Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies affecting motor and sensory nerves. CMT can cause a a child to lose feeling and movement in their extremities. Sometimes this disease affects speech, breathing and swallowing. With this condition, the peripheral nerves (the nerves outside the brain and spinal cord) don’t work properly.

Pathophysiology

CMT results from mutations in genes involved in the structure and function of peripheral nerves. The pathophysiology varies depending on the specific type:

1. Demyelinating forms (CMT1, CMT4, CMTX): Mutations affect Schwann cell function, leading to defective myelin production or maintenance. This results in reduced nerve conduction velocities.
2. Axonal forms (CMT2): Mutations primarily affect axonal structure or function, leading to axonal degeneration.
3. Intermediate forms: Show features of both demyelinating and axonal neuropathies.

The common end result is progressive axonal loss, leading to muscle weakness and sensory deficits.

Genetic Transmission

CMT can be inherited in several patterns:

1. Autosomal dominant: Most common in CMT1 and CMT2
2. Autosomal recessive: Seen in some forms of CMT4
3. X-linked: CMTX1 (mutations in GJB1 gene)

The most common mutations involve:

• PMP22 gene duplication (CMT1A)
• MPZ gene mutations (CMT1B)
• GJB1 gene mutations (CMTX1)
• MFN2 gene mutations (CMT2A)

X-linked CMT (CMTX) has a unique inheritance pattern compared to other forms of CMT

Inheritance through females

• When a female has X-linked CMT, each of her children (regardless of gender) has a 50% chance of inheriting the CMT-causing mutation.
• This is because females have two X chromosomes, and can pass either the affected or unaffected X chromosome to their children.

Inheritance through males

• When a male has X-linked CMT, all of his daughters will inherit the CMT-causing mutation.
• None of his sons will inherit the CMT-causing mutation.
• This is because males have one X and one Y chromosome. They always pass their X chromosome (which carries the mutation) to their daughters and their Y chromosome to their sons.

Key points

• X-linked CMT can be inherited through both males and females, but the pattern differs.
• Females can pass it to children of either gender.
• Males will only pass it to their daughters, not their sons.
• The inheritance pattern is different from autosomal dominant or recessive forms of CMT.

Severity

• Males with X-linked CMT typically have more severe symptoms than females.
• Females may have milder symptoms or be asymptomatic carriers due to having two X chromosomes (one normal, one with the mutation).

In summary, X-linked CMT can be inherited through both males and females, but the inheritance pattern and likelihood of passing on the condition differs based on the parent’s sex.

Signs and Symptoms

1. Motor symptoms:
   • Progressive distal muscle weakness and atrophy
   • Foot deformities (pes cavus, hammer toes)
   • Difficulty walking, frequent tripping
   • Hand weakness and atrophy in later stages
2. Sensory symptoms:
   • Reduced sensation in feet and hands
   • Neuropathic pain in some cases
3. Other features:
   • Reduced or absent deep tendon reflexes
   • Scoliosis in some patients

Progression of CMT can be Quite Different for Different People

The progression of CMT syndrome can vary significantly between individuals, even within the same family. Here are some key points about how the progression can differ:

1. Age of onset: Symptoms typically appear in adolescence or early adulthood, but can start anytime from early childhood to late adulthood. Some individuals may not realize they have CMT until later in life due to very mild symptoms.
2. Rate of progression: CMT is generally slowly progressive, but the rate can vary. Some people experience rapid progression, while others have very slow progression over decades.
3. Severity of symptoms: The severity ranges from mild cases with minimal impairment to severe cases causing significant disability. Most people fall in the moderate range.
4. Distribution of symptoms: While CMT typically affects the feet and lower legs first, some individuals may experience hand and arm involvement earlier or more severely than others.
5. Types of symptoms: The balance between motor and sensory symptoms can differ. Some people may have more muscle weakness, while others experience more sensory loss.
6. Specific impairments: The development of foot deformities, hand dexterity issues, or breathing problems can vary widely between individuals.
7. Impact on daily activities: The effect on walking, balance, fine motor skills, and overall quality of life differs for each person.
8. Genetic factors: Different genetic mutations associated with CMT can lead to variations in disease progression and severity.
9. Environmental factors: Lifestyle, overall health, and environmental factors may influence how the disease progresses in different individuals.
10. Response to interventions: The effectiveness of treatments and interventions can vary between individuals, affecting the overall course of the disease.

It’s important to note that even within families carrying the same genetic mutation, there can be significant variability in how CMT progresses. Regular monitoring and personalized management are crucial due to this variability in progression.

Treatment Plans

There is no cure for CMT, so treatment focuses on symptom management and supportive care including physical therapy, occupational therapy, orthopedic interventions, pain management, genetic counseling for parents, and regular monitoring. Physical and occupational therapy might involve stretching and strengthening exercises, gait training, use of adaptive devices to improve hand and leg function, and strategies for regular activities of daily living (such as dressing, walking, grooming, toileting). Orthopedic interventions might include ankle-foot braces (also called ankle-foot orthoses or AFOs) for foot drop, or orthopedic surgery for deformities or scoliosis. Pain management can include over the counter pain medications, alternative pain therapy, or narcotics. Adults and parents of children with CMT can undergo genetic counseling. Finally, patients will be monitored for disease progression and deterioration.

References

1. Aldihan, K. A., AlRashedi, M. J., Helayel, H. B., AlMutlak, M., & Hameed, S. T. (2023). Severe Dry Eye Disease in Charcot-Marie-Tooth Disease: A Comprehensive Case Report. American Journal of Case Reports, 24, 1–4. https://doi.org/10.12659/AJCR.941094
2. Choi, J. E., Seol, H. Y., Seok, J. M., Hong, S. H., Choi, B. ‐O., & Moon, I. J. (2020). Psychoacoustics and neurophysiological auditory processing in patients with Charcot‐Marie‐Tooth disease types 1A and 2A. European Journal of Neurology, 27(10), 2079–2088. https://doi.org/10.1111/ene.14370
3. Silsby, M., Yiannikas, C., Fois, A. F., Kennerson, M. L., Kiernan, M. C., Fung, V. S. C., & Vucic, S. (2024). Upper and lower limb tremor in Charcot-Marie-Tooth neuropathy type 1A and the implications for standing balance. Journal of Neurology, 271(4), 1776–1786. https://doi.org/10.1007/s00415-023-12124-z
4. Waldman, L. E., Michalski, M. P., Pfeffer, G. B., Giaconi, J. C., & Learch, T. J. (2023). Charcot-Marie-Tooth Disease of the Foot and Ankle: Imaging Features and Pathophysiology. Radiographics, 43(4). https://doi.org/10.1148/rg.220114