HOW CMT WORKS: THE MECHANISMS BEHIND CMT

Diving into the Details of a  Complex Disease and the Ramifications for People with CMT

To fully understand Charcot–Marie–Tooth disease (CMT), a comprehensive look into the human nervous system is required, as well as an understanding of the far-reaching impact of nerve damage. This is made all the more complex by the inherently intricate workings of the nervous system and that for each type of CMT, the mechanisms for nerve damage can be different even if the resulting symptoms are similar.

In order to outline the mechanisms of CMT, this page will go into detail about the peripheral nervous system, genetics, the structure and formation of nerves, and muscular development, including hypertrophy and hyperplasia. For a basic overview of CMT please see here and for a basic explanation of the types of CMT, please see here.

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NERVES & THE NERVOUS SYSTEMS 

The human body contains two nervous systems: the central nervous system (CNS) and the peripheral nervous system (PNS), with CMT being a disease that can impact both

 

Anatomy of the PNS

 

To explain the mechanisms behind CMT, an understanding of nerves and a healthy peripheral nervous system (PNS) is required. Nerve cells, also called neurons, transmit signals from the brain around the body. The PNS consists of the nerves outside of the brain and spinal cord, and primarily are the nerves most impacted by CMT, although the Central Nervous System can also be impacted depending on the type of CMT.

The PNS (figure 1) is the main way in which the CNS connects to limbs and organs, serving as the communication pipeline between the brain, spinal cord and the rest of the body. CMT is classified as a peripheral neuropathy, meaning the disease generally, but not exclusively, affects the peripheral nerves, rather than the brain or spinal cord (CNS). Damage to peripheral nerves can lead to issues such as impaired sensation, movement and organ function (organs include the eyes, heart, stomach, liver, pancreas and more). These three categories can be described as the motor, sensory and autonomic nerves. As CMT is also known as Hereditary Motor and Sensory Neuropathy (HMSN), the name implies that the first two peripheral neuropathies are impacted rather than the autonomic nerves. 

Nervous System Diagram of the Peripheral Nervous System for people with CMT Charcot Marie Tooth Disease

Figure 1. Peripheral Nervous System

CMT, Nerves & Schwann Cells

As one of the main functions of peripheral nerves is to communicate sensations and controls muscles, any damage to this system can lead to a myriad of issues, such as reduced sensation, lack of muscle control and more. A healthy nerve cell starts with the dendrite, which contains the nucleus, with signals travelling down the axon and ending at the axon terminal. The axon is coated in a myelin sheath, created by numerous Schwann cells, with exposed axon in between the cells, which are called nodes of Ranvier:

Anatomy of a nerve for people with CMT Charcot Marie Tooth Disease

Figure 2. A labelled diagram of a peripheral nerve

The myelin sheath covering the axon exists to help preserve the electrical signals sent through the body, as well as enabling them to travel quicker. For the most common forms of CMT, the symptoms are a result of the degradation of the myelin sheath, a process called demyelination. Where demyelination has occurred, electrical signals will travel at a slower speed, hence why a nerve conduction velocity test can be an initial indication for CMT. Demyelination of the nerve can result in damage to the axon, which in turn can result in issues such as loss of sensation to an area, loss of muscle control, muscular atrophy and more. 

Schwann Cell Detailed Look for people with CMT Charcot Marie Tooth Disease nerve damage

Figure 3.  A labelled cross-section diagram of a Schwann cell

The Schwann cell (figure 3) plays a vital role in creating and maintaining the myelin sheath that wraps around the axon. The cell produces the sheath, which consists of three proteins: PMP22, MPZ and  PRX, and any disruption in this process can result in demyelination.  For example, in CMT-1A, excessive PMP22 is produced by the Schwann cell, which causes toxic damage to the sheath, resulting in demyelination. As the breakdown of the myelin sheath in most people with CMT is gradual, the peripheral limbs (feets, legs, hands and forearms) are usually the most impacted areas as the result of demyelination is more prominent across longer nerves, such as the sciatic nerve which runs from the base of the spinal cord to the big toe on each foot.

 

CMT TYPES & SUBTYPES

There are nine individual types of CMT, with over 60 distinct subtypes of CMT currently identified. Which type and subtype of CMT a person has will determine the biological processes involved.

 

CMT Types

CMT can be broken down into types, and further again into subtypes. While sharing symptomatic similarities, the underlying mechanisms for each subtype can be greatly different. The distribution of CMT types is also not equal, with CMT 1 accounting for the majority of cases, followed by CMT 2 and CMT X (figure 4). Traditionally, CMT types were categorised by their main underlying mechanism: demyelinating (CMT1), axonal/non-demyelinating (CMT2), and a mutation in the X-chromosome (CMTX), however recent research suggests a new naming convention may be required as subtypes of each CMT type may have overlapping mechanisms, making the type classification inadequate [1]. Beyond this, the epidemiology of CMT is poorly understood, with different countries showing widely varying occurrences of types of CMT, with further research needed to fully understand the frequency of CMT types [2]. Figure 4 displays the generally accepted average spread of CMT types, including the error margin.

