What Is Charcot-Marie-Tooth (CMT) Disease? What are the Causes, Symptoms and Treatment?

Charcot-Marie-Tooth disease, also known as CMT disease, is a neurological condition that causes problems with the muscles of the feet, legs, arms, and hands. Although there is no cure yet, people with this genetic condition can use a variety of treatments and strategies to help manage their symptoms. You can find more information below.

What is Charcot-Marie-Tooth disease?

Charcot-Marie-Tooth disease , also known as CMT for short , is a group of genetic disorders that cause nerve damage . This damage mostly occurs in the arms and legs (peripheral nerves). to CMT disease; Also called hereditary motor and sensory neuropathy .

CMT disease; results in smaller, weaker muscles. Also; loss of sensation, muscle contractions, and difficulty walking may also be experienced. Foot disorders such as hammer toes and high arches are also common. Symptoms usually begin in the feet and legs, but can eventually affect the hands and arms.

Symptoms of CMT disease typically appear in adolescence or early adulthood, but can also develop in middle age.

Causes of Charcot-Marie-Tooth disease

A nerve cell transmits information to distant targets by sending electrical signals to the long and thin part of the cell called the axon. To increase the speed at which these electrical signals travel, the axon is insulated by the myelin sheath produced by another cell type called the Schwann cell .

The myelin sheath twists like a chain around the axon, preventing the loss of electrical signals. Without an intact axon and myelin sheath, peripheral (peripheral) nerve cells cannot activate target muscles or relay sensory information from the limbs back to the brain.

Charcot-Marie-Tooth disease; It is caused by mutations in genes that produce proteins that play a role in the structure and function of the peripheral nerve axon or myelin sheath. Although different proteins are abnormal in different forms of Charcot-Marie-Tooth disease, all mutations affect the normal function of peripheral nerves (peripheral nervous system).

As a result, these nerves slowly begin to deteriorate and lose the ability to communicate with their distant targets. Disruption of motor nerves; It causes muscle weakness and atrophy (developmental delay in organs) in the arms, legs, hands and feet (extremities). In some cases, degeneration of the sensory nerves causes a reduced ability to feel heat, cold, and pain.

The gene mutations in Charcot-Marie-Tooth disease are often inherited. In each of us, we normally have two copies of each gene, each inherited from a parent. Some forms of CMT are inherited in an autosomal dominant fashion, meaning that only one copy of the abnormal gene is needed to cause the disease.

Other forms of Charcot-Marie-Tooth are inherited in an autosomal recessive fashion, meaning that both copies of the abnormal gene must cause the disease. Still, other forms of CMT are inherited in an X-linked way, meaning that the abnormal gene is located on the X chromosome. (The X and Y chromosomes determine the sex of the individual. Individuals with two X chromosomes are female, and individuals with one X and one Y chromosome are male.)

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In rare cases, the gene mutation that causes Charcot-Marie-Tooth disease is a new mutation that occurs spontaneously in an individual’s genetic material and is not inherited.

Types of Charcot-Marie-Tooth disease

There are many forms of CMT disease, including CMT1, CMT2, CMT3, CMT4, and CMTX.

CMT1 type

There are three main types of CMT1 caused by abnormalities in the myelin sheath .

CMT1A is an autosomal dominant disease caused by duplication of the gene on chromosome 17 that carries instructions for producing peripheral myelin protein-22 (PMP-22). The PMP-22 protein is a critical component of the myelin sheath. Excessive use of this gene in protein synthesis (expression) causes abnormal structure and function of the myelin sheath. Patients begin to experience weakness and atrophy (blindness or weakening) of the muscles of the lower legs, which begins in adolescence; then they experience weakness and loss of sensation in the hands.

CMT1B is an autosomal dominant disease caused by mutations in the gene that carries instructions to produce the myelin protein zero (P0), another critical component of the myelin sheath. Most of these mutations are point mutations, meaning an error occurs in only one letter of the DNA genetic code. To date, scientists have identified more than 120 different point mutations in the P0 gene. As a result of abnormalities in P0, CMT1B produces symptoms similar to those found in CMT1A. The less common CMT1C , CMT1D , and CMT1E , which have symptoms similar to those found in CMT1A , are caused by mutations in the LITAF, EGR2, and NEFL genes, respectively.

