Charcot-Marie-Tooth disease type 2 (CMT2) is a type of CMT whose genetic defects, or mutations, disrupt the structure and function of axons — the long projections of nerve cells that conduct signals to the next nerve cell or muscle cell.
This damage to axons results in the slow transmission of nerve signals from the brain to the muscles, and vice versa. For this reason, CMT2 often is referred to as “axonal CMT.”
CMT2 symptoms are similar to those of CMT1, with variation in the age of onset and the degree of disability. This CMT form is characterized by muscle weakness and atrophy (wasting) and decreased sensation (heat, cold, touch).
CMT2 sometimes is associated with a treatable condition called restless leg syndrome, an irresistible urge to move the legs especially while sitting or lying down.
The defective genes causing CMT2 typically are inherited in an autosomal dominant manner, meaning that one copy of a defective gene from a biological parent is enough to cause the disease. However, in some cases the genes may be inherited in an autosomal recessive manner, wherein two copies of the mutated gene — one from each biological parent — must be present for the disease to develop.
The subtypes of CMT2 are divided on the basis of specific genes that are mutated.
CMT2 subtype A (CMT2A) is the most common form of CMT2. It is caused by dominantly inherited mutations in the MFN2 gene, located on chromosome 1, which codes for mitofusin 2 — a protein involved in the fusion of the mitochondria (energy-producing structures within the cells). It is unclear how MFN gene mutations lead to CMT2A, but research suggests that abnormal mitofusin 2 impairs mitochondrial function, depleting nerve cells of energy.
A form of CMT2A is associated with severe symptoms that begin before age 10. Mutations in the MFN2 gene causing this form may also cause vision loss, which results from degeneration of the nerves that carry information from the eyes to the brain.
CMT2B is mainly a sensory disorder, caused by defects in the RAB7A gene, located on chromosome 3. This gene codes for a protein involved in the clearance of cellular components in neurons. CMT2B is characterized by early disease onset in the second or third decade of life.
CMT2C is a very rare subtype of CMT2. It is caused by defects in the TRPV4 gene, located on chromosome 12, which codes for a protein forming a calcium channel.
In addition to the typical CMT symptoms, CMT2C patients experience hearing loss, vocal cord damage associated with a hoarse voice, and weakness of the diaphragm, or the muscle that separates the abdomen and the chest cavity. Defects in TRPV4 are thought to over-activate the channel protein, resulting in excess calcium in nerve cells, which has been linked with neurodegeneration.
CMT2D is caused by defects in the GARS gene, located on chromosome 7, which codes for an enzyme called glycyl-tRNA synthetase. It 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 the enzyme to interact with its target RNA molecule in protein production.
CMT2E is caused by dominantly inherited mutations in the NEFL gene, located on chromosome 8, which codes for the neurofilament light chain protein. Neurofilaments form the structural framework determining the shape and size of nerve cells. Notably, mutations in NEFL protein also cause CMT1F.
CMT2F is caused by dominant mutations in HSPB1 gene, located on chromosome 7, which codes for heat shock protein beta‐1 (HSPB1). This protein helps neurofilaments maintain the diameter of axons. This is essential for the transmission of nerve impulses.
The onset of muscle weakness ranges from the second to the fourth decade of life, followed by increasing weakness in leg and arm muscles.
CMT2I is caused by mutations in the myelin protein zero gene (MPZ), located on chromosome 1. Myelin protein zero is the most abundant protein in myelin, the fatty covering of nerve fibers that is essential for the transmission of nerve signals. CMT2I is characterized by a late onset with severe sensory loss and weakness, mainly of the legs.
Mutations in MPZ also cause CMT1B.
CMT2J is also caused by mutations in MPZ and is characterized by hearing loss and alterations in the pupil, or the opening of the eye through which light passes.
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% of people with mutations in the GDAP1 gene have CMT2K. GDAP1 codes for a protein called ganglioside-induced differentiation-associated protein 1 found in mitochondria. This protein may play a role in neuronal development.
The onset of symptoms varies, with about 25% of people having symptoms before age 10, 41% between ages 10 and 30, 20% over age 30, and 14% being asymptomatic until after age 50. Fewer than 10% of patients need a wheelchair full time.
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 HSPB1, impairing the function of axons.
CMT2M is caused by a mutation in the gene encoding dynamin-2 (DNM2), located on chromosome 19. This protein is involved in the trafficking of cell components. Mutations in DNM2 have been related to structural defects in neurons known to regulate movement.
People with CMT2M experience symptoms such as unsteady walk, foot deformities, muscle weakness, and wasting of the legs and hands.
CMT2O is caused by a defect in the DYNC1H1 gene that codes for a protein found in the dynein complex, which is involved in processes including transport of proteins in the cell. People with CMT2O show motor symptoms that include leg weakness and foot deformities. Few or no sensory symptoms are observed.
CMT2P is a rare subtype of CMT2, caused by mutations in the LRSAM1 gene. The symptoms are relatively mild with slow progression and begin in the second or third decade of life. Muscle cramps and erectile dysfunction have been reported in some cases.
CMT2S is caused by a rare mutation in the IGHMBP2 gene, which codes for an enzyme called immunoglobulin mu DNA binding protein 2. This enzyme has a crucial role in the production of proteins and cell division.
The mutation leads to slowly progressive weakness, wasting, and sensory loss, but typically without significant respiratory impairment. The onset of symptoms is usually before age 10.
CMT2T is caused by mutations in the MME gene. This CMT form is characterized by adult-onset, slowly progressive weakness and wasting of the legs, resulting in unsteady walking. However, patients retain the ability to walk. Sensory impairment in the extremities is also observed. Mild symptoms in the arms may be evident.
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 sensory loss. Many patients experience leg cramps as an initial symptom.
CMT2Z initially affects the nerves farthest from the spine and then travels up. Over decades, it progresses to muscles above the knees and elbows, including neck muscles. Hip muscles are also affected. People with CMT2Z may require walking aids over time, with most needing a wheelchair in their 40s.
Last updated: Nov. 19, 2021
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