What is Charcot-Marie-Tooth Disease?
Charcot-Marie-Tooth disease (CMT) is a group of rare genetic disorders that affect the peripheral nerves, which are responsible for transmitting signals between the brain and the rest of the body, including the arms, hands, legs, and feet.1-3
CMT is characterized by muscle weakness and wasting, particularly in the feet, lower legs, hands, and forearms. People with CMT may experience difficulties with walking, balance, and coordination. In some cases, it can also affect the muscles involved in breathing and swallowing.1-3
Charcot-Marie-Tooth disease was named after the physicians who first described it in 1886 – Jean-Martin Charcot and Pierre Marie (France) and Howard Henry Tooth (United Kingdom).1,3
What causes Charcot-Marie-Tooth Disease?
Charcot-Marie-Tooth is caused by mutations in specific genes. More than 100 genes have been identified as being the main cause of CMT, each one linked to a specific disease type.1,3
Knowing which gene is mutated is important to identify the CMT type, understand the symptoms and create strategies to improve quality of life.
What are the types of Charcot-Marie-Tooth Disease?
There are several types of CMT; types 1, 2, 4 and X being the most common types. 1,3 Of all the CMT cases, CMT2 (Charcot Marie Tooth type 2) is responsible for 12-36% of the disease cases.1,2
In Charcot-Marie-Tooth disease type 2 (CMT2), the cells responsible for passing along the electrical impulse through the nerves are damaged, resulting in “communication” lacks between nerve cell and muscles.1-3
CMT2 has more than 20 subtypes, classified from A to Z (some of which with their own variants), and each subtype is associated with mutations in a specific gene.1,2
The ProgettoMitofusina2 is focused on type 2 CMT, especially in CMT2A. If you would like to know more about other types of CMT please follow this link.
What is Charcot-Marie-Tooth Disease Type 2A (CMT2A)?
CMT2 A (CMT2A) is the most common subtype of CMT2, accounting for approximately 20% of all CMT2 cases.1,3
CMT2A is caused by mutations in the MFN2 gene (Mitofusin-2), which encodes a protein that is key component of mitochondria.1-3
Mitochondria are responsible for producing energy for every cell in the body, for example, the cells involved in transmitting the signals between the brain and the rest of the body. When this gene is mutated the signal transmission is compromised and patients start to feel the symptoms.3
What are the symptoms of CMT2A?
CMT2A is a peripheral neuropathy, so the initial and primary symptoms of CMT2A include muscle weakness and wasting in the lower legs, ankle, and feet.1,3,4
The symptoms of CMT2A can appear (with an early onset) in early childhood, but also during adolescence.
CMT2A is also a progressive disease, meaning that the disease worsens over time, and that the symptoms can progress towards the upper part of the body, with weakness of hands, wrists, and forearms.1,3,4
It is particularly important that if you face any of these symptoms, you seek proper advice from your doctor or medical team, so they can be evaluated for your specific context.
In the following table we list some common symptoms associated with CMT2A1,3,4:
|Progressive muscle weakness
|Weakness in the muscles of the feet, lower legs, hands, and forearms, which worsens over time.
|Loss of muscle mass, leading to reduced muscle size and strength.
|Reduced or loss of sensation, particularly in the hands and feet.
|Abnormalities in foot structure, such as high arches (pes cavus) or hammertoes.
|Difficulty with fine motor skills
|Challenges in performing precise movements with the hands and feet, like griping, turning doorknobs, buttoning and/or zippering.
|Abnormal sensations like tingling, numbness, or a “pins and needles” sensation.
|Decreased or absent reflex responses, often noticeable in the knees and ankles.
|Painful muscle contractions often occurring in the legs or feet (not as common)
In CMT2A severe cases, patients can manifest other symptoms1,3,4:
|Neuromuscular scoliosis may appear during adolescence. It is important to follow up as it can lead to breathing problems.
|Damage to the optic nerve, leading to vision problems.
|Vocal cord paralysis
|Weakness or paralysis of the vocal cords, affecting speech and swallowing.
|Partial or complete hearing loss, which may be present in some individuals.
|Difficulty breathing due to weakness in the diaphragm muscles.
In addition to physical symptoms, CMT2A can also impact a person’s daily life and emotional well-being. It is important for individuals with CMT2A to receive comprehensive care that addresses both the physical and emotional aspects of the condition. 1
CMT2A symptoms usually appear during adolescence or early adulthood, although they can develop later (around the age of 50 years old).6
The age of the first symptoms/severity of the disease can be associated with specific mutations in the MFN2 gene, and the most severe cases are sometimes associated with early ages of disease onset.4,5,7,8
You can access the updated mutation database and check information regarding your mutation.
How is CMT2A transmitted?
CMT2A is hereditary, meaning that people inherited it from their parents, most commonly in an autosomal dominant pattern (not associated with gender, and only needing one mutated copy of the gene to cause symptoms). 1,3
However, in some rare cases of CMT2A (10%) the mutation occurs spontaneously during embryonic development.3
How is CMT2A diagnosed?
To diagnose CMT2A, the physician must perform a clinical evaluation, including a detailed medical history and physical examination.
