Charcot-Marie-Tooth disease type 3, or CMT3, is a rare and severe type of CMT that begins in early childhood. It is also known as Dejerine-Sottas disease in its more severe forms, congenital hypomyelination, or Roussy-Levy syndrome. CMT3 is attributed to the same genetic mutations that are responsible for CMT1A (PMP22 gene), CMT1B (MPZ gene), CMT1D (EGR2 gene), or CMT4 (PRX gene). So, genetically speaking, CMT3 may no longer be a useful designation.
The characteristic symptoms of CMT3 are severe, with generalized muscle atrophy and weakness sometimes progressing to profound disability, loss of or decreased sensations (touch, pain, or heat), curvature of the spine (scoliosis), high foot arches, and possibly mild hearing loss. Symptoms can begin in infancy or early childhood, before the age of 3, and progress slowly. CMT3 may eventually cause severe disability.
CMT3 is caused by genetic defects that disrupt the structure and function of either peripheral nerve axons (nerve fibers that conduct nerve signals from the brain to the motor and sensory muscles), or the myelin sheath (the fat-rich layer covering the peripheral nerve axons that helps to transmit nerve signals). This can lead to axonal degeneration or demyelination (loss of myelin), disrupting the transmission of nerve signals from the brain to the muscles and vice versa.
Mutations in PMP22 gene
CMT3 can be caused by mutations in the PMP22 gene located on chromosome 17, which encodes for peripheral myelin protein 22, a critical component of the myelin sheath produced by Schwann cells. An altered PMP22 protein disrupts the structure and function of the myelin sheath. This form of the disorder usually begins in infancy. It is characterized by muscle weakness and atrophy, and delayed development of motor skills.
Mutations in MPZ gene
CMT3 can also be caused by mutations in the MPZ gene located on chromosome 1, which encodes for the myelin protein zero. This protein is an essential component of the myelin sheath. Symptoms begin during infancy or early childhood, and include delayed development of such motor skills as walking. Research suggests that MPZ mutations causing this severe form of the disorder probably disrupt the formation of myelin during early development.
Mutations in EGR2 gene
CMT3 can also be caused by defects in the EGR2 gene, located on chromosome 10, which encodes for a protein called early growth response 2. The EGR2 protein binds to the DNA and activates the expression of other genes that are important for the formation and maintenance of the myelin sheath. Defective EGR2 protein cannot bind to the DNA to drive the expression of myelin-forming and myelin-maintainig genes. The end result is the loss of the myelin sheath, and impaired nerve signal transmission. Symptoms are severe, including delayed motor milestones beginning in infancy or early childhood.
Mutations in PRX gene
CMT3 may also result from mutations in the PRX gene located on chromosome 19, which encodes for periaxin. Periaxin is necessary for the maintenance of myelin. Around 10 mutations in the PRX gene have been associated with CMT3. These mutations result in an abnormally short periaxin protein that cannot maintain the myelin structure. The result is, again, a loss of myelin and poor nerve signal transmission.
The defective genes causing CMT3 can be inherited in a manner that is either an autosomal dominant (one mutated copy is disease-causing) or autosomal recessive (mutations in both gene copies).
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