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Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT), known also as Hereditary Motor and Sensory Neuropathy (HMSN), Hereditary Sensorimotor Neuropathy (HSMN), 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. Presently incurable, this disease is one of the most common inherited neurological disorders, with 37 in 100,000 affected.

Description

The disorder is caused by the absence of proteins 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 a small proportion of 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.

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 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

A definitive diagnosis for a specific type of CMT is established via genetic testing for most types. However, some genetic markers have not yet been identified, and a diagnosis can also be established via an 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.

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

CMT Type 4 (CMT4): Type 4 affects 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. However a study published in 1997 indicates that a connexin 32 gene mutation is associated with this form which may be more common than previously thought.

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

Type	OMIM	Gene	Locus	Description
CMT1A		PMP22	17p11.2	The most common form of the disease, 70-80% of Type 1 patients. Average NCV: 20-25m/s when associated with essential tremor and ataxia, called Roussy-Levy Syndrome
CMT1B		MPZ	1q22	Caused by mutations in the gene producing protein zero (P0). 5-10% of Type 1 patients. Average NCV: <15m/s
CMT1C		LITAF	16p13.1-p12.3	Causes severe demyelination, which can be detected by measuring nerve conduction velocities. Autosomal dominant. Usually shows up in infancy. Average NCV: 26-42m/s. Identical symptoms to CMT-1A.
CMT1D		EGR2	10q21.1-q22.1	Average NCV: 15-20m/s
CMT2A		MFN2 or KIF1B	1p36	The cause is likely located on chromosome 1 for the mitofusion 2 protein. Some research has also linked this form of CMT to the protein kinesin 1B. Does not show up on nerve conduction velocity tests, because it is caused by axonopathy.
CMT2B		RAB7 (RAB7A, RAB7B)	3q21.
CMT2B1		LMNA	1q22	Autosomal recessive axonal CMT, (laminopathy)
CMT2C			12q23-q24	May cause vocal cord, diaphragm, and distal weaknesses.
CMT2D		GARS	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.
CMT2E		NEFL	8p21
CMT2F		HSPB1	7q11-q21
CMT2G			12q12-13
CMT2H		GDAP1	8q13-q21.1
CMT2J			1q22
CMT2K			8q13-q21.1
CMT2L			12q24
CMT3		varies	varies	Sometimes called Dejerine-Sottas disease. Rarely found. Autosomal recessive. Average NCV: Normal (50-60m/s)
CMT4A		GDAP1	8q13-q21.1	Autosomal recessive.
CMT4B1		MTMR2	11q22	Autosomal recessive.
CMT4B2		CMT4B2 (SBF2)	11p15	May be called "SBF2/MTMR13". Autosomal recessive.
CMT4C		KIAA1985 (SH3TC2)	5q32	May lead to respiratory compromise.
CMT4D		NDRG1	8q24.3	Autosomal recessive, demyelinating, deafness
CMT1E		PMP22	17p11.2	Autosomal dominant, demyelinating, deafness
CMT4E		EGR2	10q21.1-10q22.1	"CMT4E" is a tentative name
CMT4F		PRX	19q13.1-19q13.2	"CMT4F" is a tentative name
CMT4H		FGD4	12p11.21	Autosomal recessive
CMT4J		KIAA0274 (FIG4)	6q21	Autosomal recessive
CMTX1		GJB1	Xq13.1	Average NCV: 25-40m/s
CMTX2			Xq22.2
CMTX3			Xq26
CMT				with Ptosis and Parkinsonism
CMT				type 1 aplasia cutis congenita

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

Treatment

Although there is no current standard treatment, the use of ascorbic acid has been proposed, and has shown some benefit in animal models. There is currently a clinical trial to determine the effectiveness of high doses of ascorbic acid (vitamin C) in treating humans with CMT type 1A. Not all types of CMT are expected to respond to this treatment.

The Charcot-Marie-Tooth Association classifies the chemotherapy drug vincristine as a "definite high risk" and states that "vincristine has been proven hazardous and should be avoided by all CMT patients, including those with no symptoms.

There are also several corrective surgical procedures that can be done to improve physical condition.