Charcot-Marie-Tooth (CMT) disease: symptoms, causes and treatment

Medically reviewed: 10, December 2023

Read Time:19 Minute

Charcot-Marie-Tooth Disease: A Comprehensive Review

Charcot-Marie-Tooth disease (CMT) is a group of sicknesses that affect the nerves in our body. It makes our muscles weaker and smaller over time, and we might lose feeling in our hands and feet. Sometimes our feet might look different too. Lots of people around the world have CMT, and there are different types of it. Doctors can figure out which type we have by looking at our genes and doing tests.

The treatment of CMT is mainly supportive and symptomatic, involving physical therapy, orthotic devices, pain management, and genetic counseling. There is no cure for CMT, but research is ongoing to develop novel therapies, such as gene therapy, stem cell therapy, or pharmacological agents. This article provides an overview of the epidemiology, pathophysiology, clinical features, diagnosis, treatment, prevention, and prognosis of CMT, with an emphasis on the latest advances and challenges.

What is Charcot-Marie-Tooth disease?

Charcot-Marie-Tooth disease (CMT) is an inherited disorder that primarily affects the peripheral nerves which play a crucial role in controlling motor and sensory functions within the body. This medical condition was initially recognized and designated with its current name by a group of three neurologists back in the year 1886. CMT is alternatively known as hereditary motor and sensory neuropathy or peroneal muscular atrophy, as it exerts its influence on both the muscles and nerves in the body.

CMT is a condition that makes your muscles weak and smaller over time. It can also make it harder to feel things and can cause problems with the shape of your feet. Some people start having these symptoms when they are kids, while others might not have them until they are grown-ups. The way the condition affects people can be different, even if they have the same type of Charcot-Marie-Tooth disease. Usually, the muscles in your legs and feet are affected first, and then it can spread to the muscles in your arms.

The cranial nerves and the autonomic nervous system are usually spared, but may be affected in some rare forms of CMT.

Charcot-Marie-Tooth disease is a prevalent genetic neurological condition that impacts approximately 1 in every 2, 500 individuals globally. It affects people of all genders, ethnicities, and races.

CMT is a major cause of disability and reduced quality of life, affecting the physical, psychological, and social aspects of the patients and their families.

Charcot-Marie-Tooth disease is classified into various types depending on its genetic origin, mode of inheritance, and clinical and electrophysiological characteristics. The primary classifications include CMT1, CMT2, and CMT4, which are caused by specific mutations in genes responsible for either the myelin sheath or the axon.

Additionally, certain cellular processes such as mitochondrial function or endosomal trafficking can also give rise to CMT. It is important to note that the classification of CMT is a dynamic field, as new genes and traits are constantly being discovered and incorporated.

The process of diagnosing CMT involves a comprehensive evaluation that incorporates several techniques such as analyzing the patient’s medical history, conducting a thorough physical examination, administering nerve conduction studies, and undertaking genetic testing to confirm the presence of the condition. After a confirmed diagnosis, the main focus of managing CMT revolves around offering various forms of support and effectively addressing the associated symptoms.

These symptom management strategies can encompass a range of approaches, including engaging in physical therapy to enhance mobility and strength, utilizing orthotic devices to provide support and stability, implementing pain management techniques to alleviate discomfort, and offering genetic counseling to aid individuals and their families in understanding the hereditary nature of the condition and making informed decisions.

At present, there exists no known remedy for CMT; nevertheless, scientists and researchers are actively engaged in ongoing efforts to discover groundbreaking treatments, including gene therapy, stem cell therapy, and the development of pharmacological agents.

This article provides an overview of the epidemiology, pathophysiology, clinical features, diagnosis, treatment, prevention, and prognosis of CMT, with an emphasis on the latest advances and challenges.

Epidemiology of Charcot-Marie-Tooth disease

CMT is a heterogeneous group of inherited peripheral neuropathies, with a wide range of prevalence estimates, depending on the type, the population, and the diagnostic criteria. The overall prevalence of CMT is estimated to be about 1 in 2, 500 people worldwide, but it may vary from 1 in 1, 214 in Norway to 1 in 6, 500 in Japan. CMT affects both males and females, and occurs in all ethnic and racial groups. However, some types of CMT may have a higher prevalence or a founder effect in certain populations, such as CMT1A in European populations, CMT4C in North African populations, or CMTX1 in Chinese populations.

