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What is Charcot-Marie-Tooth Disease (CMT)?
Charcot-Marie-Tooth disease (CMT) belongs to a group of disorders that cause progressive damage to the peripheral nerves, the network of nerves that transmit signals from the central nervous system (brain and spinal cord) to the rest of the body, and carry sensory information back toward the brain.
Also known as hereditary motor and sensory neuropathy (HMSN), CMT is one of the most common inherited neurological disorders, affecting approximately 2.6 million people worldwide.
CMT can interfere with the nerves responsible for voluntary muscle control, leading to progressive muscle weakness that typically becomes evident during adolescence or early adulthood, although onset can occur at any age. Because the longest nerves are affected first, symptoms usually appear initially in the feet and lower legs, followed by the fingers, hands, and arms.
While the majority of patients experience some degree of physical disability, a small minority may never become fully aware they are affected. It is important to note that CMT is generally not life-threatening: only rarely does it affect muscles involved in vital functions such as breathing. As a result, most patients have a life expectancy comparable to that of the general population.
Who to Turn to for Support
For patients and families dealing with CMT, connecting with a support network is invaluable. There are organizations, such as the Charcot-Marie-Tooth Association (CMTA) in the United States, which provides resources, research updates, and patient community support.
Causes
The transmission of nerve signals to and from the central nervous system occurs through electrical impulses sent along a long, thin projection of the nerve cell called the axon. Much like an electrical cable, the axon is surrounded by a protective sheath called myelin, which not only insulates the axon but also significantly increases the speed of signal conduction.
When myelin is absent or damaged, the electrical signal becomes slower and weaker, making it highly inefficient to send activation signals to muscles or to receive sensory information from the limbs.
CMT is caused by mutations in the genetic code, specifically in genes containing instructions for producing proteins involved in the structure and function of either the peripheral nerve axon or its myelin sheath. More than 40 genes have been implicated in the various forms of CMT, although more than half of all cases result from a duplication of the PMP22 gene on chromosome 17 (CMT type 1, see below).
These mutations disrupt the normal architecture and function of peripheral nerves, leading to the gradual deterioration that characterizes the disease.
Heredity and Transmission
The genetic mutations responsible for Charcot-Marie-Tooth disease are transmitted according to three main inheritance patterns:
- Autosomal dominant
- Autosomal recessive
- X-linked dominant (also called “X-linked”)
To understand these patterns, it helps to recall that every human being possesses 23 pairs of chromosomes:
- 22 pairs are autosomes and are inherited independently of biological sex (one chromosome of each pair inherited from each parent).
- 1 pair consists of sex chromosomes (heterosomes):
- XX in females (one X inherited from each parent)
- XY in males (the Y chromosome inherited from the father)
A disease is considered autosomal when the genetic defect is located on one of the autosomes, making it independent of the patient’s sex:
- It is classified as recessive when the defect must be inherited from both parents to manifest the disease. For example, if neither parent is affected but both are carriers, the risk of conceiving an affected child is 25%.
- It is classified as dominant when a single defective copy is sufficient to cause the disease. For example, if one parent is affected and the other is healthy, each child has a 50% probability of inheriting the condition.
Other forms of CMT are X-linked, meaning the genetic error is located on a sex chromosome (the X chromosome). Both dominant and recessive X-linked forms are known. In the recessive variant, there is a marked prevalence of affected males, since they carry only one X chromosome and therefore lack a potentially healthy backup copy of the gene in question.
Classification
There are many forms of Charcot-Marie-Tooth disease. While they may share certain symptoms, they differ substantially in inheritance pattern, age of onset, and the specific structures affected (axon or myelin sheath).
CMT Type 1 (CMT1)
CMT1 is caused by abnormalities in the myelin sheath and is transmitted via autosomal dominant inheritance. It accounts for approximately 80% of all CMT cases and is further subdivided as follows:
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CMT1A is the most common subtype, caused by a duplication of the PMP22 gene on chromosome 17. This gene carries instructions for producing peripheral myelin protein-22 (PMP22), a critical component of the myelin sheath. Overexpression of this gene leads to structural and functional abnormalities of the sheath. CMT1A typically progresses slowly, with weakness and atrophy of the lower leg muscles becoming apparent in childhood, followed later by hand weakness, sensory loss, and foot and leg problems.
