Charcot-Marie-Tooth (CMT) disease is caused by mutations that affect the structure and function of peripheral nerves, which control movement and sensation.
The defective genes may cause degeneration of either the nerve fibers (axons) or the myelin sheath (the fat-rich layer that insulates the nerve fibers) of the peripheral nerves. This impairs the conductance of nerve signals between the brain and the extremities, causing muscle atrophy and reduced sensation.
The various types and subtypes of CMT are classified on the basis of the genes that are mutated, the way the disease is inherited, the speed of nerve conduction, the age of disease onset, the severity level of the condition, the clinical symptoms, and the site of peripheral nerve damage.
The different types of CMT disease are CMT1, CMT2, CMT3, CMT4, CMTX, and DI-CMT.
CMT1 is the most common type of CMT, accounting for about two-thirds of all cases. It is caused by genetic defects that damage the myelin sheath covering the nerves and so is commonly referred to as demyelinating CMT.
Characteristic symptoms include muscle weakness and atrophy and reduced sensation, particularly in the extremities (feet, lower legs, hands, and forearms).
CMT1 is further divided into subtypes A to F according to which genes are mutated.
It is the most common subtype of CMT1 caused by a duplication of the PMP22 gene on chromosome 17, which encodes for the peripheral myelin protein 22, a critical component of the myelin sheath. Overexpression of PMP22 disrupts the structure and function of the myelin sheath.
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 critical component of the myelin sheath.
Other subtypes of CMT1
Other rare subtypes of CMT1 include CMT1C (defects in the LITAF gene), CMT1D (defects in the ERG2 gene), CMT1E (defects in the PMP22 gene), and CMT1F (defects in the NEFL gene).
CMT2 is caused by defects in the genes that have important roles in the structure and function of the axons of the peripheral nerves. CMT2 is commonly referred to as axonal CMT.
CMT2 is typically inherited in an autosomal dominant manner, although in some cases it can be autosomal recessive.
The symptoms in CMT2 are similar to those of CMT1, but there is more variability in age of onset and degree of disability. CMT2 is less common than CMT1.
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 that codes for mitofusin 2, a protein involved in the fusion of cellular mitochondria.
Other less common subtypes of CMT2 include CMT2B (defects in the RAB7 gene); CMT2C (defects in the TRPV4 gene); CMT2D (defects in the GARS gene); CMT2E (defects in the NEFL gene); and CMTT 2I (defects in the MPZ gene).
Also, CMT 2J (defects in the MPZ gene); CMT2K (defects in the GDAP1 gene); CMT2L (defects in the HSPB8 gene); CMT2O (defects in the DYNC1H1 gene); CMT2P (defects in the LRSAM1 gene); and CMT2Z (defects in the MORC2 gene).
It is also known as Dejerine-Sottas disease. It is an early-onset severe type of CMT. It is rare and disrupts the myelin sheath, resulting in severe muscle atrophy, weakness, and sensory problems that begin in early childhood. CMT3 is no longer a useful designation since this disease is now attributed to the genetic mutations that are responsible for CMT1A (PMP22 gene); CMT1B (MPZ gene); CMT1D (EGR2 gene); or CMT4 (PRX gene).
It is also a rare type of CMT that affects the myelin sheath. It begins in early childhood and the patients lose the ability to walk over time. It is usually inherited in an autosomal recessive manner.
The subtypes of CMT4 include CMT4A (recessively inherited mutations in the GDAP1 gene); CMT4B1 (a genetic defect in the MTMR2 gene); CMT4B2 (mutation in the SBF2/MTMR13 gene); CMT4C (mutations in SH3TC2 gene); CMT4D (defect in the NDRG1 gene); CMT4E (a mutation in the EGR2 gene); CMT4F (a mutation in the PRX gene); CMT4H (mutation in the FGD4 gene); and CMT4J (mutations in the FIG4 gene).
CMT-X is caused by mutations in the GJB1 gene, located on the X-chromosome, which encodes for a protein called connexin-32. This protein is expressed in Schwann cells — the cells involved in the production of the myelin sheath — and forms channels between the Schwann cells and the myelin sheath. The abnormal connexin-32 protein is thought to impair the formation of channels and subsequent myelin layer, causing CMT disease. It is inherited in an X-linked manner.
Dominant intermediate CMT
There is a final group of CMT disease called dominant intermediate CMT (DI-CMT), which takes its name from the nerve conduction velocity (NCV), which is considered intermediate. The nerve biopsies from patients with DI-CMT have shown both axonal degeneration as well as demyelination. Dominant mutations in the genes DNM2, MPZ, and YARS are associated with DI-CMT types B, D, and C, respectively.
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