Charcot-Marie-Tooth disease is a genetic disorder that can be inherited in different ways, depending on the specific type.

  1. The most prevalent mode of inheritance is autosomal dominant, wherein only one copy of the mutated gene is sufficient to trigger the disease. This type accounts for approximately 70% of CMT cases and encompasses CMT1, CMT2, and certain variants of CMT4.
  2. The second most common mode is autosomal recessive, which necessitates two copies of the mutated gene for the disease to manifest. This form constitutes around 15% of CMT cases and includes most forms of CMT4 as well as some rare forms of CMT1 and CMT2.
  3. The third most common mode is X-linked inheritance, which means that the mutated gene is located on the X chromosome and has a more severe impact on males than females. This mode accounts for approximately 10% of CMT cases and encompasses CMTX1, CMTX2, and CMTX3.
  4. The remaining 5% of CMT cases are caused by other less common modes of inheritance such as mitochondrial, digenic, or sporadic occurrences.

CMT is a progressive disorder, with symptoms usually appearing in childhood or adolescence, but sometimes manifesting in adulthood or later in life.

There is a significant variation in the onset, severity, and progression of the disease, known as CMT, among individuals and families, even when considering the same type of CMT. The reasons behind this variability in CMT are not completely comprehended at present, but may include the type and location of the mutation, the expression and function of the mutated gene, the interaction with other genes or environmental factors, and the adaptation or compensation of the nervous system.

CMT is a major cause of disability and reduced quality of life, affecting the physical, psychological, and social aspects of the patients and their families.

The physical impact of CMT includes muscle weakness and atrophy, sensory loss, foot deformities, gait abnormalities, balance problems, falls, fractures, pain, fatigue, and reduced mobility and independence.

The psychological impact of CMT includes depression, anxiety, stress, low self-esteem, poor body image, and coping difficulties. The social impact of CMT includes reduced education and employment opportunities, increased health care costs, and decreased social participation and support .

Charcot-Marie-Tooth disease (CMT) is a condition that arises due to genetic mutations in multiple genes responsible for the development and maintenance of peripheral nerves. These mutations can be diverse, with over 1, 000 variations known to cause Charcot-Marie-Tooth disease. The inheritance pattern of CMT depends on the specific gene affected, with some mutations occurring spontaneously in each cell (de novo mutations), while others are inherited from one or both parents who possess a faulty gene (autosomal dominant or recessive inheritance).

Additionally, certain mutations may exclusively impact specific cell types or tissues, while others affect all cells throughout the body. The symptoms and severity of CMT depend on which type of mutation is present.

Types of Charcot-Marie-Tooth disease

There are over 100 types of CMT, each with its own characteristics.

The main types are: On the other hand, Type II, also known as axonal CMT, specifically affects nerve fibers responsible for transmitting signals from the brain or spinal cord to other parts of the body. This type of CMT leads to degeneration and loss of these nerve fibers, resulting in muscle weakness and wasting.

Similar to Type I, Type II can be further divided into various subtypes based on the specific gene mutation involved, such as CMT2A (caused by the duplication or deletion of the MPZ gene), CMT2B (caused by the duplication or deletion of the PMP22 gene), CMT2X (caused by the deletion or duplication of the GJB2 gene), and so on.

Type I, also known as demyelinating Charcot-Marie-Tooth disease, impacts the myelin sheath that surrounds certain nerve fibers, resulting in inflammation and damage. This damage leads to decreased nerve conduction speed and sensory loss. Type I can be further categorized into different subtypes based on the specific gene mutation involved, including CMT1A (caused by the duplication of the PMP22 gene), CMT1B (caused by the duplication or deletion of the MPZ gene), CMT1X (caused by the deletion or duplication of the GJB2 gene), and so on.

Causes of Charcot-Marie-Tooth disease

The underlying cause of CMT remains largely unknown, although it is widely acknowledged that genetic factors significantly contribute to the likelihood of developing this condition. It is thought that abnormalities in specific genes can disrupt the proper growth and functioning of peripheral nerves either during the prenatal stage or in the early years of life. These gene mutations can be passed down from one or both parents who possess an imperfect version of these genes, despite not experiencing any symptoms themselves.

