Charcot-Marie-Tooth Syndrome

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

Synonyms and keywords: Charcot-Marie-Tooth disease

Overview

Charcot-Marie-Tooth disease (CMT), 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. 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.

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. About the chemotherapy drug vincristine, the Charcot-Marie-Tooth Association classifies the drug 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.

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.

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 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:

Type	OMIM	Gene	Locus	Description
CMT1A	118220	PMP22	17p11.2	The most common form of the disease, 70-80% of Type 1 patients. Average NCV: 15-20m/s when associated with essential tremor and ataxia, called Roussy-Levy Syndrome
CMT1B	118200	MPZ	1q22	Caused by mutations in the gene producing protein zero (P0). 5-10% of Type 1 patients. Average NCV: <20m/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.
CMD1D		EGR2	10q21.1-q22.1	Average NCV: 15-20m/s
CMT2A	118210	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 condution velocity tests, because it is caused by axonopathy.
CMT2B	600882	RAB7 (RAB7A, RAB7B)	3q21.
CMT2B1		LMNA	1q22	Autosomal recessive axonal CMT, (laminopathy)
CMT2C	606071		12q23-q24	May cause vocal cord, diaphragm, and distal weaknesses.
CMT2D	601472	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	606595	HSPB1	7q11-q21
CMT2G	608591		12q12-13
CMT2H	607731	GDAP1	8q13-q21.1
CMT2J	607736		1q22
CMT2K	607831		8q13-q21.1
CMT2L	608673		12q24
CMT3	145900	varies	varies	Sometimes called Dejerine-Sottas disease. Rarely found. Autosomal recessive. Average NCV: Normal (50-60m/s)
CMT4A	214400	GDAP1	8q13-q21.1	Autosomal recessive.
CMT4B1	601382	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	601455	NDRG1	8q24.3	Autosomal recessive, demyelinating, deafness
CMT1E	118300	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
CMT4J	611228	KIAA0274 (FIG4)	6q21	Autosomal recessive
CMTX1	302800	GJB1	Xq13.1	Average NCV: 25-40m/s
CMTX2	302801		Xq22.2
CMTX3	302802		Xq26
CMT	118301			with Ptosis and Parkinsonism
CMT	302803			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

External links

• Template:DMOZ

Sources

www.wikipedia.org

Acknowledgements

The content on this page was first contributed by: C. Michael Gibson, M.S., M.D.

List of contributors: