Charcot-Marie-Tooth Disease

NORD gratefully acknowledges Steven Scherer, MD, PhD, Department of Neurology, University of Pennsylvania and Mustafa Saifi, PhD, Department of Molecular and Human Genetics, Baylor College of Medicine, for assistance in the preparation of this report.

Synonyms of Charcot-Marie-Tooth Disease

CMT
hereditary motor and sensory neuropathy
HSMN
peroneal muscular atrophy

General Discussion

Charcot-Marie-Tooth (CMT) disease is a group of disorders in which the motor and/or sensory peripheral nerves are affected, resulting in muscle weakness and atrophy, as well as sensory loss. These manifestations occur first in the distal legs and later in the hands. The nerve cells in individuals with this disorder are not able to send electrical signals properly because of abnormalities in the nerve axon or abnormalities in the insulation (myelin) around the axon. Specific gene mutations are responsible for the abnormal function of the peripheral nerves. CMT disease can be inherited in an autosomal dominant, autosomal recessive or X-linked mode of inheritance.

Signs & Symptoms

Symptoms of CMT disease usually begin gradually in adolescence, but can begin earlier or later. In almost all cases, the longest nerve fibers are affected first. Over time, affected individuals may lose the normal use of their feet, hands, legs and arms. Common red flags can include decreased sensitivity to heat, touch or pain, muscle weakness in the hand, foot or lower leg, trouble with fine motor skills, high-stepped gait (foot drop), loss of muscle mass in the lower leg, frequent tripping or falling, hammertoe, high foot arch and flat feet. Stretch reflexes may be lost. The disease is slowly progressive and variable and those affected may remain active for years and live a normal life span. In the most severe cases, breathing difficulties can hasten death.

Causes

CMT disease can be inherited in an autosomal dominant, autosomal recessive or X-linked dominant manner.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

X-linked dominant genetic disorders are caused by an abnormal gene on the X chromosome. Females with an abnormal gene are affected with the disease. Males with an abnormal gene are more severely affected than females.

CMT hereditary neuropathy is subdivided into several types termed CMT1, CMT2, CMT3, CMT4 and CMTX.

CMT1 is the dominant form of the condition in which nerve conduction velocities are slow, and is much more common that CMT2. CMT1 is caused by abnormal genes involved in the structure and function of myelin. CMT1 has been further subdivided into CMT1A, CMT1B, CMT1C, CMT1D, and CMT1X, based on specific gene abnormalities. CMT1A is caused by a duplication of the PMP22 gene that is located on chromosome 17 at 17p11.2. CMT1A is the most common type of CMT1. CMT1B is caused by an abnormality in the MPZ gene located on chromosome 1 at 1q22. CMT1C is caused by an abnormality in the SIMPLE gene located on chromosome 16 at 16p13.1-p12.3. CMT1D is caused by an abnormality in the EGR2 gene located on chromosome 10 at 10q21.1-q22.1. CMT1X is caused by mutations in GJB1 (located at Xq13.1), the gene that encodes the gap junction protein connexin32. Rarer subtypes of CMT1 may yet be found.

CMT2 is an autosomal dominant form of the condition in which nerve conduction velocities are usually normal or slightly slower than normal. CMT2 is caused by abnormal genes involved in the structure and function of axons. CMT2 has been further subdivided into CMT2A – 2L based on mutations in specific genes. CMT2A, is the most common, and is caused by mutations in the MFN2 gene located on chromosome 1 at 1p36.2. CMT2B is caused by mutations in the RAB7 gene located on chromosome 3 at 3q21. CMT2C is caused by an unknown gene located on chromosome 12 at 12q23-34. CMT2D is caused by mutations in the GARS gene located on chromosome 7 at 7p15. CMT2E is caused by mutations in the NEFL gene located on chromosome 8 at 8p21. CMT2F is caused by mutations in the HSPB1 gene. CMT2L is caused by mutations in the HSPB8 gene.

Dominant Intermediate CMT (DI-CMT) is so named owing to their “intermediate” conduction velocities and thus an uncertainty regarding whether the neuropathy is primarily axonal or demyelinating. Dominant mutations in DMN2 and YARS are known to cause this phenotype.

CMT3, also called Dejerine-Sottas disease, is no longer a useful genetic designation because individuals with this condition have been found to have a gene mutation in one of the genes responsible for CMT1A, CMT1B, CMT1D or CMT4.

