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 |
|---|---|---|---|---|---|---|
| CMT1 | CMT1A[2] | 118220 | PMP22 | 17p11.2 | Autosomal dominant | The 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 | 118200 | MPZ | 1q23.3 | Autosomal dominant | Responsible for 5–10% of Type 1 patients. Average NCV: < 15 m/s | |
| CMT1C | 601098 | LITAF | 16p13.13 | Autosomal dominant | Usually shows up in infancy. Average NCV: 26–42 m/s. Symptoms are identical to CMT1A. | |
| CMT1D | 607678 | EGR2 | 10q21.3 | Autosomal dominant | Average NCV: 15–20 m/s | |
| CMT1E | 118300 | PMP22 | 17p11.2 | Autosomal dominant | Characterised by demyelination and loss of hearing; allelic with subtype CMT1A | |
| CMT1F | 607734 | NEFL | 8p21.2 | Autosomal dominant | ||
| CMT2 | CMT2A1 | 118210 | KIF1B | 1p36.22 | Autosomal dominant | |
| CMT2A2 | 609260 | MFN2 | 1p36.22 | Autosomal dominant | ||
| CMT2B | 600882 | RAB7A RAB7B | 3q21.3 | Autosomal dominant | ||
| CMT2B1 | 605588 | LMNA | 1q22 | Autosomal recessive | A laminopathy | |
| CMT2B2 | 605589 | MED25 | 19q13.33 | Autosomal dominant | ||
| CMT2C | 606071 | TRPV4 | 12q24.11 | Autosomal dominant | May cause vocal cord, diaphragm, and distal weakness | |
| CMT2D | 601472 | GARS | 7p14.3 | Autosomal dominant | Symptoms are more severe in the upper extremities (hands), which is atypical for CMT | |
| CMT2E | 607684 | NEFL | 8p21.2 | Autosomal dominant | ||
| CMT2F | 606595 | HSPB1 | 7q11.23 | Autosomal dominant | ||
| CMT2G | 608591 | ? | 12q12–q13.3 | Autosomal dominant | ||
| CMT2H | 607731 | GDAP1 | 8q21.11 | Autosomal dominant | Allelic with subtype CMT2K | |
| CMT2I | 607677 | MPZ | 1q23.3 | Autosomal dominant | Allelic with subtype CMT2J and forms of CMT3 | |
| CMT2J | 607736 | MPZ | 1q23.3 | Autosomal dominant | Allelic with subtype CMT2I and forms of CMT3 | |
| CMT2K | 607831 | GDAP1 | 8q21.11 | Autosomal dominant | Allelic with subtype CMT2H | |
| CMT2L | 608673 | HSPB8 | 12q24.23 | Autosomal dominant | Allelic with Autosomal dominant distal spinal muscular atrophy | |
| CMT2M | 606482 | DNM2 | 19p13.2 | Autosomal dominant | Full name: CMT2M, included; more commonly classified as subtype CMTDIB | |
| CMT2N | 613287 | AARS | 16q22.1 | Autosomal dominant | ||
| CMT2O | 614228 | DYNC1H1 | 14q32.31 | Autosomal dominant | Allelic with spinal muscular atrophy with lower extremity predominance | |
| CMT2P | 614436 | LRSAM1 | 9q33.3 | Autosomal dominant Autosomal recessive | Juvenile or adult onset, slowly progressive | |
| CMT2Q | 615025 | DHTKD1 | 10p14 | Autosomal dominant | ||
| CMT2R | 615490 | TRIM2 | 4q31.3 | Autosomal recessive | ||
| CMT2S | 616155 | IGHMBP2 | 11q13.3 | Autosomal recessive | ||
| CMT2T | 616233 | DNAJB2 | 2q35 | Autosomal recessive | ||
| CMT2U | 616280 | MARS | 12q13.3 | Autosomal dominant | ||
| CMT3 | CMT3 | 145900 | MPZ 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 |
| CMT4 | CMT4A | 214400 | GDAP1 | 8q21.11 | Autosomal recessive | Allelic with subtype CMTRIA |
| CMT4B1 | 601382 | MTMR2 | 11q21 | Autosomal recessive | ||
| CMT4B2 | 604563 | SBF2 | 11p15.4 | Autosomal recessive | ||
| CMT4B3 | 615284 | SBF1 | 22q13.33 | Autosomal recessive | ||
| CMT4C | 601596 | SH3TC2 | 5q32 | Autosomal recessive | May lead to respiratory compromise | |
| CMT4D | 601455 | NDRG1 | 8q24.3 | Autosomal recessive | Characterised by demyelination and loss of hearing | |
| CMT4E | 605253 | MPZ EGR2 | 1q23.3 10q21.3 | Autosomal recessive | Also known as congenital hypomyelinating neuropathy; phenotype largely overlapping with subtype CMT4F | |
| CMT4F | 145900 | PRX | 19q13.2 | Autosomal recessive | Phenotype largely overlapping with subtype CMT4E; may be the same as CMT3 | |
| CMT4G | 605285 | HK1 | 10q22.1 | Autosomal recessive | Also known as Russe-type hereditary motor and sensory neuropathy (HMSNR); second most common cause of CMT in the Spanish Roma population | |
| CMT4H | 609311 | FGD4 | 12p11.21 | Autosomal recessive | ||
| CMT4J | 611228 | FIG4 | 6q21 | Autosomal recessive | Allelic to amyotrophic lateral sclerosis type 11 | |
| CMT5 | CMT5 | 600361 | ? | 4q34.3–q35.2 | Autosomal dominant | Also known as CMT with pyramidal features; onset in 2nd decade of life with distal muscle wasting, particularly in legs |
| CMT6 | CMT6 | 601152 | MFN2 | 1p36.22 | Autosomal dominant | Characterised by optic atrophy, hence known also as CMT with optic atrophy. Also known as hereditary motor and sensory neuropathy type VI. |
| CMTDI | CMTDIA | 606483 | ? | 10q24.1–q25.1 | Autosomal dominant | |
| CMTDIB | 606482 | DNM2 | 19p13.2 | Autosomal dominant | Also classified as subtype CMT2M | |
| CMTDIC | 608323 | YARS | 1p35.1 | Autosomal dominant | ||
| CMTDID | 607791 | MPZ | 1q23.3 | Autosomal dominant | ||
| CMTDIE | 614455 | INF2 | 14q32.33 | Autosomal dominant | ||
| CMTDIF | 615185 | GNB4 | 3q26.33 | Autosomal dominant | ||
| CMTRI | CMTRIA | 608340 | GDAP1 | 8q21.11 | Autosomal recessive | Allelic with subtype CMT4A |
| CMTRIB | 613641 | KARS | 16q23.1 | Autosomal recessive | ||
| CMTX | CMTX1 | 302800 | GJB1 | Xq13.1 | X-linked dominant | Responsible 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 | 302801 | CMTX2 | Xq22.2 | X-linked recessive | ||
| CMTX3 | 302802 | CMTX3 | Xq26 | X-linked recessive | ||
| CMTX4 | 310490 | NAMSD | Xq24–q26.1 | X-linked recessive | Also known as Cowchock syndrome | |
| CMTX5 | 311070 | PRPS1 | Xq22.3 | X-linked recessive | Also known as Rosenberg–Chutorian syndrome; signs include optic atrophy, polyneuropathy and deafness | |
| CMTX6 | 300905 | PDK3 | Xp22.11 | X-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
- 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.
- 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.
- 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.
- 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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