However, not all people who inherit these mutations will develop Charcot-Marie-Tooth disease. Other factors such as environmental triggers may also influence whether a person will develop symptoms or not. For example:

  • Diabetes: High blood sugar levels can damage peripheral nerves over time.
  • Infections: Some viral infections such as HIV can affect peripheral nerves.
  • Medications: Some drugs such as chemotherapy agents can damage peripheral nerves.
  • Nutritional deficiencies: Lack of certain vitamins such as B12 can affect nerve function.
  • Hormonal imbalances: Abnormal levels of thyroid hormones can affect nerve function.

Therefore, having a family history of CMT does not necessarily mean that you will develop it yourself. Likewise, having no family history does not guarantee that you will not develop it yourself.

Symptoms of Charcot-Marie-Tooth disease

The symptoms of Charcot-Marie-Tooth disease (CMT) can vary widely depending on the type and subtype of the condition, as well as the individual characteristics of each person. However, some common symptoms that affect most people with CMT are:

  • Muscle weakness and atrophy:

Charcot-Marie-Tooth disease causes damage to the peripheral nerves that control the muscles in the feet, legs, hands, and arms. This leads to progressive loss of muscle strength and bulk, especially in the lower limbs. People with CMT may have difficulty walking, running, climbing stairs, or lifting objects. They may also develop foot deformities such as high arches, flat feet, or curled toes, which can affect their balance and gait. Muscle weakness and atrophy can also affect the hands and arms, causing problems with fine motor skills, such as writing, typing, or buttoning clothes.

  • Sensory loss:

Charcot-Marie-Tooth disease also affects the peripheral nerves that carry sensory information from the skin, joints, and muscles to the brain. This leads to reduced or absent sensation of touch, pain, temperature, or vibration in the feet, legs, hands, and arms. People with CMT may not feel injuries, infections, or temperature changes in their extremities, which can increase the risk of complications. They may also experience numbness, tingling, or burning sensations in their affected areas.

  • Pain:

Some people with Charcot-Marie-Tooth disease may experience pain in their feet, legs, hands, or arms, due to nerve damage, muscle cramps, or joint problems. The pain may be constant or intermittent, and may vary in intensity and quality. Some people may also have neuropathic pain, which is a type of chronic pain caused by abnormal nerve function. Neuropathic pain may be described as shooting, stabbing, burning, or electric-like sensations.

  • Coldness:

Charcot-Marie-Tooth disease can affect the blood vessels and the autonomic nervous system, which regulate the body temperature and blood flow. This can cause poor circulation and coldness in the hands and feet, especially in cold weather. People with CMT may need to wear warm socks, gloves, or shoes to prevent frostbite or skin damage.

  • Fatigue:

Charcot-Marie-Tooth disease can cause fatigue, which is a feeling of tiredness, exhaustion, or lack of energy. Fatigue can result from the extra effort and strain required to perform daily activities, as well as from the reduced oxygen and nutrient supply to the muscles and nerves. Fatigue can affect the physical, mental, and emotional well-being of people with CMT, and may interfere with their work, school, or social life.

The symptoms of CMT usually begin in childhood or adolescence, but they can also appear later in life. The symptoms tend to worsen gradually over time, but the rate and extent of progression can vary from person to person. Some people may have mild symptoms that do not affect their daily functioning, while others may have severe symptoms that limit their mobility and independence. The symptoms of Charcot-Marie-Tooth disease can also fluctuate depending on factors such as age, activity level, environmental conditions, or other health problems.

Diagnosis of Charcot-Marie-Tooth disease

There is no single test that can diagnose all types and subtypes of CMT at once. The diagnosis depends on several factors such as:

  • The type and subtype(s) suspected based on clinical features
  • The family history available for each parent
  • The genetic testing results for each parent

The diagnosis process usually involves several steps:

Physical examination

A physical examination by a doctor may reveal some signs and symptoms suggestive of Charcot-Marie-Tooth disease, such as:

  • Muscle weakness can be experienced in various parts of the body, including the feet, ankles, legs, hands, and arms. This can lead to difficulties in walking or maintaining balance, making simple tasks more challenging.
  • Additionally, individuals may notice foot deformities such as high arches or flat feet, which can further contribute to mobility issues.
  • Numbness or tingling sensations may also be felt in the feet and hands, potentially causing discomfort and affecting daily activities.
  • Poor circulation may result in coldness specifically in the hands and feet, highlighting the impact on blood flow.
  • Furthermore, muscle wasting or thinning may become apparent, leading to a loss of strength and muscle definition.
  • Muscle cramps or spasms can also occur, causing involuntary contractions and discomfort.
  • Finally, tremors may be experienced, causing uncontrollable shaking or trembling in certain body parts.

