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