CMT4 is an autosomal recessive form of the condition. It has been further subdivided into CMT4A, CMT4B1, CMT4B2, CMT4C, CMT4D, CMT4E and CMT4F. CMT4A is caused by an abnormality in the GDAP1 gene located on chromosome 8 at 8q13-q21. CMT4B1 is caused by an abnormality in the MTMR2 gene located on chromosome 11 at 11q22. CMT4B2 is caused by an abnormality in the SBF2/MTMR13 gene located on chromosome 11 at 11p15. CMT4C is caused by an abnormality in the KIAA1985 gene located on chromosome 5 at 5q32. CMT4D is caused by an abnormality in the NDRG1 gene located on chromosome 8 at 8q24.3. CMT4E, also known as congenital hypomyelination neuropathy, is caused by an abnormality in the EGR2 gene located on chromosome 10 at 10q21.1-q22.1. CMT4F is caused by an abnormality in the PRX gene located on chromosome 19 at 19q13.1-q13.2. CMT4H is caused by an abnormality in the FDG4 gene. CMT4J is caused by an abnormality in the FIG4 gene. Most cases of CMT2 are not caused by mutations in these genes, however, so that many genetic causes remain to be discovered.

CMTX is an X-linked dominant form of the condition. CMT1X accounts for approximately 90% of CMTX. The specific gene(s) responsible for the remaining 10% of individuals with CMTX have not yet been identified.

Autosomal recessive CMT2 is caused by mutations in LMNA and GDAP1.

Affected Populations

Symptoms of CMT hereditary neuropathy usually begin gradually sometime in adolescence, early adulthood or middle age. The condition affects an equal number of males and females. CMT hereditary neuropathy is the most common inherited neurological disorder affecting more than 250,000 Americans. Since this condition is frequently undiagnosed, misdiagnosed or diagnosed very late in life, the true number of affected persons may be higher.

Related Disorders

In hereditary sensory and autonomic neuropathies, sensory (and variably autonomic) neurons/axons are affected, with relative or complete sparing of motor neurons/axons. Dominant and recessive mutations in neuronally expressed genes cause HSAN and related disorders. These are dominant or recessive hereditary disorders.

Hereditary motor neuropathies are either dominantly or recessively inherited. In most forms, sensory fibers are spared, and some kinds are associated with a myelopathy.

Hereditary neuralgic amyotrophy (inherited brachial plexus neuropathy) is an autosomal dominant genetic disorder in which those affected have a sudden onset of pain or weakness in the shoulder or upper arm. Symptoms often begin in childhood but can begin at any age. Sensory loss may also occur. Partial or full recovery is common and symptoms can recur in the same or opposite limb. Physical features that have been noted in some families include short stature and close-set eyes.

Congenital hypomyelination neuropathy (CHN) is a neurological disorder present at birth. Major symptoms may include respiratory difficulty, muscle weakness and incoordination, poor muscle tone, absence of reflexes, difficulty in walking, and/or impaired abilities to feel or move part of the body. (For more information, choose “neuropathy, congenital hypomyelination” as your search term in the Rare Disease Database).

Refsum syndrome (phytanic acid storage disease) is a rare recessive genetic disorder of fat (lipid) metabolism characterized by peripheral neuropathy, impaired muscle coordination (ataxia), retinitis pigmentosa (RP), deafness, and bone and skin changes. It is associated with marked accumulation of phytanic acid in the blood plasma and tissues. The disorder may be due to the absence of phytanic acid hydroxylase, an enzyme needed for the metabolism of phytanic acid. Prolonged treatment with a diet lacking in phytanic acid may be therapeutic. (For more information, choose “Refsum” and “RP” as your search terms in the Rare Disease Database.)

Familial amyloid neuropathy has autosomal dominant inheritance. It is characterized by abnormal accumulations of amyloid in the peripheral nerves. Most cases are caused by mutation in the TTR gene, which encodes the serum protein transthyretin. Dominant mutations in APOA1 are a rare cause.

Hereditary neuropathy with liability to pressure palsy (HNPP) is rare disorder that follows autosomal dominant inheritance. HNPP is characterized by focal neuropathies at typical sites of compression (peroneal neuropathy at the fibular head, ulnar neuropathy at the elbow, median neuropathy at the wrist). HNPP is caused by an abnormality in one of the two copies of PMP22 gene located on chromosome 17 at 17p11.2.

Peripheral neuropathy is part of at least 100 inherited syndromes, though it is typically overshadowed by the other manifestations. Nevertheless, de/dysmyelination of peripheral axons is a feature of a variety of disorders. Syndromes associated with axonal neuropathies are even more common. Several types of hereditary spastic paraglegias have an axonal neuropathy, involving both motor and sensory axons or just motor axons. An axonal neuropathy is a feature of many hereditary ataxias. The clinical phenotypes are consistent with the idea that these diseases are length-dependent axonopathies of both CNS and PNS neurons.