The doctor may also perform some tests to confirm the diagnosis of CMT, such as:

  • Blood tests to check for signs of diabetes or other conditions that can worsen CMT symptoms
  • Nerve conduction studies to measure how fast electrical signals travel along the nerves
  • Electromyography (EMG) to measure how well the muscles respond to electrical stimulation
  • Genetic testing to identify the specific gene mutation that causes Charcot-Marie-Tooth disease

These tests can help determine the type and subtype of CMT, as well as the inheritance pattern.

Genetic testing

Genetic testing can confirm the diagnosis of Charcot-Marie-Tooth disease by identifying the specific gene mutation that is responsible for the condition. Genetic testing can also help determine the type and subtype of CMT, as well as the inheritance pattern. Genetic testing can be done on a blood sample or a nerve biopsy.

Genetic testing can have several benefits for people with CMT, such as:

  • Knowing the cause and severity of their condition
  • Planning for future pregnancies and family planning
  • Accessing appropriate treatments and support services
  • Joining research studies and clinical trials
  • Sharing information and experiences with other people with Charcot-Marie-Tooth disease

However, genetic testing can also have some drawbacks, such as:

  • The cost and availability of the test
  • The emotional impact of learning about their condition
  • The potential for discrimination or stigma from others
  • The possibility of false positives or negatives

Therefore, it is important to discuss the pros and cons of genetic testing with a doctor, a genetic counselor, and a family member before deciding to undergo the test.

Treatment of Charcot-Marie-Tooth disease

There is no cure for CMT, but there are treatments that can help manage the symptoms and improve the quality of life of people with the condition. These treatments may include:
Medications

Some medications may help relieve pain, muscle spasms, nerve damage, or inflammation caused by CMT. These medications may include:

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or naproxen to reduce pain and inflammation
  • Muscle relaxants such as baclofen or tizanidine to ease muscle stiffness and spasms
  • Anticonvulsants such as gabapentin or pregabalin to control nerve pain
  • Corticosteroids such as prednisone or methylprednisolone to suppress immune system activity in severe cases

Some medications may also help prevent or treat complications of Charcot-Marie-Tooth disease, such as:

  • Diuretics such as furosemide or hydrochlorothiazide to reduce fluid retention and swelling in the legs
  • Vasodilators such as nitroglycerin or hydralazine to improve blood flow in the legs
  • Antibiotics such as ciprofloxacin or doxycycline to prevent infections in people with diabetes who have poor circulation in their feet

Some medications may have side effects or interactions with other drugs, so it is important to consult a doctor before taking any medication.

Physical therapy

Physical therapy is an essential part of treatment for people with CMT. Physical therapy can help improve muscle strength, flexibility, balance, coordination, and mobility. Physical therapy can also help prevent contractures (shortening of muscles) that can limit movement and cause deformities.

Physical therapy may involve exercises that target specific muscles affected by CMT. Some examples are:

  • Strengthening exercises that use resistance bands, weights, machines, or body weight to build muscle mass and endurance
  • Stretching exercises that use elastic bands, foam rollers, massage tools, or heat pads to improve range of motion and flexibility
  • Functional exercises that use activities of daily living (ADLs) such as walking, climbing stairs, getting up from a chair, dressing oneself can help improve the ability of people with Charcot-Marie-Tooth disease to perform these tasks independently and safely. Functional exercises can also help prevent falls and injuries, improve self-esteem and confidence, and enhance social participation and quality of life.

Some examples of functional exercises are:

  • Walking exercises that use a treadmill, a walker, a cane, or a brace to improve gait and balance
  • Stair climbing exercises that use a stair stepper, a handrail, or a step stool to improve leg strength and coordination
  • Chair rising exercises that use a chair, a bench, or a cushion to improve lower body strength and mobility
  • Dressing exercises that use adaptive devices such as zipper pulls, button hooks, or Velcro to improve hand function and dexterity

Functional exercises should be tailored to the individual needs and goals of each person with CMT. They should be performed under the guidance and supervision of a physical therapist or an occupational therapist who can monitor the progress and adjust the intensity and frequency of the exercises as needed. They should also be combined with other forms of physical therapy such as strengthening, stretching, and functional exercises to achieve optimal results.

