Charcot-Marie-Tooth disease

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

Charcot-Marie-Tooth disease is a heterogeneous inherited disorder of nerves (neuropathy) that is characterized by loss of muscle tissue and touch sensation, predominantly in the feet and legs but also in the hands and arms in the advanced stages of disease.

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

The disease is named for those who classically described it: Jean-Martin Charcot (1825-1893) and his pupil Pierre Marie (1853-1940) (“Sur une forme particulière d’atrophie musculaire progressive, souvent familiale débutant par les pieds et les jambes et atteignant plus tard les mains”, Revue médicale, Paris, 1886; 6: 97-138.), and Howard Henry Tooth (1856-1925) (“The peroneal type of progressive muscular atrophy”, dissertation, London, 1886.)

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

• CMT Type 1 (CMT1): Type 1 affects approximately 80% of CMT patients and is the most common type of CMT. The subtypes share clinical symptoms. Autosomal dominant. Causes demyelination, which can be detected by measuring nerve conduction velocities.

• CMT Type 2 (CMT2): Type 2 affects approximately 20-40% of CMT patients. Type 2 CMT is Autosomal dominant neuropathy with its main effect on the axon. The average nerve conduction velocity is slightly below normal, but generally above 38 m/s

• CMT Type 3 (CMT3): Type 3 affects a very few CMT patients.

• CMT Type 4 (CMT4): Type 4 affects a very few CMT patients.

• CMT X-Linked (CMTX): CMTX affects approximately 10-20% of CMT patients and is X-linked dominant. Approx 10% of X-linked CMT patients have some other form than CMTX.

More details on the types are provided in the table below:

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

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]

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

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]

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

Though presently incurable, this disease is one of the most common inherited neurological disorders, with 36 in 100,000 affected.^[1]

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

• Progressive inability to walk
• Progressive weakness
• Injury to areas of the body that have decreased sensation

Charcot-Marie-Tooth disease slowly gets worse. Some parts of the body may become numb, and pain can range from mild to severe. Eventually the disease may cause disability.

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