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CMT1B is caused by mutations in the gene encoding myelin protein zero (MPZ or P0), another critical myelin component. Most of these mutations are point mutations, single errors in the DNA code (analogous to a single misspelled letter in a book). More than 120 different point mutations in the P0 gene have been described. CMT1B produces symptoms similar to those found in CMT1A.
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Other less common CMT1 forms result from mutations in additional genes involved in myelin maintenance and structure.
CMT Type 2 (CMT2)
CMT2 arises from abnormalities in the axon of the peripheral nerve cell itself, rather than in the myelin sheath. It is a relatively uncommon autosomal dominant disease that can be divided into more than a dozen subtypes (some with further variants). Symptoms are similar to those observed in CMT1, but patients with CMT2 often show reduced disability and sensory loss. Onset usually occurs during childhood or adolescence. Some subtypes of CMT2 may involve the vocal cords or the phrenic nerve, causing speech or breathing difficulties.
CMT Type 3 (CMT3) - Dejerine-Sottas Disease
CMT3, also known as Dejerine-Sottas disease, is a particularly severe demyelinating neuropathy beginning in infancy. Newborns present with severe muscle atrophy, weakness, delayed motor development, and sensory problems. Symptoms can evolve into severe disability, loss of sensation, and spinal curvature (scoliosis). It can be caused by mutations in multiple genes and may be transmitted via either dominant or recessive patterns.
CMT Type 4 (CMT4)
CMT4 comprises several subtypes of demyelinating and axonal motor neuropathies inherited in an autosomal recessive manner. Each subtype is caused by a mutation in a different gene, distributed unevenly across specific ethnic populations and presenting with distinctive clinical features. Onset involves the development of leg weakness symptoms during childhood and adolescence, in some cases progressing to loss of the ability to walk.
CMTX1
CMTX1 is the second most common form of CMT. Its transmission pattern is X-linked:
- Males who inherit the mutated gene typically exhibit moderate to severe disease symptoms beginning in late childhood or adolescence.
- Females who inherit the mutated gene often develop milder symptoms than males, or may show no symptoms at all.
Symptoms
CMT affects both sensory nerves (responsible for collecting sensations such as heat, cold, pressure, and pain) and motor nerves (nerves that trigger muscle contraction):
- Affected nerves degenerate slowly, progressively losing their ability to communicate with the periphery.
- Degeneration of motor nerves causes muscle weakness and decreased muscle mass (atrophy) in the arms, legs, hands, and feet.
- Degeneration of sensory nerve axons can result in a reduced ability to sense heat, cold, and touch, with vibration sense and proprioception (position sense) often being compromised early.
Early Symptoms
Onset typically involves weakness or even paralysis of the muscles of the foot and lower leg, manifesting as:
- Difficulty lifting the foot (foot drop)
- A characteristic steppage gait (high-stepping walk to avoid tripping)
- Frequent stumbling and falls
- Balance problems
Common Findings
- Foot deformities: High arched feet (pes cavus) and curled toes (hammer toes) are relatively common.
- Inverted champagne bottle appearance of the lower legs due to loss of muscle mass (hypotrophy and atrophy).
- Hand weakness and atrophy: As the disease progresses, fine motor skills become increasingly difficult.
- Reduced sensation: Decreased ability to perceive temperature, pain, vibration, and joint position.
- Spinal curvature: CMT can cause scoliosis and hip displacement.
- Contractures and muscle cramps: Chronic shortening of muscles and/or tendons around joints limits movement.
- Neuropathic pain: The intensity of neuropathic pain can range from mild to severe.
Less Common Symptoms
Some patients may also experience:
- Tremor
- Visual disturbances
- Hearing loss
- In rare cases, breathing difficulties if the nerves controlling the diaphragm muscles are involved.
The progression of symptoms is generally gradual, but severity can vary considerably even among individuals within the same family, making it difficult to predict disease course for any individual patient.
Diagnosis
The diagnosis of Charcot-Marie-Tooth disease begins with:
- Detailed medical history, including thorough investigation of family history.
