Charcot-Marie-Tooth Disease – NIH – https://www.ninds.nih.gov/health-information/disorders/charcot-marie-tooth-disease
Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth disease (CMT) is a group of genetic conditions that affect the nerves connecting the brain and spinal cord to the rest of the body. CMT is the most common inherited neuropathy. Neuropathy describes a nerve condition that causes pain, swelling, or other symptoms. CMT causes a range of sensory and motor symptoms, including numbness, tingling, pain, muscle weakness and atrophy, and foot deformities that get worse over time. In some cases, CMT affects the nerves that control automatic body functions, leading to problems with sweating and dizziness.
The disease was described in 1886 by three doctors: Jean-Martin Charcot and Pierre Marie of France, and Howard Henry Tooth of the United Kingdom.
Gene mutations are changes in a gene’s DNA that can affect how the gene works. These changes can cause the body to not function properly. More than 100 genes are linked to CMT. Depending on the gene problem, CMT can affect the axon, the myelin sheath, or both. Peripheral nerves send electrical signals over long distances down a long, thin part of the nerve cell called the axon. The axon is covered by myelin, which works like the insulation on an electrical wire to help signals travel quickly. The protective coating that wraps around the axon is called the myelin sheath. It helps the signals travel quickly and smoothly through the nerves. When the axon or myelin sheath is damaged, signals slow down, weaken, or fail to transmit properly. This makes it harder for nerves to control muscles or send sensory information from the skin, muscles, or other organs back to the spinal cord and the brain.
Although different forms of CMT involve mutations in different genes that produce proteins needed for the axon or myelin to work, all forms of CMT affect the function of peripheral nerves. Gene defects in myelin and the axons can cause them to stop working as they should, disrupting nerve signals and sometimes leading to nerve loss.
CMT often affects nerves that control a person’s muscles, causing muscle weakness or muscle shrinking (called atrophy). Muscle weakness from CMT usually starts in the feet and lower legs during the teen years or early adulthood, but symptoms can appear at any age. Over time, the weakness can spread to the fingers, hands, and arms. Some people with CMT may not even know they have it, while others experience physical disabilities.
There is no cure for CMT. Treatments such as physical therapy, orthopedic devices (such as braces), surgery, and medication prescribed by a doctor can help manage symptoms
CMT affects sensory and motor nerves in the arms, hands, legs, and feet. Sensory nerves are nerves that send messages to the brain about things like touch, temperature, pain, or pressure. Motor nerves control muscle movements. When motor nerves break down (degenerate), they lose the ability to communicate with muscles. In CMT, this leads to muscle weakness in the arms, legs, hands, or feet. When sensory nerves fail to function properly, the person may experience numbness, tingling sensations, or pain.
Symptoms may include:
- Weakness or paralysis in the foot and lower leg muscles, making it hard to lift the foot (foot drop)
- A high-stepping walking pattern with frequent tripping or falling
- Balance problems
- Foot deformities, like high arches and curled toes (hammertoes)
- Lower legs with an “inverted champagne bottle” shape due to the loss of muscle bulk
- Trouble feeling heat, cold, and touch
- Possible hand weakness and atrophy, causing difficulty with small, precise movements
- Decreased ability to sense vibrations or know body position (proprioception)
- Curved spine (scoliosis)
- A hip joint out of its normal position (hip displacement)
- A chronic shortening of muscles or tendons around joints (contractures)
- Muscle cramps
- Nerve pain
Some people with CMT may need foot or leg braces or other supportive equipment to stay mobile. Others experience tremor, or problems with hearing and vision. In rare cases, breathing difficulties may happen if the nerves that control the diaphragm muscles (which help with breathing) are affected.
The severity of symptoms can be very different from person to person, even among family members with CMT and the same gene mutation. Symptoms tend to progress slowly over time.
There are many different types of CMT. How a person inherits CMT, how old they are when they first have symptoms, and whether their CMT affects axons or myelin are all factors in what symptoms the person has.
There are several different types of CMT:
- CMT1 is caused by problems in the myelin sheath.
- A subtype of CMT1 called CMT1A is the most common type of CMT. It happens when a gene that is important to making the myelin sheath is duplicated and too much of the protein PMP22 is made in the cells that wrap around the axon. Symptoms of CMT1A often begin during childhood and slowly get worse over time. Another type of CMT, called Hereditary Neuropathy with liability to Pressure Palsy (HNPP), results from the deletion of one copy of the PMP22 gene. It causes recurring nerve damage in episodes, triggered by pressure on affected nerves. Muscle weakness is more common in people with CMT1A, while numbness and tingling are more common in HNPP.
