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. __TOC__ Clinical categories

TypeNameIncidence 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 GeneLocusInheritance Notes CMT1 CMT1A 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 MPZ 1q23.3 Autosomal dominant Responsible for 5–10% of Type 1 patients. Average NCV: < 15 m/s CMT1C LITAF 16p13.13 Autosomal dominant Usually shows up in infancy. Average NCV: 26–42 m/s. Symptoms are identical to CMT1A. CMT1D EGR2 10q21.3 Autosomal dominant Average NCV: 15–20 m/s CMT1E PMP22 17p11.2 Autosomal dominant Characterised by demyelination and loss of hearing; allelic with subtype CMT1A CMT1F NEFL 8p21.2 Autosomal dominant CMT1G PMP2 8q21.13 Autosomal dominant CMT2 CMT2A1 KIF1B 1p36.22 Autosomal dominant CMT2A2A MFN2 1p36.22 Autosomal dominant CMT2A2B MFN2 1p36.22 Autosomal recessive CMT2B RAB7ARAB7B 3q21.3 Autosomal dominant CMT2B1 LMNA 1q22 Autosomal recessive A laminopathy CMT2B2 PNKP 19q13.33 Autosomal dominant CMT2C TRPV4 12q24.11 Autosomal dominant May cause vocal cord, diaphragm, and distal weakness CMT2D GARS 7p14.3 Autosomal dominant Symptoms are more severe in the upper extremities (hands), which is atypical for CMT CMT2E NEFL 8p21.2 Autosomal dominant CMT2F HSPB1 7q11.23 Autosomal dominant CMT2H GDAP1 8q21.11 Autosomal dominant Allelic with subtype CMT2K CMT2I MPZ 1q23.3 Autosomal dominant Allelic with subtype CMT2J and forms of CMT3 CMT2J MPZ 1q23.3 Autosomal dominant Allelic with subtype CMT2I and forms of CMT3 CMT2K GDAP1 8q21.11 Autosomal dominant Allelic with subtype CMT2H CMT2L HSPB8 12q24.23 Autosomal dominant Allelic with Autosomal dominant distal spinal muscular atrophy CMT2M DNM2 19p13.2 Autosomal dominant Full name: CMT2M, included; more commonly classified as subtype CMTDIB CMT2N AARS 16q22.1 Autosomal dominant CMT2O DYNC1H1 14q32.31 Autosomal dominant Allelic with spinal muscular atrophy with lower extremity predominance 1 CMT2P LRSAM1 9q33.3 Autosomal dominantAutosomal recessive Juvenile or adult onset, slowly progressive CMT2Q DHTKD1 10p14 Autosomal dominant CMT2R TRIM2 4q31.3 Autosomal recessive CMT2S IGHMBP2 11q13.3 Autosomal recessive CMT2T MME 3q25 Autosomal recessive CMT2U MARS 12q13.3 Autosomal dominant CMT2V NAGLU 17q21.2 Autosomal dominant CMT2W HARS1 5q31.3 Autosomal dominant CMT2X SPG11 15q21.1 Autosomal recessive CMT2Y VCP 9p13.3 Autosomal dominant CMT2Z MORC2 22q12.2 Autosomal dominant CMT2CC NEFH 22q12.2 Autosomal dominant CMT2DD ATP1A1 1p13.1 Autosomal dominant CMT2EE MPV17 2p23.3 Autosomal recessive CMT3 CMT3 MPZEGR2PMP22PRX 1q23.310q21.317p1219q13.2 Autosomal dominantAutosomal recessive More commonly known as Dejerine–Sottas disease; subtype CMT4F sometimes included here CMT4 CMT4A GDAP1 8q21.11 Autosomal recessive Allelic with subtype CMTRIA CMT4B1 MTMR2 11q21 Autosomal recessive CMT4B2 SBF2 11p15.4 Autosomal recessive CMT4B3 SBF1 22q13.33 Autosomal recessive CMT4C SH3TC2 5q32 Autosomal recessive May lead to respiratory compromise CMT4D NDRG1 8q24.3 Autosomal recessive Characterised by demyelination and loss of hearing CMT4E MPZEGR2 1q23.310q21.3 Autosomal recessive Also known as congenital hypomyelinating neuropathy; phenotype largely overlapping with subtype CMT4F CMT4F PRX 19q13.2 Autosomal recessive Phenotype largely overlapping with subtype CMT4E; may be the same as CMT3 CMT4G 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 FGD4 12p11.21 Autosomal recessive CMT4J FIG4 6q21 Autosomal recessive Allelic to amyotrophic lateral sclerosis type 11 CMT5 CMT5 ? 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 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 SLC25A46 5q22.1 Autosomal recessive CMT6C PDXK 21q22.3 Autosomal recessive CMTDI CMTDIA 620378 ? 10q24.1–q25.1 Autosomal dominant CMTDIB DNM2 19p13.2 Autosomal dominant Also classified as subtype CMT2M CMTDIC YARS 1p35.1 Autosomal dominant CMTDID MPZ 1q23.3 Autosomal dominant CMTDIE INF2 14q32.33 Autosomal dominant CMTDIF GNB4 3q26.33 Autosomal dominant CMTRI CMTRIA GDAP1 8q21.11 Autosomal recessive Allelic with subtype CMT4A CMTRIB KARS 16q23.1 Autosomal recessive CMTX CMTX1 GJB1 Xq13.1 X-linked dominant Responsible for approximately 90% of CMTX patients; some studies put this number significantly higher. Note that different mutations of GJB1 may produce markedly different forms of Charcot–Marie–Tooth disease. CMTX2 CMTX2 Xq22.2 X-linked recessive CMTX3 CMTX3 Xq26 X-linked recessive CMTX4 AIFM1 Xq24–q26.1 X-linked recessive Also known as Cowchock syndrome CMTX5 PRPS1 Xq22.3 X-linked recessive Also known as Rosenberg–Chutorian syndrome; signs include optic atrophy, polyneuropathy and deafness CMTX6 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