Diagnosis

The diagnosis of CMT hereditary neuropathy can be challenging. The diagnosis is based on physical symptoms, family history and clinical tests. Clinical tests include nerve conduction velocity (NCV) which measures the speed at which impulses travel along the nerves and electromyogram (EMG) which records the electrical activity of muscle cell. . Molecular genetic testing is currently available for CMT1A, CMT1B, CMT1D, CMT2E, CMT4A, CMT4E, CMT4F and CMTX.

Standard Therapies

Treatment

Treatment of CMT hereditary neuropathy is symptomatic and supportive. A cure is not available so it is important to minimize or stall the symptoms. Comprehensive treatments include physical therapy, shoe orthotics, leg braces and surgery to correct deformities. Complementary therapies may help psychologically, relieve pain and discomfort, and improve overall quality of life. Vocational counseling, anticipating progression of the disorder, may be useful for young patients.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

NORD Member Organizations

Charcot-Marie-Tooth Association
- PO Box 105
- Glenolden, PA 19036
- Phone: (610) 499-9264
- Toll-free: (800) 606-2682
- Email: info@charcot-marie-tooth.org
- Website: http://www.charcot-marie-tooth.org
Hereditary Neuropathy Foundation, Inc.
- 401 Park Avenue South
- 10th Floor
- New York, NY 10016
- Phone: (212) 722-8396
- Toll-free: (855) 435-7268
- Email: info@hnf-cure.org
- Website: http://www.hnf-cure.org

Other Organizations

Center for Peripheral Neuropathy
- University of Chicago
- 5841 South Maryland Ave, MC 2030
- Chicago, IL 60637
- Phone: (773) 702-5659
- Website: http://peripheralneuropathycenter.uchicago.edu/
Child Neurology Foundation
- 201 Chicago Ave, #200
- Minneapolis, MN 55415 USA
- Phone: (952) 641-6100
- Toll-free: (877) 263-5430
- Email: jstone@childneurologyfoundation.org
- Website: http://www.childneurologyfoundation.org
Genetic and Rare Diseases (GARD) Information Center
- PO Box 8126
- Gaithersburg, MD 20898-8126
- Phone: (301) 251-4925
- Toll-free: (888) 205-2311
- Website: http://rarediseases.info.nih.gov/GARD/
Let Them Hear Foundation
- 1900 University Avenue, Suite 101
- East Palo Alto, CA 94303
- Phone: (650) 462-3174
- Email: info@letthemhear.org
- Website: http://www.letthemhear.org
Muscular Dystrophy Association
- 3300 East Sunrise Drive
- Tucson, AZ 85718-3208 USA
- Phone: (520) 529-2000
- Toll-free: (800) 572-1717
- Email: mda@mdausa.org
- Website: http://www.mda.org/
NIH/National Institute of Neurological Disorders and Stroke
- P.O. Box 5801
- Bethesda, MD 20824
- Phone: (301) 496-5751
- Toll-free: (800) 352-9424
- Website: http://www.ninds.nih.gov/
Potocki-Lupski Syndrome Outreach Foundation, Inc
- P.O.Box 250245
- Plano, TX 75025-0245
- Phone: (214) 435-8288
- Email: info@PTLSFoundation.org
- Website: http://www.ptlsfoundation.org

References

TEXTBOOKS

Shy ME, Lupski JR, Chance PF, Klein CJ, Dyck PJ (2005) Hereditary motor and sensory neuropathies: an overview of clinical, genetic, electrophysiologic, and pathologic features. In: Peripheral Neuropathy, 4th Edition (Dyck PJ, Thomas PK, eds), pp 1623-1658. Philadelphia: Saunders.

Wrabetz L, Feltri ML, Kleopa KA, Scherer SS (2004) Inherited neuropathies: clinical, genetic, and biological features. In: Myelin Biology and Disorders (Lazzarini RA, ed), pp 905-951. San Diego: Elsevier Academic Press.

ARTICLES

Saifi GM, Szigeti K, Snipes GJ, Garcia CA, Lupski JR. Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for charcot-marie-tooth disease and related peripheral neuropathies. J Invest Med 2003;51:261-83.

Irobi J, DeJonghe P, Timmerman V (2004) Molecular genetics of distal hereditary motor neuropathies. Hum Mol Genet 13:R195-R202.

Scherer SS (2006) Finding the causes of inherited neuropathies. Arch Neurol 63:812-816.

INTERNET

Bird TD. Charcot-Marie-Tooth Hereditary Neuropathy Overview. 1998 Sep 28 [Updated 2015 May 7]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1358/ Accessed June 2, 2015.

Online Mendelian Inheritance in Man (OMIM): http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim

Years Published

1986, 1987, 1988, 1989, 1991, 1993, 1994, 1996, 1997, 1999, 2003, 2004, 2009

The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.

The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.

National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100