What is CMT4?
Charcot-Marie-Tooth disease type 4 (CMT4) is a rare type of CMT that causes damage to the myelin sheath, an insulating fat-rich layer surrounding the axons of peripheral nerve cells that connect the brain and spinal cord to the motor and sensory muscles.
CMT4 causes muscle weakness, mostly in the distal muscles (those far from the center of the body), but sometimes also in proximal muscles (those close to the center of the body). Changes in sensations (touch, pain, sound, or temperature) also may occur. Individuals with CMT4 generally develop symptoms of leg weakness in early childhood; by adolescence, they may not be able to walk. When CMT4 begins in infancy, it is characterized by low muscle tone (loose, floppy muscles).
CMT4 patients also may develop other symptoms such as cataracts or deafness. The symptoms vary from mild to severe. Some subtypes of CMT4 exhibit severe symptoms with early-onset and are classified as Dejerine-Sottas disease.
Each subtype is caused by different genetic mutations and has characteristic symptoms.
CMT4 subtype A (CMT4A) is caused by recessively inherited mutations in the GDAP1 gene, (as opposed to dominantly inherited mutations in the same gene, as in the case of CMT2K). About 75 percent of people with mutations in the GDAP1 gene have CMT4A.
GDAP1 encodes for a protein called ganglioside-induced differentiation-associated protein 1 found in mitochondria (energy-producing centers in the cell). It is unclear how these mutations lead to CMT4A.
CMT4A patients have the onset of symptoms in the first two decades of life, and mostly before the age of 10. Symptoms affect both lower and upper limbs and include muscle wasting and contractures (permanent shortening of the muscles), and delayed milestones such as sitting and walking. Most patients need walking assistance by 30 years of age and about 75 percent need a wheelchair after the age of 30. As the disease progresses, a hoarse voice can develop due to the vocal cord muscles being affected. Partial paralysis of the vocal cord muscle also has been reported. Life expectancy and intelligence are not affected.
The MTMR2 gene encodes for an enzyme called myotubularin-related protein 2, which modifies chemical messengers that regulate processes such as the transport of lipids (fats) and proteins within the cell. Researchers have identified at least 10 MTMR2 gene mutations that cause CMT4B1 but it is unclear how MTMR2 gene mutations lead to the characteristic features of CMT4B1.
The SBF2 gene (also called MTMR13) encodes for a protein called SET binding factor 2. The function of this protein is unknown. At least five SBF2 gene mutations have been identified in patients with CMT4B2. Although it is unclear how SBF2 gene mutations lead to this disorder, it is thought that myelin production probably is disrupted.
A so-called out-folding myelin is a characteristic sign of CMT4B. CMT4B patients become symptomatic early in life, with an average age of onset at 34 months. Unlike most types of CMT, both proximal and distal weakness is common. Individuals with this disorder also may experience a buildup of fluid pressure within the eye (glaucoma) beginning in childhood or adolescence.
CMT4 subtype C (CMT4C) is caused by mutations in the SH3TC2 gene, which is active in the nervous system and encodes for a protein whose function is unknown. Researchers have identified at least 19 SH3TC2 gene mutations associated with CMT4C. It is unclear how SH3TC2 gene mutations cause the signs and symptoms of CMT4C.
CMT4C is characterized by early-onset severe spine deformities. The majority of affected children present with scoliosis (curvature of the spine) between ages 2 and 10 years. Slow, progressive CMT symptoms such as muscle weakness and numbness usually manifest in the first decade or at adolescence. Foot deformities such as high-arched or flat feet are common. Patients often have mild difficulty with walking, and some may need a wheelchair. It is common to have lower limb and upper limb weakness, beginning in the hands and feet, and sometimes extending above the elbows and knees. Hearing loss, vocal cord involvement, and facial paresis (partial paralysis) have been reported. The nerve conduction velocity (the speed at which nerve signals travel across nerve cells) is slow and usually ranges between 16 and 36 m/s in the arms.
CMT4 subtype D (CMT4D) is caused by defects in the NDRG1 gene, located on chromosome 8, which encodes for a protein whose function is not well understood. Researchers have identified at least two NDRG1 gene mutations that cause CMT4D. It is unclear how NDRG1 gene mutations lead to CMT4D.
This form of the disease was first described as a separate disorder in a Gypsy population. Symptoms include distal weakness, muscle wasting, sensory loss, foot and hand deformities, and loss of deep tendon reflexes (nerve reflexes that determine muscle contraction upon tapping). CMT4D patients always develop deafness, which usually occurs by the third decade. Nerve conduction is severely reduced in younger patients and completely unattainable after 15 years of age.
CMT4 subtype E (CMT4E) is caused by defects in the EGR2 gene, located on chromosome 10, which encodes for a DNA-binding protein called early growth response 2. This protein activates the expression of several other genes involved in the formation and maintenance of myelin. Mutations in EGR2 result in an abnormal protein that is unable to bind to the DNA, preventing the expression of genes involved in myelin production. This results in loss of myelin and impaired nerve signal transmission.
Symptoms are severe, including delayed motor milestones and nerve conduction velocities of 10 m/sec or less, which begin during infancy or early childhood.
CMT subtype 4F (CMT4F) is a severe form of CMT that has been defined in a large Lebanese family with mutations in the PRX gene. PRX is located on chromosome 19 and encodes for periaxin, a protein required for the maintenance of myelin.
Researchers have identified at least 10 mutations in the PRX gene that cause CMT4F, sometimes called Dejerine-Sottas syndrome. These mutations result in an abnormally short periaxin protein that cannot maintain the myelin structure. Disrupted myelin structure can lead to the loss of myelin (demyelination) and impaired transmission of nerve impulses.
Nerve conduction studies are markedly slow and onion bulb formations — structures formed due to the proliferation of Schwann cells and deposition of collagen around axons — are observed in nerve biopsies.
Recently, a protein called dystrophin-related protein 2 (DRP2) that forms a complex with periaxin has also been shown to contribute to the development of CMT4F. DRP2 forms a complex with two proteins – periaxin and dystroglycan. This complex facilitates the formation of structures called Cajal bands. In a case study, mutations in the DRP2 gene have been found to contribute to neuropathy in CMT4F. In another case, a mutation in the DRP2 gene inhibited the production of DRP2 protein, which resulted in the disruption of the Cajal bands.
CMT4 subtype H (CMT4H) is caused by defects in the FGD4 gene, which encodes for a protein called frabin. Frabin plays an important role in the nervous system, where it regulates a type of cell-signaling involved in myelin production.
At least five mutations in the FGD4 gene have been identified in people with CMT4H. The altered protein causes abnormal myelination of the peripheral nervous system, resulting in the signs and symptoms of CMT4H.
CMT4 subtype J (CMT4J) is caused by mutations in the FIG4 gene, located on chromosome 6, which encodes for a protein called Fig4, whose function is not well understood.
At least five mutations in the FIG4 gene have been identified in individuals with CMT4J. Researchers are working to determine how mutations in the FIG4 gene lead to the specific signs and symptoms of CMT4J.
Symptoms and age of onset are variable. Some people have a classic presentation, while others have slowly progressing symptoms. The disease progresses with more severe changes later in adulthood. CMT4J causes intermediate to slow nerve conductions due to changes in the myelin.
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