- CMT1B is caused by changes (mutations) in the gene (MPZ) responsible for making another key part of the myelin sheath. CMT1B produces symptoms similar to those found in CMT1A. Onset of symptoms for CMT1B can be in infants, children, or adults.
- CMT2 affects the axon of peripheral nerve cells and is less common than CMT1. There are more than a dozen types of CMT2, linked to specific gene changes. In addition to the more typical symptoms of CMT, some types of CMT2 can cause speech or breathing problems due to nerve damage.
- CMT4 is a rare and severe form of CMT that has a profound impact on peripheral nerves. While CMT1 and CMT2 are usually dominantly inherited, CMT4 is recessive. In a dominant inheritance, only one parent must pass on the gene for a child to have the condition. In recessive inheritance, both parents must pass on the gene for a child to be affected, even if the parents don’t have the condition themselves. CMT4 usually begins in childhood with leg weakness, and many lose the ability to walk by their teen years.
- CMTX is the second most common form of CMT, caused by mutations in genes on the X chromosome that make proteins in the myelin sheath. Symptoms include muscle weakness, foot deformities, and nerve issues. Boys typically have moderate to severe symptoms starting in late childhood, while girls may have milder symptoms or none.
The fragile X syndrome inheritance is in an X-linked dominant pattern. That means the mutated gene that causes it is located on the X chromosome. The inheritance is dominant because only one copy of the mutated gene is necessary to cause the condition.
Fragile X syndrome occurs more frequently in males because they only have one X chromosome. Their symptoms are also more severe. Females have two X chromosomes. The condition may not affect both X chromosomes. Therefore, females can be carriers without having symptoms, but males with fragile X will always have symptoms.
To diagnose CMT, doctors start with a detailed medical and family history. It may be necessary to see a specialist—like a neurologist—to confirm diagnosis.
A doctor will look for evidence of:
- Muscle weakness in the arms, legs, hands, and feet
- Reduced muscle size (decreased muscle bulk)
- Slower tendon reflexes
- Sensory loss
- Issues with bones, joints, or muscles, such as mild scoliosis or an abnormal formation of the hip joint.
People with CMT1 may have enlarged nerves. This may be felt or even seen through the skin, especially at the elbow. These enlarged nerves, called hypertrophic nerves, are caused by thickened myelin sheaths.
The doctor may order diagnostic tests, which can include:
- Nerve conduction studies
- Electromyography (EMG)
- Genetic testing
- Nerve biopsy
There is no cure for CMT, but treatments can help manage symptoms. It is important to maintain mobility, flexibility, and muscle strength as much as possible. Starting a treatment program soon after symptoms begin can help people maintain quality of life. Physical and occupational therapy, braces and other orthopedic devices, and orthopedic surgery may help with symptoms of CMT. In addition, doctors may prescribe medication for severe nerve pain.
High-top shoes or boots can support weak ankles, while thumb splints can help with hand weakness and fine motor skills (using small hand muscles to do things). Using assistive devices like these early on (before disability sets in) may prevent muscle strain and reduce muscle weakening.
CMT is mostly an inherited disorder, and people with a family history of Charcot-Marie-Tooth (CMT) disease are more likely to develop it. If a person has CMT, that doesn’t mean their children will have it, but it does increase the risk. People who are concerned about their risk for CMT, including the likelihood that it may be passed to a child, can talk to a healthcare provider for advice and, if needed, genetic testing.
People inherit CMT gene mutations in three main ways: autosomal dominant, autosomal recessive, and X-linked. Autosomal dominant means one gene from either parent causes the disease, with a 50% chance of passing it to a child. Autosomal recessive requires two mutated genes, one from each parent, giving the child a 25% chance of inheriting the disorder. X-linked CMT affects the X chromosome, which is related to a child’s biological sex. A boy has a 50% chance of inheriting X-linked CMT from his mother.
Sometimes, a new genetic mutation occurs during early development, and the child develops CMT with no prior family history of the disease.
CMT is more common in certain parts of the world, including Europe and Japan. Scientists do not know why this is the case, and it may be that CMT is just less well studied or less often diagnosed in some parts of the world, leading to these perceived differences.
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