Charcot–Marie–Tooth disease classifications explained

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] __TOC__

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]		PMP22	17p11.2		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		MPZ	1q23.3		Responsible for 5–10% of Type 1 patients. Average NCV: < 15 m/s
	CMT1C		LITAF	16p13.13		Usually shows up in infancy. Average NCV: 26–42 m/s. Symptoms are identical to CMT1A.
	CMT1D		EGR2	10q21.3		Average NCV: 15–20 m/s
	CMT1E		PMP22	17p11.2		Characterised by demyelination and loss of hearing; allelic with subtype CMT1A
	CMT1F		NEFL	8p21.2
	CMT1G		PMP2	8q21.13
CMT2	CMT2A1		KIF1B	1p36.22
	CMT2A2A		MFN2	1p36.22
	CMT2A2B		MFN2	1p36.22
	CMT2B		RAB7A RAB7B	3q21.3
	CMT2B1		LMNA	1q22		A laminopathy
	CMT2B2		MED25	19q13.33
	CMT2C		TRPV4	12q24.11		May cause vocal cord, diaphragm, and distal weakness
	CMT2D		GARS	7p14.3		Symptoms are more severe in the upper extremities (hands), which is atypical for CMT
	CMT2E		NEFL	8p21.2
	CMT2F		HSPB1	7q11.23
	CMT2H		GDAP1	8q21.11		Allelic with subtype CMT2K
	CMT2I		MPZ	1q23.3		Allelic with subtype CMT2J and forms of CMT3
	CMT2J		MPZ	1q23.3		Allelic with subtype CMT2I and forms of CMT3
	CMT2K		GDAP1	8q21.11		Allelic with subtype CMT2H
	CMT2L		HSPB8	12q24.23		Allelic with Autosomal dominant distal spinal muscular atrophy
	CMT2M		DNM2	19p13.2		Full name: CMT2M, included; more commonly classified as subtype CMTDIB
	CMT2N		AARS	16q22.1
	CMT2O		DYNC1H1	14q32.31		Allelic with spinal muscular atrophy with lower extremity predominance 1
	CMT2P		LRSAM1	9q33.3		Juvenile or adult onset, slowly progressive
	CMT2Q		DHTKD1	10p14
	CMT2R		TRIM2	4q31.3
	CMT2S		IGHMBP2	11q13.3
	CMT2T		MME	3q25
	CMT2U		MARS	12q13.3
	CMT2V		NAGLU	17q21.2
	CMT2W		HARS1	5q31.3
	CMT2X		SPG11	15q21.1
	CMT2Y		VCP	9p13.3
	CMT2Z		MORC2	22q12.2
	CMT2CC		NEFH	22q12.2
	CMT2DD		ATP1A1	1p13.1
	CMT2EE			MPV17	2p23.3
CMT3	CMT3		MPZ EGR2 PMP22 PRX	1q23.3 10q21.3 17p12 19q13.2		More commonly known as Dejerine–Sottas disease; subtype CMT4F sometimes included here
CMT4	CMT4A		GDAP1	8q21.11		Allelic with subtype CMTRIA
	CMT4B1		MTMR2	11q21
	CMT4B2		SBF2	11p15.4
	CMT4B3		SBF1	22q13.33
	CMT4C		SH3TC2	5q32		May lead to respiratory compromise
	CMT4D		NDRG1	8q24.3		Characterised by demyelination and loss of hearing
	CMT4E		MPZ EGR2	1q23.3 10q21.3		Also known as congenital hypomyelinating neuropathy; phenotype largely overlapping with subtype CMT4F
	CMT4F		PRX	19q13.2		Phenotype largely overlapping with subtype CMT4E; may be the same as CMT3
	CMT4G		HK1	10q22.1		Also known as Russe-type hereditary motor and sensory neuropathy (HMSNR); second most common cause of CMT in the Spanish Roma population
	CMT4H		FGD4	12p11.21
	CMT4J		FIG4	6q21		Allelic to amyotrophic lateral sclerosis type 11
CMT5	CMT5		?	4q34.3–q35.2		Also known as CMT with pyramidal features; onset in 2nd decade of life with distal muscle wasting, particularly in legs
CMT6	CMT6A		MFN2	1p36.22		Characterised by optic atrophy, hence known also as CMT with optic atrophy. Also known as hereditary motor and sensory neuropathy type VI.
	CMT6B		SLC25A46	5q22.1	Autosomal recessive
	CMT6C		PDXK	21q22.3	Autosomal recessive
CMTDI	CMTDIA		?	10q24.1–q25.1
	CMTDIB		DNM2	19p13.2		Also classified as subtype CMT2M
	CMTDIC		YARS	1p35.1
	CMTDID		MPZ	1q23.3
	CMTDIE		INF2	14q32.33
	CMTDIF		GNB4	3q26.33
CMTRI	CMTRIA		GDAP1	8q21.11		Allelic with subtype CMT4A
CMTRI	CMTRIB		KARS	16q23.1
CMTX	CMTX1		GJB1	Xq13.1		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		CMTX2	Xq22.2
	CMTX3		CMTX3	Xq26
	CMTX4		NAMSD	Xq24–q26.1		Also known as Cowchock syndrome
	CMTX5		PRPS1	Xq22.3		Also known as Rosenberg–Chutorian syndrome; signs include optic atrophy, polyneuropathy and deafness
	CMTX6		PDK3	Xp22.11
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.

Notes and References

Lupski JR, Reid JG, Gonzaga-Jauregui C, Rio Deiros D, Chen DC, Nazareth L, Bainbridge M, Dinh H, Jing C, Wheeler DA, McGuire AL, Zhang F, Stankiewicz P, Halperin JJ, Yang C, Gehman C, Guo D, Irikat RK, Tom W, Fantin NJ, Muzny DM, Gibbs RA . 6 . Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy . The New England Journal of Medicine . 362 . 13 . 1181–1191 . April 2010 . 20220177 . 4036802 . 10.1056/NEJMoa0908094 .
Inoue K, Dewar K, Katsanis N, Reiter LT, Lander ES, Devon KL, Wyman DW, Lupski JR, Birren B . 6 . 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 . June 2001 . 11381029 . 311111 . 10.1101/gr.180401 .
Latour P, Fabreguette A, Ressot C, Blanquet-Grossard F, Antoine JC, Calvas P, Chapon F, Corbillon E, Ollagnon E, Sturtz F, Boucherat M, Chazot G, Dautigny A, Pham-Dinh D, Vandenberghe A . 6 . New mutations in the X-linked form of Charcot-Marie-Tooth disease . European Neurology . 37 . 1 . 38–42 . 1997 . 9018031 . 10.1159/000117403 .
Book: Abrams CK, Rash JE . Connexins in the Nervous System . Harris . Andrew . Locke . Darren . Connexins . Springer . 2009 . New York . 323–57 . 10.1007/978-1-59745-489-6_15 . 978-1-934115-46-6.