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 edit

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 edit

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
CMT1G 618279 PMP2 8q21.13 Autosomal dominant
CMT2 CMT2A1 118210 KIF1B 1p36.22 Autosomal dominant
CMT2A2A 609260 MFN2 1p36.22 Autosomal dominant
CMT2A2B 617087 MFN2 1p36.22 Autosomal recessive
CMT2B 600882 RAB7A
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
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 1
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 617017 MME 3q25 Autosomal recessive
CMT2U 616280 MARS 12q13.3 Autosomal dominant
CMT2V 616491 NAGLU 17q21.2 Autosomal dominant
CMT2W 616625 HARS1 5q31.3 Autosomal dominant
CMT2X 616668 SPG11 15q21.1 Autosomal recessive
CMT2Y 616687 VCP 9p13.3 Autosomal dominant
CMT2Z 616688 MORC2 22q12.2 Autosomal dominant
CMT2CC 616924 NEFH 22q12.2 Autosomal dominant
CMT2DD 618036 ATP1A1 1p13.1 Autosomal dominant
CMT2EE 618400 MPV17 2p23.3 Autosomal recessive
CMT3 CMT3 145900 MPZ
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
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 CMT6A 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.
CMT6B 616505 SLC25A46 5q22.1 Autosomal recessive
CMT6C 618511 PDXK 21q22.3 Autosomal recessive
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 arbitrary.

References edit

  1. ^ Lupski JR, Reid JG, Gonzaga-Jauregui C, Rio Deiros D, Chen DC, Nazareth L, et al. (April 2010). "Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy". The New England Journal of Medicine. 362 (13): 1181–1191. doi:10.1056/NEJMoa0908094. PMC 4036802. PMID 20220177.
  2. ^ Inoue K, Dewar K, Katsanis N, Reiter LT, Lander ES, Devon KL, et al. (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): 1018–1033. doi:10.1101/gr.180401. PMC 311111. PMID 11381029.
  3. ^ Latour P, Fabreguette A, Ressot C, Blanquet-Grossard F, Antoine JC, Calvas P, 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 CK, Rash JE (2009). "Connexins in the Nervous System". In Harris A, Locke D (eds.). Connexins. New York: Springer. pp. 323–57. doi:10.1007/978-1-59745-489-6_15. ISBN 978-1-934115-46-6.