Charcot-Marie-Tooth disease causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Causes

The disorder is caused by the absence of molecules that are essential for normal function of the nerves due to errors in the genes coding these molecules. The absence of these chemical substances gives rise to dysfunction either in the axon or the myelin sheath of the nerve cell. Most of the mutations identified result in disrupted myelin production, however the most common mutations occur in gene MFN2, which doesn't seem to have anything to do with myelin. Instead MFN2 controls behaviour of mitochondria. Recent research showed that the mutated MFN2 causes mitochondria to form large clusters. In nerve cells these large clusters of mitochondria failed to travel down the axon towards the synapses. It is suggested these mitochondria clots make the synapses fail, resulting in CMT disease.[1]

The different classes of this disorder have been divided into the primary demyelinating neuropathies (CMT1, CMT3, and CMT4) and the primary axonal neuropathies (CMT2). Recent studies, however, show that the pathologies of these two classes are frequently intermingled, due to the dependence and close cellular interaction of Schwann cells and neurons. Schwann cells are responsible for myelin formation, enwrapping neural axons with their plasma membranes in a process called “myelination”.[2]

The molecular structure of the nerve depends upon the interactions between neurons, Schwann cells, and fibroblasts. Schwann cells and neurons, in particular, exchange signals that regulate survival and differentiation during development. These signals are important to CMT disease because a disturbed communication between Schwann cells and neurons, resulting from a genetic defect, is observed in this disorder.[2]

It is clear that interaction with demyelinating Schwann cells causes the expression of abnormal axonal structure and function, but we still do not know how these abnormalities result in CMT. One possibility is that the weakness and sensory loss experienced by patients with CMT is a result of axonal degradation. Another possibility is that axonal dysfunction occurs, not degeneration, and that this dysfunction is induced by demyelinating Schwann cells.[3]

Most patients experience demyelinating neuropathies, and this is characterized by a reduction in nerve conduction velocity (NCV), due to a partial or complete loss of the myelin sheath. Axonopathies, on the other hand, are characterized by a reduced compound muscle action potential (CMAP), while NCV is normal or only slightly reduced.[2]

References

  1. Baloh, R., Schmidt, R., Pestronk, A. and Milbrandt, J. (2007) The Journal of Neuroscience 27(2):422-430, http://www.jneurosci.org/cgi/content/abstract/27/2/422 accessed 070122
  2. 2.0 2.1 2.2 Berger, P., Young, P. and U. Suter (2002) Neurogenetics 4:1-15. http://www.springerlink.com/, accessed 060220
  3. Krajewski, K.M., Lewis, R.A., Fuerst, D.R., Turansky, C., Hinderer, S.R., Gerbern, J., Kamholz, J. and M.E. Shy (2000) Brain 123:1516-1527 accessed 060220

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