CMT2 type

CMT2 is caused by abnormalities in the axon of the peripheral nerve cell instead of the myelin sheath. It is less common than CMT1. CMT2A , the most common axonal form of CMT , is caused by mutations in Mitofusin-2, a protein associated with mitochondrial fusion. CMT2A has also been linked to mutations in the gene encoding the kinesin family member 1B-beta protein. Kinesins are proteins that act as motors to power the transport of materials throughout the cell. Other less common forms of CMT2 have been recently identified and are associated with several genes.

CMT3 type

CMT3 or Dejerine-Sottas disease is a severe demyelinating neuropathy that begins in infancy. (Inflammation and weakening of the nerves in the body) It causes severe muscle atrophy, weakness and sensory problems in infants. This rare disorder can be caused by a specific point mutation in the P0 gene or a point mutation in the PMP-22 gene.

CMT4 type

CMT4 includes different subtypes of autosomal recessive (recessive) demyelinating motor and sensory neuropathies. Each neuropathy (group of nervous diseases) subtype is caused by a different genetic mutation, may affect a particular ethnic population, and different physiological or clinical features may occur. Individuals with CMT4 often develop signs of leg weakness in childhood and may not be able to walk during adolescence.

CMTX type

CMTX, connexin-32 on the X chromosomeIt is caused by a point mutation in the gene. The Connexin-32 protein is resynthesized by being read in Schwann cells that wrap around nerve axons, which form a single segment of the myelin sheath. This protein may play a role in Schwann cell communication with axon. Males who inherit a mutated gene from their mothers show moderate or severe symptoms of the disease with onset in late childhood or adolescence (males do not have the Connexin-32 gene of the Y chromosome inherited from their fathers). Girls who inherit the gene from the parent with the mutated gene and the other parent with the normal gene may develop mild symptoms or no symptoms of the disease at all during or after puberty. (Men can be sick, and women can be carriers or sick.)

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Symptoms of Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease affects both motor and sensory nerves. (Motor nerves cause the muscles to contract and control voluntary muscle activity such as speaking, walking, breathing, and swallowing.) A typical feature includes weakness of the foot and lower leg muscles, which can cause foot drop and high-stepping.

Foot disorders such as high arches and hammer toes (a condition in which the middle joint of the toe bends upward) are also characteristic due to weakness of the small muscles in the feet. In addition, the lower legs may take on an “inverted champagne bottle” appearance due to loss of muscle mass. Later in the disease, weakness and muscle atrophy in the hands may occur.

The onset of Charcot-Marie-Tooth symptoms most often occurs in adolescence or early adulthood, although some individuals develop symptoms in mid-adulthood. The severity of symptoms varies widely among individuals and even among family members who have the disease.

The progression of symptoms is gradual. Pain can range from mild to severe, and some people may need foot or leg supports to maintain their mobility, or may need to use other orthopedic devices.

In rare cases, individuals may have respiratory muscle weakness. However, Charcot-Marie-Tooth is not considered a fatal disease, and people with most forms of CMT have a normal life expectancy.

Diagnosis of Charcot-Marie-Tooth disease

The Charcot-Marie-Tooth diagnosis begins with a standard medical history, family health history, and neurological exam. Individuals will be asked about their symptoms, duration, and whether other family members have the disease. During the neurological examination, the doctor; will look for signs of muscle weakness, decreased muscle mass, decreased tendon reflexes, and loss of sensation in the individual’s arms, legs, hands, and feet.

Doctors look for evidence of foot deformities such as high arches, hammer toes, inverted heels, or flat feet. Other orthopedic problems may also be present, such as mild scoliosis (curvature of the spine) or hip dysplasia (instability of the hip bone). A specific sign that can be found in people with CMT1 is nerve enlargement, which can be felt and even seen on the skin. These enlarged nerves, called hypertrophic (overgrowth) nerves, are caused by abnormally thickened myelin sheaths.