Risks of Charcot-Marie-Tooth disease

People with CMT may face some risks associated with their condition, such as:

  • Foot deformities and injuries:

People with Charcot-Marie-Tooth disease may have foot abnormalities such as high arches, flat feet, or curled toes. They often have difficulty flexing the foot or walking on the heel of the foot. These difficulties may cause a higher than normal step (steppage gait) and increase the risk of ankle injuries and tripping. In some cases, surgery may be needed to correct problems such as flat feet and muscle contractures.

  • Nerve damage and pain:

People with CMT may experience nerve damage that can cause numbness, tingling, burning, or loss of temperature sensation in their hands and feet. They may also have nerve pain that can affect their quality of life. Some medications may help relieve nerve pain, but they may also have side effects or interactions with other drugs.

  • Respiratory problems:

People with Charcot-Marie-Tooth disease may have difficulty breathing due to muscle weakness in the chest and abdomen. This can lead to respiratory infections, sleep apnea, or chronic obstructive pulmonary disease (COPD).

  • Diabetes complications:

Patients with Charcot-Marie-Tooth disease who have diabetes may have poor blood circulation in their feet due to nerve damage. This can increase the risk of developing foot ulcers, infections, or gangrene. They may also need to monitor their blood sugar levels more closely and take insulin injections if needed.

  • Depression and anxiety:

You may experience emotional distress due to the progressive nature of their condition, the impact on their daily activities and independence, the stigma or discrimination they may face from others, or the fear of losing their ability to walk or perform basic tasks. They may benefit from psychological support such as counseling or therapy.

Prevention of Charcot-Marie-Tooth disease

There is no sure way to prevent CMT from occurring in families. However, some possible strategies that may reduce the risk of passing on Charcot-Marie-Tooth disease to future generations are:

  • Genetic testing:

Genetic testing can help identify people who carry a faulty gene for CMT without having any symptoms themselves. They can then decide whether they want to have children or not based on their personal preferences and values. Genetic testing can also help people who are carriers of a faulty gene for CMT plan for future pregnancies and family planning by using assisted reproductive technologies (ART) such as preimplantation genetic diagnosis (PGD) or prenatal testing.

  • Genetic counseling:

Genetic counseling is a service that provides information and guidance about genetic conditions such as Charcot-Marie-Tooth disease. It can help people who are carriers of a faulty gene for CMT understand their risks of having children with Charcot-Marie-Tooth disease, weigh the benefits and drawbacks of genetic testing and ART, cope with emotional issues related to genetic testing and family planning, and make informed decisions about their reproductive options.

  • Healthy lifestyle:

A healthy lifestyle can help maintain good health and prevent or delay complications associated with diabetes or other conditions that can worsen symptoms of CMT. Some examples of healthy lifestyle habits are:

  • Eating a balanced diet that provides adequate nutrients for nerve function
  • Exercising regularly to improve muscle strength, flexibility, balance, coordination, mobility
  • Avoiding smoking and excessive alcohol consumption
  • Managing stress levels
  • Getting enough sleep

Charcot-Marie-Tooth disease is a complex and heterogeneous condition that affects the peripheral nerves and causes progressive muscle weakness, sensory loss, and foot deformities. CMT can have a significant impact on the quality of life and independence of those affected. There is no cure for Charcot-Marie-Tooth disease, but there are treatments that can help manage the symptoms and improve the quality of life of people with CMT. These treatments include medications, physical therapy, orthotics, surgery, and psychological support.

Genetic testing and counseling can help patients with Charcot-Marie-Tooth disease understand their condition, plan for future pregnancies and family planning, and access appropriate treatments and support services.

A healthy lifestyle can help maintain good health and prevent or delay complications associated with diabetes or other conditions that can worsen symptoms of CMT. Research is ongoing to find new ways to diagnose, treat, and prevent CMT. People with CMT can participate in research studies and clinical trials to contribute to the advancement of knowledge and the development of new therapies for CMT.

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