessiveA laminopathy
CMT2B2 605589MED2519q13.33Autosomal dominant
CMT2C 606071TRPV412q24.11Autosomal dominantMay cause vocal cord, diaphragm, and distal weakness
CMT2D 601472GARS7p14.3Autosomal dominantSymptoms are more severe in the upper extremities (hands), which is atypical for CMT
CMT2E 607684NEFL8p21.2Autosomal dominant
CMT2F 606595HSPB17q11.23Autosomal dominant
CMT2H 607731GDAP18q21.11Autosomal dominantAllelic with subtype CMT2K
CMT2I 607677MPZ1q23.3Autosomal dominantAllelic with subtype CMT2J and forms of CMT3
CMT2J 607736MPZ1q23.3Autosomal dominantAllelic with subtype CMT2I and forms of CMT3
CMT2K 607831GDAP18q21.11Autosomal dominantAllelic with subtype CMT2H
CMT2L 608673HSPB812q24.23Autosomal dominantAllelic with Autosomal dominant distal spinal muscular atrophy
CMT2M 606482DNM219p13.2Autosomal dominantFull name: CMT2M, included; more commonly classified as subtype CMTDIB
CMT2N 613287AARS16q22.1Autosomal dominant
CMT2O 614228DYNC1H114q32.31Autosomal dominantAllelic with spinal muscular atrophy with lower extremity predominance 1
CMT2P 614436LRSAM19q33.3Autosomal dominant
Autosomal recessive
Juvenile or adult onset, slowly progressive
CMT2Q 615025DHTKD110p14Autosomal dominant
CMT2R 615490TRIM24q31.3Autosomal recessive
CMT2S 616155IGHMBP211q13.3Autosomal recessive
CMT2T 617017MME3q25Autosomal recessive
CMT2U 616280MARS12q13.3Autosomal dominant
CMT2V 616491NAGLU17q21.2Autosomal dominant
CMT2W 616625HARS15q31.3Autosomal dominant
CMT2X 616668SPG1115q21.1Autosomal recessive
CMT2Y 616687VCP9p13.3Autosomal dominant
CMT2Z 616688MORC222q12.2Autosomal dominant
CMT2CC 616924NEFH22q12.2Autosomal dominant
CMT2DD 618036ATP1A11p13.1Autosomal dominant
CMT2EE 618400MPV172p23.3Autosomal recessive
CMT3CMT3 145900MPZ
EGR2
PMP22
PRX
1q23.3
10q21.3
17p12
19q13.2
Autosomal dominant
Autosomal recessive
More commonly known as Dejerine–Sottas disease; subtype CMT4F sometimes included here
CMT4CMT4A 214400GDAP18q21.11Autosomal recessiveAllelic with subtype CMTRIA
CMT4B1 601382MTMR211q21Autosomal recessive
CMT4B2 604563SBF211p15.4Autosomal recessive
CMT4B3 615284SBF122q13.33Autosomal recessive
CMT4C 601596SH3TC25q32Autosomal recessiveMay lead to respiratory compromise
CMT4D 601455NDRG18q24.3Autosomal recessiveCharacterised by demyelination and loss of hearing
CMT4E 605253MPZ
EGR2
1q23.3
10q21.3
Autosomal recessiveAlso known as congenital hypomyelinating neuropathy; phenotype largely overlapping with subtype CMT4F
CMT4F 145900PRX19q13.2Autosomal recessivePhenotype largely overlapping with subtype CMT4E; may be the same as CMT3
CMT4G 605285HK110q22.1Autosomal recessiveAlso known as Russe-type hereditary motor and sensory neuropathy (HMSNR); second most common cause of CMT in the Spanish Roma population
CMT4H 609311FGD412p11.21Autosomal recessive
CMT4J 611228FIG46q21Autosomal recessiveAllelic to amyotrophic lateral sclerosis type 11
CMT5CMT5 600361 ?4q34.3–q35.2Autosomal dominantAlso known as CMT with pyramidal features; onset in 2nd decade of life with distal muscle wasting, particularly in legs
CMT6CMT6 601152MFN21p36.22Autosomal dominantCharacterised by optic atrophy, hence known also as CMT with optic atrophy. Also known as hereditary motor and sensory neuropathy type VI.
CMTDICMTDIA 606483 ?10q24.1–q25.1Autosomal dominant
CMTDIB 606482DNM219p13.2Autosomal dominantAlso classified as subtype CMT2M
CMTDIC 608323YARS1p35.1Autosomal dominant
CMTDID 607791MPZ1q23.3Autosomal dominant
CMTDIE 614455INF214q32.33Autosomal dominant
CMTDIF 615185GNB43q26.33Autosomal dominant
CMTRICMTRIA 608340GDAP18q21.11Autosomal recessiveAllelic with subtype CMT4A
CMTRIB 613641KARS16q23.1Autosomal recessive
CMTXCMTX1 302800GJB1Xq13.1X-linked dominantResponsible for approximately 90% of CMTX patients; some studies put this number significantly higher.[3][4] Note that different mutations of GJB1 may produce markedly different forms of Charcot–Marie–Tooth disease.
CMTX2 302801CMTX2Xq22.2X-linked recessive
CMTX3 302802CMTX3Xq26X-linked recessive
CMTX4 310490NAMSDXq24–q26.1X-linked recessiveAlso known as Cowchock syndrome
CMTX5 311070PRPS1Xq22.3X-linked recessiveAlso known as Rosenberg–Chutorian syndrome; signs include optic atrophy, polyneuropathy and deafness
CMTX6 300905PDK3Xp22.11X-linked dominant
Type Subtype OMIM Gene Locus Inheritance Notes

It has to be kept in mind that sometimes a particular patient diagnosed with CMT can exhibit a combination of any of the above gene mutations; thus, in these cases precise classification can be a little arbitrary.

References

  1. Lupski, James R.; Reid, Jeffrey G.; Gonzaga-Jauregui, Claudia; Rio Deiros, David; Chen, David C.Y.; Nazareth, Lynne; Bainbridge, Matthew; Dinh, Huyen; et al. (2010). "Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy". New England Journal of Medicine. 362 (13): 1181–91. doi:10.1056/NEJMoa0908094. PMC 4036802. PMID 20220177.
  2. Inoue, K; Dewar, K; Katsanis, N; Reiter, LT; Lander, ES; Devon, KL; Wyman, DW; Lupski, JR; Birren, B (June 2001). "The 1.4-Mb CMT1A duplication/HNPP deletion genomic region reveals unique genome architectural features and provides insights into the recent evolution of new genes". Genome Research. 11 (6): 1018–33. doi:10.1101/gr.180401. PMC 311111. PMID 11381029.
  3. Latour, Philippe; Fabreguette, Anne; Ressot, Catherine; Blanquet-Grossard, FranÇOise; Antoine, Jean-Christophe; Calvas, Patrick; Chapon, FranÇOise; Corbillon, Emmanuel; et al. (1997). "New Mutations in the X-Linked Form of Charcot-Marie-Tooth Disease". European Neurology. 37 (1): 38–42. doi:10.1159/000117403. PMID 9018031.
  4. Abrams, Charles K.; Rash, John E. (2009). "Connexins in the Nervous System". In Harris, Andrew; Locke, Darren (eds.). Connexins. New York: Springer. pp. 323–57. doi:10.1007/978-1-59745-489-6_15. ISBN 978-1-934115-46-6.
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