If CMT is suspected, the doctor may order electrodiagnostic (measurement of bioelectricity in the body and comparison with findings) tests. This test consists of two parts; nerve conduction studies and electromyography (EMG). During nerve conduction studies, electrodes are placed on the skin over a peripheral motor or sensory nerve. These electrodes produce a small electrical shock that may cause mild discomfort.

This electrical impulse stimulates sensory and motor nerves and provides measurable information that the doctor can use to reach a diagnosis. EMG involves placing a needle electrode on the skin to measure the bioelectrical activity of the muscles. Specific abnormalities in measurements indicate axon degeneration.

Genetic testing is available for some types of CMT and the results are often sufficient to confirm the diagnosis. Genetic counseling is also available to help individuals make their situation and future plans.

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If all diagnostic studies on tests or genetic testing are negative, the neurologist may perform a nerve biopsy to confirm the diagnosis. Nerve biopsy involves removing a small piece of peripheral (peripheral) nerve from a cut in the skin. This is most often done by removing a piece of nerve that runs down the calf. The nerve is then examined under a microscope.

Treatment of Charcot-Marie-Tooth disease

There is no cure for CMT, but physical therapy , occupational therapy, braces, other orthopedic devices, and even orthopedic surgery can help individuals cope with the uncomfortable symptoms of the disease. Additionally, pain relievers can be prescribed for people with severe pain.

Physical and occupational therapy, the treatment of choice for Charcot-Marie-Tooth disease, includes muscle strength training, muscle and ligament stretching, endurance training, and moderate aerobic exercise. Most therapists recommend a tailored treatment program designed with the approval of a person’s physician to suit individual abilities and needs.

Therapists also recommend starting a treatment program early. Muscle strengthening can delay or reduce muscle atrophy, so it is best for the patient to begin a treatment program before nerve degeneration and muscle weakness progress to the point of disability.

Stretching and stretching exercises can prevent or reduce joint disorders that result from uneven muscle pulling on bones. Exercises aimed at building endurance or increasing endurance will help the resulting fatigue perform daily activities that require strength and mobility.

Moderate aerobic activity can help maintain cardiovascular fitness (cardiovascular health) and overall health. Most therapists recommend low-stress exercises such as cycling or swimming, rather than activities such as walking or jogging that can put stress on fragile muscles and joints.

Many CMT patients require orthopedic devices to maintain daily mobility and prevent injury. Ankle devices can help prevent ankle sprains by providing support and stability during activities such as walking or climbing stairs. Orthopedic shoes or boots can also provide support for weak ankles.

Thumb splints can help with hand weakness and loss of fine motor skills. Assistive devices should be used before the disease begins to progress because the devices can prevent muscle tension and reduce muscle wasting. Some individuals with CMT may decide to have orthopedic surgery to reverse or further improve their foot and joint disorders.

Treatment research

the National Institute of Neurological Disorders and Stroke (NINDS), a division of the US National Institutes of Health ; supports research on Charcot-Marie-Tooth disease and other peripheral neuropathies to learn how to better treat, prevent, and even cure these disorders.

Ongoing research includes efforts to identify more of the mutant genes and proteins that cause various disease subtypes, discover mechanisms of nerve degeneration and muscle atrophy in hopes of developing interventions to stop or slow these damaging processes, and treatments aimed at reversing the progression of this disease.

A promising area of ​​research includes gene therapy experiments. Research with cell cultures and animal models has shown that it is possible to introduce genes into Schwann cells and muscles. Another area of ​​research involves the use of trophic factors or nerve growth factors such as the hormone androgen to prevent nerve degeneration.

Vitamin C has been studied in CMT1A and the results of a multicenter trial will be announced soon. Curcumin, found as a structural pigment in turmeric, is currently being studied as a treatment strategy in an animal model of CMT1B.

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