What is the pathophysiology of Charcot-Marie-Tooth disease (CMT)?

Updated: Jun 23, 2021
  • Author: Divakara Kedlaya, MBBS; Chief Editor: Elizabeth A Moberg-Wolff, MD  more...
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Charcot-Marie-Tooth disease (CMT) is actually a heterogeneous group of genetically distinct disorders with a similar clinical presentation. CMT-1A is a disorder of peripheral myelination resulting from a duplication in the peripheral myelin protein-22 (PMP22) gene. [16, 17]  PMP22 -related neuropathies should be viewed as the consequence of impaired neuron–Schwann cell interactions that are likely to be operative during fetal development. [18]

A study by Duchesne et al indicated that in addition to myelinated nerve fibers, small unmyelinated fibers are also involved in CMT-1A, with the authors finding significantly reduced intraepidermal nerve fiber density in patients with CMT-1A compared with healthy controls. The study also reported epidermal Langerhans cell density to be significantly lower in patients with CMT-1A, possibly demonstrating that Langerhans cells are associated with the neuropathic pain some patients experience. The study’s results, according to the investigators, may reveal that along with PMP22 dosage, other factors influence the development of CMT-1A. [19]

Mutation in the gene encoding the major peripheral nervous system myelin protein, myelin protein zero (MPZ), [20, 21] causes CMT-1B and it accounts for 5% of patients with CMT. The mutation results in abnormal myelin that is unstable and spontaneously breaks down. This process results in demyelination, leading to uniform slowing of conduction velocity. Autosomal dominant hereditary motor and sensory neuropathies (HMSNs), CMT neuropathy) account for 60-70% of families with CMT. [22]

Slowing of conduction in motor and sensory nerves was believed to cause weakness and numbness. A study by Krajewski and colleagues suggested that neurologic dysfunction and clinical disability in CMT-1A are caused by loss or damage to large-diameter motor and sensory axons. [23] Pain and temperature sensations usually are not affected, because they are carried by unmyelinated (type C) nerve fibers.

In response to demyelination, Schwann cells proliferate and form concentric arrays of remyelination. Repeated cycles of demyelination and remyelination result in a thick layer of abnormal myelin around the peripheral axons. These changes cause what is referred to as an onion bulb appearance.

CMT-2 is primarily a neuronal (ie, axonal) disorder, not a demyelinating disorder. Type 2 results in peripheral neuropathy through direct axonal death and wallerian degeneration. CMT-2 is likely to display much more genetic heterogeneity than CMT-1. [24] Some cases of CMT-2 have also been linked to mutations in the MPZ gene. [25] CMT-3 (also known as Dejerine-Sottas disease) is characterized by infantile onset.

Type 3 results in severe demyelination with delayed motor skills and is a much more severe form than type 1. Marked segmental demyelination with thinning of the myelin around the nerve is observed on histologic examination.

CMT-X (X-linked CMT) and CMT-4 are also demyelinating neuropathies.

CMT type 4C appears to be the most prevalent (18%) autosomal recessive CMT subtype. Common features of CMT-4C include childhood onset, thoracic spine scoliosis, moderate to severe neuropathy, and cranial nerve deficits. [26]  A report by Jerath et al delineated the clinical and physiologic features of five patients with CMT-4C, each of whom demonstrated biallelic private mutations of SH3TC2. Scoliosis occurred universally, and nerve conduction studies pointed to the existence of demyelination. Three new mutations in the patients were described, and the presence of at least two different genetic diseases in the same patient was observed. [27]

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