What is Charcot-Marie-Tooth syndrome? |

Risk Factors

The primary risk factor for developing CMT is having family members with this disease.

Etiology and Genetics

There are many variations of Charcot-Marie-Tooth syndrome, and at least fifteen different genes have been identified in which mutations leading to the condition might occur. The most common group, known as CMT1, includes all those with identifiable abnormalities in the myelin sheath that surrounds nerve cells. CMT1A disease results from a duplication of the PMP22 gene, found at position 17p12 on the short arm of chromosome 17. Since PMP22 (peripheral myelin protein 22) is an integral part of the myelin sheath, an excess of this protein causes an abnormal sheath to develop. CMT1B disease results from a mutation in a different gene, MPZ, found on the long arm of chromosome 1 (at position 1q22). The myelin zero protein, encoded by this gene, is also a critical component of the myelin sheath. Both of these disease variants are inherited in an autosomal dominant manner, meaning that a single copy of the mutation is sufficient to cause full expression of the disease. An affected individual has a 50 percent chance of transmitting the mutation to each of his or her children. Many cases, however, result from a spontaneous new mutation, so in these instances affected individuals will have unaffected parents. The much rarer variants, CMT1C and CMT1D, result from mutations in the LITAF (lipopolysaccharide-induced TNF factor) gene, at position 16p13.3-p12, and the EGR2 (early growth response 2) gene, at position 10q21.1, respectively.

CMT2 disease (several different subtypes, designated A–L) is also inherited in an autosomal dominant manner. The molecular defect in this case always involves an abnormality in the axons themselves, rather than in the surrounding myelin sheath.

There are at least six different subtypes of CMT4 disease, resulting from mutations in several different genes. Most of these are identifiable as demyelinating neuropathies, and they are distinguished by an autosomal recessive pattern of inheritance, meaning that both copies of the particular gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected. If one parent has CMT4 disease and the other is a carrier, there is a 50 percent probability that each child will be affected.

Finally, CMTX disease can result from mutations in at least three distinct genes found on the X chromosome. CMTX1 is a sex-linked dominant disease due to a mutation in the GJB1 (gap junction protein, beta 1, 32kDa) gene, at position Xq13.1, while CMTX2 and CMTX3 are sex-linked recessive diseases resulting from mutations in genes found at positions Xq22.2 and Xq26, respectively.

Symptoms

Symptom onset and type vary depending on the type of CMT. Usually, symptoms first appear in children and young adults. The first sign of CMT is often a high-arched foot or difficulty walking.

Other symptoms may include hammertoes, decreased sensation in the feet and legs, muscle cramping in legs and forearms, difficulty holding the foot up in a horizontal position, frequent sprained ankles and ankle fractures, and problems with balance.

Patients may also experience muscle weakness and atrophy in the lower extremities, which can spread to the upper extremities later in life; foot drop; a diminished ability to detect hot and cold, vibration, and position; difficulty writing, fastening buttons and zippers, and manipulating small objects; and scoliosis. Delay in learning how to walk is a symptom of CMT3; congenital glaucoma is a symptom only of CMT4.

Screening and Diagnosis

The doctor will ask about a patient’s symptoms and medical history and will perform a physical exam. Tests may include a nerve conduction study, a test that measures the speed and amplitude of nerve impulses in the extremities; an electromyogram (EMG), a test that records the electrical activity of muscle cells; and a deoxyribonucleic acid (DNA) blood test to confirm certain types of CMT, even if there are no symptoms.

Treatment and Therapy

Although there is no cure for CMT, treatment may help to improve function, coordination, and mobility. Treatment is also essential to protect against injury due to muscle weakness and diminished sensation. Treatment may include physical and occupational therapy, moderate exercise, braces of lower legs, shoe inserts to correct foot deformity, foot care and routine exams with a specialist (podiatrist), and orthopedic surgery.

Prevention and Outcomes

There are no known ways to prevent CMT once a person is born with the condition. Individuals who have CMT or have risk factors may want to talk to a genetic counselor before deciding to have children.

Bibliography

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