Charcot Marie Tooth Disease
|Charcot Marie Tooth Disease|
|Genetics||More than 80 different genes have been identified|
Charcot Marie Tooth (CMT) is a group of diseases that are characterised by a hereditary peripheral motor and sensory polyneuropathy. Patients experience gradual symmetrical weakness and atrophy of the muscles in the feet and/or hands typically beginning in the first to third decade of life.
CMT1A is the most common form of CMT and accounts for up to 70% of cases. It has an autosomal dominant pattern of inheritance.
It is caused by a duplication on chromosome 17 in the region that carries the PMP22 gene. This gene encodes for a protein that plays an essential role in the formation and maintenance of myelin, the fatty substance that insulates the peripheral nerves. The duplication leads to an overproduction of PMP22, causing abnormal myelin formation and demyelination, which, in turn, leads to slowed nerve conduction velocity.
As more genes have been discovered the classification system has become increasingly complex. The traditional system is based on nerve conduction velocities and classifies three types: CMT1 (demyelinating), CMT2 (axonal), and DI-CMT (dominant intermediate). Later letters were added to further classify them such as CMT1A.
CMT1: NCV <35 m/s with slowly progressive symptoms, including distal muscle weakness and atrophy, sensory loss, and pes cavus foot deformity.
CMT2: NCV > 45 m/s. Shares many clinical features with demyelinating CMT, those with axonal CMT tend to have less severe symptoms.
DI-CMT: NCV between 35-45 m/s, exhibits a CMT phenotype that is variable within a family, with some individuals falling into the demyelinating range and others into the axonal range.
Patients usually present with lower limb motor symptoms, such as difficulty walking and foot deformity, in the first to third decades of life. CMT is usually painless but can sometimes be painful.
Examination typically shows distal muscle atrophy, pes cavus foot deformity, distal weakness, hyporeflexia, distal sensory loss, and reduced vibration and proprioception. Severe distal weakness can lead to the "knee bob sign," where the knees bob up and down when attempting to stand still. This sign indicates ankle plantar flexion weakness with pre-existing ankle dorsi flexion weakness. Knee bobbing is a marker of progression of the disease leading to significant functional deterioration.
Sensorineural hearing loss can also occur.
Neurophysiology in CMT1 typically shows median and ulnar motor conduction velocities (MCVs) below 38 m/s, with reduced or absent sensory action potentials. Nerve biopsy demonstrates demyelination and remyelination with onion bulb formation, but genetic testing is now widely available and is the gold standard for diagnosing CMT.
CMT1A is a very slowly progressive neuropathy, and patients have normal life spans. However, they often need ankle-foot orthoses and occasionally a stick to walk. There is currently no cure for CMT, and treatment is symptomatic and supportive. Physical therapy and orthopedic interventions can help improve function and prevent deformities.
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