In these first steps, the physician will look for2,9:
- Muscle weakness in the arms, legs, hands, and feet
- Decreased muscle bulk
- Reduced tendon reflexes (looks for sensory loss)
- Sensory loss
- Foot and orthopedic problems
To help assess nerve function and identify characteristic abnormalities, electrophysiological tests can be performed, which include nerve conduction velocity test (NCV test) and electromyography (EMG)2,9,10:
- Nerve conduction velocity test (NCV test) measures the strength and speed of the electrical signs transmitted through nerves. Delay in the response is a sign for demyelination, whereas small response is associated with an axonal neuropathy.9,10
- Electromyography (EMG) looks at the electrical signals made by the muscles while in rest and when they are being used.9,10
To confirm the diagnosis of CMT2A, genetic testing can be done. Specifically, sequencing the MFN2 gene is crucial to identify specific mutations. A biological sample is needed to perform a genetic test, which can be blood or saliva.9
There are many kinds of genetic tests11:
- Single gene testing – Looks for changes of only one gene (for example MNF2 gene);
- Panel testing – Looks for changes in many genes, frequently a group of genes that are associated with a specific condition. In this case, it may analyze the genes involved in all CMT types;
- Large-scale genetic or genomic testing – There are two different options in these genetic tests, Exome sequencing (looks at all the genes in the DNA) and Genome sequencing (looks for all the DNA of a person, not just the genes).
What is the treatment for CMT2A?
There is not yet a cure for CMT2A. However, there are ongoing investigations on promising therapeutic targets for CMT2A, some of that involving mitofusin agonists.
Some of the research projects involve a strategy for genetic therapy, stem cell-based therapies, and others. In the table below you can find some of the ongoing research therapies:
|Ongoing research therapies
|Mitofusin agonists small molecules that target specific domains in the mitochondria, switching its conformation and restoring its correct traffic flow.1,2,6
|Targeting mitochondrial dysfunction Mfn2 and Mfn1 are proteins required for mitochondrial fusion. Increasing expression of Mnf1 can compensate Mfn2 deficiency and restoring mitochondrial function.6
|Gene therapy This type of strategy aims to introduce the “healthy” gene and switch off the “diseased” gene.9
|Stem Cells-based approach This approach is based on the transplantation of stem cell to deliver molecules that could have a therapeutic role.9
|Discover new pathogenic mutations or genes involved in CMT2A Expand the knowledge regarding the clinical and genetic spectrum of CMT2A.9
If you want to know more about some of the specific projects to find a cure for CMT2A, check the Progetto mitofusina 2 ongoing research project on CMT2A.
Living with CMT2A: Manage the disease
Living with CMT2A can present unique challenges, but with proper support and self-care, individuals can live fulfilling lives.
We strongly recommend you ask your physician’s advice to understand what is best for your situation. Nevertheless, here are some generic good practices for living with CMT2A:
Maintain a healthy, balanced diet, and practice physical activity: these will help you improve your quality of life. To know more about the effect of a healthy diet in CMT patients read the article “Following the rhythm of the seasons for our CMT diet”.
Use supportive treatments/devices to manage the disabling symptoms of CMT2A and improve your daily life. Wearing boots or high-top shoes may help with muscle weakness and waste in the lower legs, ankle, and feet. Leg braces, such as an ankle-foot orthosis (AFO)- a removable frame that fits snugly around the foot and ankle, may be useful for some patients, as well as splints (to prevent flexing of the toes).1,2 These devices should be used as soon as the disability appears, to prevent the worsening of the symptoms.1,2 Contact your medical team to address the right support for you.1,2
Note: CMT medical teams should be composed by multiple specialists, like neurologists, genetic counselors, nurses, physical and occupational therapists, psychologists, and others.1,2
Contact an occupational therapist, this kind of therapy will help in making homes more accessible by removing hazards and/or installing accessibility devices. Patients whose symptoms occur and/or progress to the hands and forearms (for example, difficulties in griping, turning doorknobs, buttoning and/or zippering), may benefit from these specialists.1
Seek genetic counseling if you have CMT2A. Since CMT2A is normally transmitted from parents to children, genetic counseling can provide information on the transmission pattern and reproductive options. 1,2
Get emotional support. Living with CMT disease may have a significant psychological impact on patients, relatives, and caregivers, getting psychological support will help people managing their disease and improving their quality of life.1
Contact with other patients and share experiences, doubts and fears can help you feel understood and accepted.1
Want to know more about CMT2A?
Charcot-Marie-Tooth type 2A (CMT2A) is a subtype of CMT disease characterized by progressive muscle weakness, sensory loss, and foot deformities. Prompt diagnosis, ongoing research efforts, and support from peers are essential for improving understanding, and quality of life for individuals affected by CMT2A. If you want to know more about these topics, click on the links bellow:
A correct diagnosis is essential to identify the right treatment. If you desire to know how to get your diagnosis, visit the Progetto Mitofusina 2.
If you’d like to know more about the ongoing research project on CMT2A, visit the Progetto Mitofusina 2.
Would you like to contact CMT patients and patient associations?
Visit the Associations page on Progetto Mitofusina 2.
1. Muscular Dystrophy Association: Charcot-Marie-Tooth Disease (CMT). Available at: https://www.mda.org/disease/charcot-marie-tooth. Accessed at 26.06.2023;
2. National Institute of Neurological Disorders and Stroke: Charcot-Marie-Tooth Disease. Available at: https://www.ninds.nih.gov/health-information/disorders/charcot-marie-tooth-disease. Accessed at 26.06.2023;
3. CMT Research Foundation. Available at: https://cmtrf.org/. Accessed at 29.06.2023;
4. Morena J., et al. Int. J. Mol. Sci. 2019, 20, 3419;
5. Pipis M., et al. Brain. 2020, 143:3589-3602;
6. McCray BA., et al. Neurotherapeutics. 2021, 18:2269-2285;
7. Chung KW., et al. Brain. 2006, 129:2103-2118;
8. Zuchner S. et al. Nat Genet. 2004, 36(5):449-51;
9. Progetto Mitofusina 2. Available at: https://www.progettomitofusina2.com/en/portfolio-articoli/our-research-project/. Accessed at 30.06.2023;