CMT Charcot Marie Tooth Disease Type Occurrence Graph

Figure 4.  Bar chart showing the average spread of CMT across patients, including the estimated range for each type.

It is worth noting that CMT types 3, 5, 6 and 7 are classifications no longer used, with CMT type 3 being renamed as Dejerine–Sottas disease, and types 5 through 7 are now classified as CMT along with their associated symptoms [3]. Furthermore, the error margin for CMT types is still quite large, with CMT type 2 ranging from 12% to 36% depending on sources used, with more sources suggesting symptoms, such as pyramidal features, are overlooked [4]

 

CMT Subtypes

Each CMT type can be divided into a subtype, each with their own mechanism of action and inheritance pattern with over 100 individual genes identified tied to subtypes. A regularly updated overview of each type can be found in the online book "Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview" available for free here [5]. As with CMT types, subtypes are not equally distributed, with different subtypes making up proportionally more cases than others. Below is an overview of some of the most common subtypes:

CMT-1A
CMT-1A accounts for 70-80% of CMT-1 cases and is well researched, with an end-to-end understanding of the disease. Originating in chromosome fragment 17p11.2 as a 1.5-Mb PMP22 duplication, the duplication results in the Schwann Cell overproducing the protein PMP22. This protein collects within the cell and potentially becomes toxic as it is not able to be folded and transported to the correct place within the cell membrane. This toxicity results in the myelin sheath breaking down, damaging the axon and resulting in the symptoms associated with CMT-1A [6]
CMT-1B
The second most common form of CMT-1, CMT-1B is caused by a defect in the MPZ gene, located on chromosome 1. The defect causes a cellular deficit of the MPZ protein within the Schwann cell, resulting in damage to the myelin sheath, axon damage and symptoms similar to that of CMT-1A.
CMT-2A
With >20  individual subtypes of CMT-2​, CMT-2A is the most common, making up about 20% of cases. Unlike most subtypes of CMT-1, CMT-2 generally involves damage directly to the axon rather than through demyelination, with CMT-2A caused by a defect in the MFN2 gene [7]. In general, CMT-2 is less severe than type 1[6] with as many as 25% of individuals with the mutation being asymptomatic [7] but is also less well understood [8]
CMT-X1
CMT-X1 is caused by over 260 distinct mutations in the gap junction beta 1 (GJB1) gene, located on the X chromosome, which encodes the gap junction protein connexin 32 (Cx32).  Cx32 has an essential role in myelinating Schwann cells, therefore interference in this process results in demyelination, with CMT-X1 accounting for ~50% of all X-linked cases.
 

Comprehensive CMT Subtype Information

Each CMT type can be divided into a subtype, each with its own mechanism of action and inheritance pattern. Below is an excerpt from Bussman et al., 2017; covering the known genes, their associated CMT subtype, the subcellular localisation and more:

 

References

[1] Magy L, Mathis S, Le Masson G, Goizet C, Tazir M, Vallat JM. Updating the classification of inherited neuropathies: Results of an international survey. Neurology. 2018;90(10):e870-e876. doi:10.1212/WNL.0000000000005074

[2]  Barreto LC, Oliveira FS, Nunes PS, et al. Epidemiologic Study of Charcot-Marie-Tooth Disease: A Systematic Review. Neuroepidemiology. 2016;46(3):157-165. doi:10.1159/000443706

[3] Harding AE, Thomas PK. Peroneal muscular atrophy with pyramidal features. J Neurol Neurosurg Psychiatry. 1984;47(2):168-172. doi:10.1136/jnnp.47.2.168

[4] Vucic S, Kennerson M, Zhu D, Miedema E, Kok C, Nicholson GA. CMT with pyramidal features. Charcot-Marie-Tooth. Neurology. 2003;60(4):696-699. doi:10.1212/01.wnl.0000048561.61921.71

5] Bird TD. Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; September 28, 1998

[6] Marinko JT, Carter BD, Sanders CR. Direct relationship between increased expression and mistrafficking of the Charcot-Marie-Tooth-associated protein PMP22. J Biol Chem. 2020;295(34):11963-11970. doi:10.1074/jbc.AC120.014940

[7] Feely SM, Laura M, Siskind CE, et al. MFN2 mutations cause severe phenotypes in most patients with CMT2A. Neurology. 2011;76(20):1690-1696. doi:10.1212/WNL.0b013e31821a441e

[8] Lawson VH, Graham BV, Flanigan KM. Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology. 2005;65(2):197-204. doi:10.1212/01.wnl.0000168898.76071.70