CMT is one of the most common inherited neurological disorders, affecting approximately 1 in 2,500 people worldwide. It occurs across all ethnic groups and affects males and females equally

 CMT is caused by mutations in genes that affect the structure and function of peripheral nerves. Over 100 different genes have been associated with various forms of CMT. These mutations can disrupt the nerve’s ability to transmit signals (due to defective myelin sheath or axons), leading to progressive nerve damage. Longer nerves are especially susceptible to degeneration when certain proteins are not produced, leading to peripheral nerve damage in the hands, fee, and legs. The condition is inherited in several patterns, including autosomal dominant, autosomal recessive, and X-linked forms (see Rareshare Guide on Genetic Inheritance). Genetic mutations associated with Charcot-Marie-Tooth continue to grow, and below are some of the most common along with the type of CMT they cause. 

The most common form, CMT1A, is caused by a duplication of the PMP22 gene. About 70-80% of individuals with CMT1 have this particular genetic mutation. This gene encodes the peripheral myelin protein 22, a component of myelin that protects the nerve cell axon and enables transmission of nerve impulses. This is especially important in cases where nerves become pinched or compressed, and can cause the sensation of prickling or “falling asleep”. Some people with CMT1 will experience numbness or tingling in their hands and feet alight to this “falling asleep” sensation. 

About 10-12% of individuals with CMT1 have mutations in the MPZ gene. This encodes myelin protein zero, the most abundant protein in myelin, and acts as an adhesion molecule to tightly pack nerve axons together in the peripheral nervous system. 

CMT2 is caused by mutations in the MFN2 gene in about 20% of cases. This encodes the protein mitofusin 2, which determines the shape of the mitochondria organelle. It is important for the formation of mitochondria in the muscles, spinal cord, and brain, and its dysfunction can cause reduced sensory functions such as touch, heat, pain, and even sound. 

About 90% of cases of CMTX are caused by mutations in the GJB1 gene. THis gene encodes protein gap junction beta-1, also known as connexin-32. Gap junctions play an important role in sending signals and nutrients between cells, especially neurons. Connexin-32 is specifically expressed in organs such as the liver, pancreas, and kidneys, and forms channels in the myelin sheaths of nerve cells. Its dysfunction can lead to abnormalities of these organs or a lack of communication between neurons.

Symptoms typically begin in childhood or adolescence but may also appear in adulthood. They include:

• Muscle weakness in the lower legs and feet, leading to foot drop and difficulty walking

• High arches (pes cavus) or flat feet

• Hammertoes (abnormal bending of the toes)

• Weakness and atrophy in the hands and forearms

• Numbness or reduced sensation in the limbs

• Poor balance and frequent tripping or falls

• Fatigue from increased effort in mobility 

Symptoms tend to worsen slowly over time and can vary significantly in severity even within the same family.

Diagnosis is based on clinical evaluation, family history, and confirmation through genetic testing. Neurologists typically look for characteristic signs such as muscle weakness, atrophy, and sensory loss in a stocking-glove pattern. Another frequent characteristic of those with CMT are abnormally arched or flattened feet, which can be a clue for geneticists to pursue a diagnosis of CMT.

• Electromyography (EMG) and Nerve Conduction Studies (NCS): Evaluate the electrical activity of muscles and the speed of nerve signals, helping differentiate between axonal and demyelinating forms of CMT.

• Genetic Testing: Identifies specific gene mutations associated with different subtypes of CMT.

• Nerve Biopsy: Rarely used, but can show loss of myelin or axonal degeneration.

Physical and Neurological Exams: Assess reflexes, muscle tone, and coordination.

There is currently no cure for CMT, but treatment focuses on symptom management and improving quality of life:

• Physical Therapy: Maintains muscle strength and flexibility.

• Occupational Therapy: Helps individuals manage daily activities and preserve hand function.

• Orthopedic Devices: Braces (such as ankle-foot orthoses) can help with foot drop and walking stability.

• Pain Management: Medications may be used to treat neuropathic pain.

• Genetic Counseling: Important for affected individuals and families planning for children.

Surgical Intervention: In some cases, corrective surgery for foot deformities may be recommended.

The prognosis for CMT varies based on the type and severity. While the disease is progressive, it does not typically affect life expectancy. Most individuals with CMT remain able to walk and lead active lives with appropriate supportive care, though some may require assistive devices. Quality of life can be impacted by physical limitations, but regular therapy and management can help maintain function and independence.

1. PMP22 gene

2. Medline Plus: Charcot-Marie-Tooth

3. MPZ gene

4. MFN2 gene

5. GJB1 gene