Charcot-Marie-Tooth syndrome
Charcot-Marie-Tooth syndrome (CMT) is a group of inherited neurological disorders that primarily affect the peripheral nerves, leading to gradual damage that impacts movement and sensation in the limbs. The onset of symptoms typically occurs in childhood or early adulthood and may include high-arched feet, muscle weakness, decreased sensation, and difficulties with balance and coordination. CMT encompasses various genetic mutations, with the most common forms being CMT1A and CMT1B, which are associated with abnormalities in the myelin sheath surrounding nerve cells. These variants follow an autosomal dominant inheritance pattern, meaning that an affected individual has a 50% chance of passing the mutation to their offspring.
Diagnosis often involves a combination of patient history, physical examinations, and nerve conduction studies. While there is currently no cure for CMT, treatment strategies such as physical therapy, orthopedic interventions, and assistive devices can help manage symptoms and improve quality of life. A recently identified variant, known as SORD-CMT, shows potential for treatment with existing medications, which may provide new hope for patients. Individuals with a family history of CMT may consider genetic counseling to understand risks related to family planning. Overall, CMT represents a diverse set of conditions with varying symptoms and impacts, necessitating a personalized approach to management and care.
Charcot-Marie-Tooth syndrome
ALSO KNOWN AS: Charcot-Marie-Tooth disease; hereditary motor and sensory neuropathies
DEFINITION Charcot-Marie-Tooth (CMT) disease is a group of genetic disorders that affects movement and sensation in the limbs. The disease progresses slowly and causes damage to the peripheral nerves that control muscles and transmit sensation.
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.
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.
In 2020, researchers discovered a previously unidentified form of CMT resulting from a deficiency of Sorbitol dehydrogenase (SORD), a protein coding gene. SORD-CMT, or SORD Syndrome, is a recessive form of the disease typically found in people who previously had a diagnosis of CMT2 or distal hereditary motor neuropathy (dHMN). It is believed that between 3,000 and 5,000 people in the United States are affected by this condition, part of as many as 60,000 throughout the world. The researchers who made the discovery also noted that unlike most other forms of CMT, this form may respond to other drugs already approved to treat SORD deficiencies. This could speed approval of a drug treatment, the first such treatment for any form of CMT.
Symptoms
Symptom onset varies 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. Sypmtoms of SORD-related CMT are similar to those of other variations of the disease, but occur in people with no previous family history of CMT.
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 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. Clinical trials have been undertaken to determine if drugs used for other SORD deficiences will help treat SORD-CMT.
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.
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