- Neurological examination to assess muscle strength, bulk, reflexes, and sensation.
A physician will specifically look for:
- Muscle weakness in the limbs
- Decreased muscle mass
- Reduced tendon reflexes
- Reduced sensory sensitivity
- Foot deformities and other orthopedic problems, such as mild scoliosis or abnormal hip joint formation
A rather characteristic sign is the enlargement of one or more nerves that may be felt (or even seen through the skin), for example at the level of the elbow. These enlarged nerves, called hypertrophic nerves, are the product of abnormally thickened myelin sheaths.
Diagnostic Tests
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Nerve conduction studies (NCS): Electrodes are placed on the skin over muscles or nerves. Small electrical impulses stimulate the nerves and provide information about signal conduction velocity and amplitude, helping to distinguish between demyelinating and axonal forms of CMT.
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Electromyography (EMG): A needle electrode is inserted through the skin into the muscle to measure bioelectric activity. Specific abnormalities indicate axon loss and help characterize the distribution, activity, and severity of peripheral nerve involvement.
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Genetic testing: Analysis of a blood sample can detect the most common types of CMT. DNA testing is now available for many, though not all, CMT subtypes. Genetic confirmation is especially useful for family counseling and precise classification of the disease.
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Nerve biopsy: In selected cases, a small fragment of peripheral nerve (usually from the calf) is surgically removed and examined under a microscope. People with CMT1 typically show signs of abnormal myelination (e.g., onion bulb formations). This test is less frequently performed today given the advances in genetic testing.
Treatment
As a genetic disease, there is currently no cure for CMT. However, a range of supportive therapies can significantly help patients manage the most disabling symptoms and maintain quality of life.
Physical and Occupational Therapy
Maintaining mobility, flexibility, and muscle strength is essential. Starting a treatment program early can delay or reduce nerve degeneration and muscle weakness, preventing progression to severe disability. Beneficial approaches include:
- Muscle strengthening exercises
- Stretching (muscles and ligaments)
- Moderate aerobic exercise (activities that increase heart rate, such as swimming or cycling, which are often well tolerated)
Occupational therapy involves learning new strategies to manage daily activities. For example:
- Velcro closures and clips instead of buttons on clothing
- Specially designed utensils and tools to aid with self-feeding and other fine motor tasks
Orthopedic Devices and Bracing
Many people with CMT require ankle-foot orthoses (AFOs) and other orthopedic devices to maintain daily mobility and prevent injury. Braces can help prevent ankle sprains by providing support and stability during activities such as walking or climbing stairs. High shoes or boots can also provide useful support in cases of ankle weakness; similar evaluations can be made for hand and thumb supports.
Pain Management
Several analgesic and neuropathic pain medications may be prescribed to manage nerve pain, including anticonvulsants (such as gabapentin or pregabalin) and antidepressants (such as duloxetine), which are commonly used for neuropathic pain.
Surgical Options
Selected cases of severe foot and joint deformities may benefit from orthopedic surgery, which can improve walking ability and reduce pain. Surgical procedures may include tendon lengthening, osteotomy, or joint stabilization depending on the specific deformity.
Emerging Research and Future Therapies
Research into gene therapy and molecular treatments targeting the underlying genetic causes of CMT is actively ongoing. Clinical trials are exploring approaches to reduce PMP22 overexpression in CMT1A and address other molecular mechanisms in different subtypes. Patients are encouraged to consult with specialist centers and patient advocacy organizations to learn about potential trial opportunities.
Sources and Bibliography
- National Institute of Neurological Disorders and Stroke (NINDS) - NIH: Charcot-Marie-Tooth Disease
- Rossor AM, Polke JM, Houlden H, Reilly MM. Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nature Reviews Neurology. 2013;9(10):562–571.
- Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurology. 2009;8(7):654–667.
- Bird TD. Charcot-Marie-Tooth Hereditary Neuropathy Overview. GeneReviews® . Seattle: University of Washington; 1998–2023. Available from NCBI Bookshelf
- Charcot-Marie-Tooth Association (CMTA): https://www.cmtausa.org
