Types of Charcot-Marie-Tooth Disease


There are six different types of Charcot-Marie-Tooth (CMT) disease, a rare disorder caused by mutations that affect the structure and function of peripheral nerves, which control movement and sensation.

These mutated or defective genes may cause degeneration of either the nerve fibers (axons) or the myelin sheath, the fat-rich layer that insulates the nerve fibers. Such degeneration impairs nerve conduction of signals, causing muscle wasting and reduced sensation, specifically to touch, pain, or heat.

The types — and subtypes — of CMT are based on which genes are mutated, the way the disease is inherited, and the speed of nerve conduction. Age of disease onset, its severity and symptoms, and the site of peripheral nerve damage also are used to characterize the varying types of CMT.

The different types of CMT disease are CMT1, CMT2, CMT3, CMT4, CMTX, and DI-CMT.


CMT1 is the most common type of the disorder, accounting for about two-thirds of all cases. It is caused by genetic defects that damage the myelin sheath, so it is commonly referred to as demyelinating CMT.

Characteristic symptoms include muscle weakness and wasting and reduced sensation, particularly in the feet, lower legs, hands, and forearms.

CMT1 is further divided into subtypes A to F, according to which genes are mutated.


This is the most common subtype of CMT1 and is usually caused by a duplication, or extra copy, of the PMP22 gene on chromosome 17, which encodes for the peripheral myelin protein 22 (PMP22), a critical component of the myelin sheath. Overexpression of PMP22 disrupts the structure and function of myelin.


CMT1B is the second-most common subtype of CMT1. It is caused by mutations in the MPZ gene on chromosome 1 that encodes for the myelin protein zero (P0), which is another key myelin component.

Nearly 40% of CMT1B patients have infantile-onset disease, with symptoms developing before age 5. Some patients have childhood-onset disease, in which the onset of symptoms is between ages 6 and 20. Other patients have a late-onset disease with symptoms beginning after age 40.

Other subtypes of CMT1

Other rare subtypes of CMT1 include CMT1C, caused by defects in the LITAF gene, and CMT1D, which is due to defects in the ERG2 gene.  CMT1E, the result of defects in the PMP22 gene, and CMT1F, caused by defects in the NEFL gene, are other rare CMT1 subtypes.


CMT2 is caused by defects in genes that have important roles in the structure and function of the axons of peripheral nerves. This type is commonly referred to as axonal CMT.

It is typically inherited in an autosomal dominant manner, meaning that one mutated copy is disease-causing, although in some cases it can be autosomal recessive. That means that mutations in both gene copies are needed for the disease to develop.

The symptoms in CMT2 are similar to those of CMT1, but there is variability in age of onset and degree of disability. CMT2 is less common than CMT1, accounting for about 12% to 36% of all CMT cases.

CMT2 has been further subdivided into subtypes based on which genes are mutated.

Subtypes of CMT2

CMT2A is the most common subtype of CMT2 and is caused by defects in the MFN2 gene, which codes for mitofusin 2, a protein involved in the fusion of mitochondria. Mitochondria are known for their role as the cell’s powerhouses.

Other less common subtypes of CMT2 include CMT2B, resulting from defects in the RAB7A gene, CMT2C, due to defects in the gene TRPV4, and CMT2D, caused by mutations in the GARS gene. Additional subtypes, also less common, are CMT2E, due to changes in the NEFL gene, CMT2F, caused by mutations in HSPB1, and CMT2I, which results from defects in MPZ.

CMT2J is due to defects in the MPZ gene, CMT2K to mutations in GDAP1, CMT2L to defects in HSPB8, and CMT2M to mutations in DNM2. Alterations in DYNC1H1 lead to CMT2O, while changes in LRSAM1 cause CMT2P. Meanwhile, CMT2S is due to defects in IGHMBP2, CMT2T to mutations in MME, and CMT2Z to defects in the MORC2 gene.


This is a rare, early onset, severe type of CMT that is known as Dejerine-Sottas disease. It is usually autosomal recessive and results in severe muscle wasting, weakness, and sensory problems that begin in early childhood. Scoliosis, a sideways curvature of the spine, also is common in this type, and patients who have this form of CMT may have severe disability.

CMT3 also is characterized by nerve conduction velocities (NCV) of less than 10 m/s in the arms. Normal values are higher than 50 m/s. However, CMT3 is rarely used as a designation since genetic testing has revealed that patients have mutations in genes linked to CMT1A, CMT1B, CMT1D, or CMT4.


Also a rare type, CMT4 can affect the myelin sheath and nerve fibers. It begins in early childhood, and patients generally, over time, lose the ability to walk. This disease type is inherited in an autosomal recessive manner.

The subtypes of CMT4 include CMT4A (caused by mutations in the GDAP1 gene), CMT4B1 (defects in MTMR2), CMT4B2 (mutations in SBF2/MTMR13), CMT4C (mutations in SH3TC2), and CMT4D (alterations in NDRG1). CMT4E is due to mutations in EGR2, while CMT4F is caused by mutations in PRX. Meanwhile, CMT4G results from mutations in HK1, CMT4H is due to mutations in FGD4, CMT4J results from mutations in FIG4, and CMT4K is due to mutations in SURF1.


CMT-X is caused by mutations on the X chromosome. As such, this type is inherited in an X-linked manner. Females who carry the mutation in one gene copy, with a normal gene copy on the other X chromosome, tend to be affected less severely than males, who have only one X chromosome.

There are six different subtypes of CMTX. One of them is CMTX1, which is the second most common type of CMT.

CMTX1 is caused by mutations in the GJB1 gene, which codes for a protein called connexin-32. This protein is expressed in Schwann cells — the cells that form myelin in peripheral nerves — and it forms channels between this type of cells. The faulty connexin-32 protein is thought to impair the formation of Schwann channels and myelin.

Other subtypes include CMTX2 and CMTX3 — for which no genes have been related — CMTX4, caused by mutations in the AIFM1 gene, CMTX5, due to defects in PRPS1, and CMTX6, caused by changes in PDK3.

Dominant intermediate CMT

A further group of CMT disease is called dominant intermediate CMT (DI-CMT), which takes its name from NCV values that are intermediate between CMT1 and CMT2. Nerve biopsies from patients with DI-CMT have shown both axonal degeneration and demyelination.

Besides typical symptoms seen in other CMT types, people with DI-CMT may experience neutropenia, or a low number of a type of white blood cells called neutrophils, early onset cataracts, and tremors in the arms.

Dominant mutations in the genes DNM2YARS, MPZ, and INF2 are associated with DI-CMT types B, C, D, and E, respectively. Mutations in GNB4 and NEFL are responsible for DI-CMT type F.


Last updated: Dec. 9, 2021


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