What is CMT2?
Charcot-Marie-Tooth disease type 2 (CMT2) is a type of CMT with genetic defects that disrupt the structure and function of the axons of the peripheral nerves. So, CMT2 often is referred to as “axonal CMT.”
CMT2 symptoms are similar to those of CMT1, but there is variation in the age of onset and the degree of disability. CMT2 is characterized by muscle weakness and atrophy, and decreased sensation (heat, cold, touch), mostly in the periphery of the body, such as the feet, lower legs, hands, and forearms.
CMT2 sometimes is associated with a treatable condition called restless leg syndrome, an irresistible urge to move the legs while sitting or lying down.
CMT2 is caused by genetic defects that directly damage the axons — the long, slender projection of a nerve cell that conducts signals to the next nerve cell or a muscle cell. This damage to the axon results in the slow transmission of nerve signals from the brain to the muscles, and vice versa.
The defective genes causing CMT2 typically are inherited in an autosomal dominant manner, but in some cases, the genes may be inherited in an autosomal recessive manner.
The subtypes of CMT2 are divided on the basis of specific genes that are mutated.
CMT2 subtype A (CMT2A) is the most common subtype of CMT2. It is caused by dominantly inherited mutations in the MFN2 gene, located on chromosome 1, which encodes for mitofusin 2, a protein involved in the fusion of the mitochondria (energy-producing chambers within the cells). It is unclear how MFN gene mutations lead to CMT2A, but research suggests that abnormal mitofusin 2 impairs mitochondrial function, depleting the nerve cells from energy supply.
CMT2A patients usually experience severe symptoms that begin before age 10. Mutations in the MFN2 gene may cause vision loss, which is caused by the degeneration of the nerves that carry information from the eyes to the brain.
CMT2 subtype B (CMT2B) is mainly a sensory disorder, caused by defects in the RAB7A gene, located on chromosome 3. This gene encodes for a protein that is involved in the transport of neurotransmitters (chemical messengers transported from one nerve cell to another). It is not clear how the gene mutations cause CMT2B, but researchers suggest that impaired transport of neurotransmitters by the defective RAB7A protein may play a role. CMT2B is characterized by a severe reduction of sensation, especially in the arms and legs.
CMT2 subtype C (CMT2C) is a very rare subtype of CMT2. It is caused by defects in the TRPV4 gene, located on chromosome 12, which encodes for a protein forming a calcium channel.
In addition to the typical CMT symptoms, CMT2C patients experience additional symptoms, including hearing loss caused by nerve damage in the inner ear, weakness in the vocal cords causing a hoarse voice, and weakness of the muscle that separates the abdomen and the chest cavity (diaphragm), causing breathing problems. The defects in the TRPV4 gene are thought to over-activate the channel protein, but it is unclear how it affects the nervous system causing CMT.
CMT2 subtype D (CMT2D) is caused by defects in the GARS gene, located on chromosome 7, which encodes for glycyl t-RNA synthetase that is involved in protein synthesis in the cell. The symptoms of CMT2D vary in patients, ranging from motor symptoms only, to both sensory and motor symptoms.
It is unclear how mutations in the GARS gene result in CMT2D, but scientists suggest that mutations may reduce the activity of glycyl-tRNA synthetase, which may impair the ability of axons to transmit nerve impulses.
CMT2 subtype E (CMT2E) is caused by dominantly inherited mutations in the NEFL gene, located on chromosome 8, which encodes for the neurofilament light chain protein. Neurofilaments form the structural framework determining the shape and size of nerve cells. The defective NEFL protein is thought to disrupt the assembly of neurofilaments in the axons and subsequently impair the transmission of nerve impulses.
CMT2 subtype K (CMT2K) is caused by dominantly inherited mutations in the GDAP1 gene, as opposed to recessively inherited mutations in the same gene in the case of CMT4A. About 25 percent of people with mutations in the GDAP1 gene have CMT2K. GDAP1 encodes for a protein called ganglioside-induced differentiation-associated protein 1 found in mitochondria (energy centers in the cell). It is unclear how these mutations lead to CMT2K.
The onset of symptoms varies, with about 25 percent of people having symptoms before the age of 10, 41 percent having them between ages 10 and 30, 20 percent having them over age 30, and 14 percent being asymptomatic until after age 50. Less than 10 percent of people with CMT2K need a wheelchair full-time.
CMT2 subtype L (CMT2L) is caused by mutations in the HSPB8 gene that encodes for a protein called heat shock protein beta-8, which helps protect the cell from adverse conditions such as an infection or elevated temperature. It is unclear how these mutations lead to CMT2L, but research suggests that the altered protein likely forms aggregates with another protein called heat shock protein beta-1 impairing the function of axons.
CMT2 subtype O (CMT2O) is caused by a genetic defect in the DYNC1H1 gene that encodes for a protein found in the dynein complex, a complex involved in many cellular processes including transport of proteins in the cell. People with CMT2O show only motor symptoms with little or no sensory symptoms.
CMT2 subtype P (CMT2P) is a rare subtype of CMT2, caused by mutations in the LRSAM1 gene. The symptoms are relatively mild with very slow progression, and begin in the second or third decade of life. Most CMT2P patients have some motor symptoms and foot deformities only after age 30. Involuntary muscle twitches and erectile dysfunction have been reported in some cases.
CMT2 subtype Z (CMT2Z) is caused by mutations in the MORC2 gene. Some patients have generalized weakness in infancy, while others have adult-onset weakness that may include proximal muscles and sensory loss. Many patients experience leg cramps as an initial symptom. CMT2Z affects the nerves farthest from the spine first and then travels up. Over decades, it progresses to muscles above the knees and elbows, including the hip and neck muscles. People with CMT2Z may require walking aids over time, with most requiring a wheelchair in their 50s.
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