Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease, known also as Hereditary Motor and Sensory Neuropathy (HMSN) or Peroneal Muscular Atrophy, 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. Though presently incurable, this disease is one of the most common inherited neurological disorders, with 36 in 100,000 affected.

Description
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.

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”.

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.

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.

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.

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.)

Symptoms
Symptoms usually begin in late childhood or early adulthood. Usually, the initial symptom is foot drop due to involvement of the peroneal nerve, which is responsible for raising the feet, early in the course of the disease. This can also cause hammer toe, where the toes are always curled. Wasting of muscle tissue of the lower parts of the legs may give rise to "stork leg" or "inverted bottle" appearance. Weakness in the hands and forearms occurs in many people later in life as the disease progresses.

Symptoms and progression of the disease can vary. Breathing can be affected in some; so can hearing, vision, and the neck and shoulder muscles. Scoliosis is common. Hip sockets can be malformed. Gastrointestinal problems can be part of CMT, as can chewing, swallowing, and speaking (as vocal cords atrophy). A tremor can develop as muscles waste. Pregnancy has been known to exacerbate CMT, as well as extreme emotional stress.

Diagnosis
The diagnosis is established by electromyography examination (which shows that the velocity of nerve impulse conduction is decreased and the time required to charge the nerve is increased) and nerve biopsy. Genetic markers have been identified for some, but not all forms of the disease.

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 1A - CMT1A - The most common form of the disease, caused by mutations in the PMP22 gene (locus 17p11.2).  70-80% of Type 1 patients.  Average NCV: 15-20m/s
 * CMT type 1B - CMT1B (OMIM 118200) - Caused by mutations in the MPZ gene (1q22) producing protein zero (P0). 5-10% of Type 1 patients. Average NCV: <20m/s
 * CMT type 1C - CMT1C - Sometimes called Dejerine-Sottas disease - Causes severe demyelination, which can be detected by measuring nerve conduction velocities. Autosomal dominant.  Usually shows up in infancy.  LITAF Gene (16p13.1-p12.3) Average NCV: 26-42m/s.  Identical symptoms to CMT-1A.
 * CMT type 1D - CMD1D - EGR2 Gene (10q21.1-q22.1) - Average NCV: 15-20m/s

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 38m/s
 * CMT type 2A - CMT2A (OMIM 118210) - The cause is likely located on chromosome 1 for the mitofusion 2 (MFN2) protein (locus 1p36).  Some research has also linked this form of CMT to the protein kinesin 1B (KIF1B) (1p36.2). Does not show up on nerve condution velocity tests, because it is caused by axonopathy.
 * CMT type 2B - CMT2B (OMIM 600882) - RAB7 gene (3q21).
 * CMT type 2C - CMT2C - (12q23-q24) - May cause vocal cord, diaphragm, and distal weaknesses.
 * CMT type 2D - CMT2D (OMIM 601472) - GARS gene (7p15). Patients with mutations in the GARS gene tend to have more severe symptoms in the upper extremities (hands), which is atypical for CMT in general.
 * CMT type 2E - CMT2E - NEFL gene (8p21).
 * CMT type 2F - CMT2F (OMIM 606595) - HSPB1 gene (7q11-q21).
 * CMT type 2G - CMT2G - (12q12-13)
 * CMT type 2H - CMT2H (OMIM 607731)
 * CMT type 2J - CMT2J (OMIM 607736) - (1q22)
 * CMT type 2K - CMT2K (OMIM 607831) - (8q13-q21.1)
 * CMT type 2L - CMT2L (OMIM 608673) - (12q24)

CMT Type 3 (CMT3)
Type 3 affects a very few CMT patients.
 * CMT type 3 - CMT3 - Rarely found. Autosomal recessive. Average NCV: Normal (50-60m/s)

CMT Type 4 (CMT4)
Type 4 affects a very few CMT patients.
 * CMT type 4A - CMT4A (OMIM 214400) - GDAP1 Gene (locus 8q13-q21.1) - Autosomal recessive.
 * CMT type 4B1 - CMT4B1 (OMIM 601382) - MTMR2 Gene (11q22) - Autosomal recessive.
 * CMT type 4B2 - CMT4B2 - CMT4B2 Gene, may be called "SBF2/MTMR13" (11p15) - Autosomal recessive.
 * CMT type 4C - CMT4C - KIAA1985 Gene (5q32) - May lead to respiratory compromise.
 * CMT type 4D - CMT4D - NDRG1 Gene (8q24.3)
 * CMT type 4E - CMT4E - EGR2 (10q21.1-10q22.1) - "CMT4E" is a tentative name
 * CMT type 4F - CMT4F - PRX (19q13.1-19q13.2) - "CMT4F" is a tentative name

CMT X-Linked (CMTX)
CMTX affects approximately 10-20% of CMT patients and is X-linked dominant.
 * CMTX (OMIM 302800) - GJB1 Gene (locus Xq13.1) - Average NCV: 25-40m/s
 * Other X-linked forms - Approx 10% of X-linked CMT patients have some other form than CMTX.

Genetic testing
Genetic testing is available for many of the different types of Charcot-Marie-Tooth. For a listing of test availabilities, see GeneTests.org