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Charcot-marie-tooth Disease Type 2

Disease Details

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Description: Charcot-Marie-Tooth Disease Type 2 is a hereditary motor and sensory neuropathy characterized by progressive muscle weakness and atrophy, primarily affecting the legs and feet, with a later onset and less severe demyelination compared to Type 1.
Type: Charcot-Marie-Tooth disease type 2 (CMT2) is classified as an axonal form of the disease, meaning it primarily affects the axons of peripheral nerves rather than the myelin sheath. The type of genetic transmission for CMT2 is typically autosomal dominant, although there are rarer instances of autosomal recessive inheritance.
Signs And Symptoms: Symptoms of CMT usually begin in early childhood or early adulthood but can begin later. Some people do not experience symptoms until their early 30s or 40s. Usually, the initial symptom is foot drop or high arches early in the course of the disease. This can be accompanied by hammertoe, where the toes are always curled. Wasting of muscle tissue of the lower parts of the legs may give rise to a "stork leg" or "inverted champagne bottle" appearance. Weakness in the hands and forearms occurs in many people as the disease progresses.Loss of touch sensation in the feet, ankles, and legs as well as in the hands, wrists, and arms occurs with various types of the disease. Early- and late-onset forms occur with 'on and off' painful spasmodic muscular contractions that can be disabling when the disease activates. High-arched feet (pes cavus) or flat-arched feet (pes planus) are classically associated with the disorder. Sensory and proprioceptive nerves in the hands and feet are often damaged, while unmyelinated pain nerves are left intact. Overuse of an affected hand or limb can activate symptoms including numbness, spasm, and painful cramping.Symptoms and progression of the disease can vary. Involuntary grinding of teeth and squinting are prevalent and often go unnoticed by the person affected. Breathing can be affected in some, as can hearing, vision, and neck and shoulder muscles. Scoliosis is common, causing hunching and loss of height. Hip sockets can be malformed. Gastrointestinal problems can be part of CMT, as can difficulty chewing, swallowing, and speaking (due to atrophy of vocal cords). A tremor can develop as muscles waste. Pregnancy has been known to exacerbate CMT, as well as severe emotional stress. Patients with CMT must avoid periods of prolonged immobility such as when recovering from a secondary injury, as prolonged periods of limited mobility can drastically accelerate symptoms of CMT.Pain due to postural changes, skeletal deformations, muscle fatigue, and cramping is fairly common in people with CMT. It can be mitigated or treated by physical therapies, surgeries, and corrective or assistive devices. Analgesic medications may also be needed if other therapies do not provide relief from pain. Neuropathic pain is often a symptom of CMT, though, like other symptoms of CMT, its presence and severity vary from case to case. For some people, pain can be significant to severe and interfere with daily life activities. However, pain is not experienced by all people with CMT. When neuropathic pain is present as a symptom of CMT, it is comparable to that seen in other peripheral neuropathies, as well as postherpetic neuralgia and complex regional pain syndrome, among other diseases.
Prognosis: The severity of symptoms varies widely even for the same type of CMT. Cases of monozygotic twins with varying levels of disease severity have been reported, showing that identical genotypes are associated with different levels of severity (see penetrance). Some patients are able to live a normal life and are almost or entirely asymptomatic. A 2007 review stated that, "life expectancy is not known to be altered in the majority of cases."
Onset: Charcot-Marie-Tooth disease type 2 (CMT2) generally has an onset in adolescence or early adulthood. However, symptoms can appear at various ages, sometimes even in childhood or later in adult life.
Prevalence: The prevalence of Charcot-Marie-Tooth Disease Type 2 is approximately 1 in 2,500 individuals.
Epidemiology: Charcot-Marie-Tooth disease type 2 (CMT2) is a form of inherited peripheral neuropathy characterized by axonal degeneration. The epidemiology of CMT2 is as follows:

- **Prevalence:** CMT2 is less common than CMT1, but the combined prevalence of all CMT subtypes is estimated to be about 1 in 2,500 people. Within the spectrum of CMT disorders, CMT2 accounts for approximately 12-40% of cases.
- **Age of Onset:** Symptoms often begin in adolescence or early adulthood, though they can start at any age.
- **Inheritance:** CMT2 is typically inherited in an autosomal dominant manner, though autosomal recessive and X-linked patterns have also been reported.
- **Geographic Distribution:** CMT2 occurs worldwide, affecting all ethnic groups similarly.

Further epidemiological data specific to CMT2 may vary by region and specific genetic mutations involved.
Intractability: Charcot-Marie-Tooth Disease Type 2 (CMT2) is generally considered intractable in terms of a complete cure. It is a genetic disorder with no current cure, and treatment focuses on managing symptoms and slowing the progression of the disease. This can involve physical therapy, occupational therapy, and, in some cases, orthopedic devices or surgery.
Disease Severity: Charcot-Marie-Tooth disease type 2 (CMT2) is a subtype of Charcot-Marie-Tooth disease that primarily affects the peripheral nerves. The severity of CMT2 can vary widely among individuals. It typically progresses more slowly than type 1 and presents with symptoms such as muscle weakness, atrophy, and sensory loss, often in the lower extremities. In many cases, individuals with CMT2 remain ambulatory and can have a normal life expectancy, though the impact on quality of life can be significant. Severity can range from mild to moderate, depending on the specific genetic mutation and other individual factors.
Healthcare Professionals: Disease Ontology ID - DOID:0050539
Pathophysiology: Charcot-Marie-Tooth disease type 2 (CMT2) is a group of inherited peripheral neuropathies characterized by axonal degeneration. The pathophysiology of CMT2 involves mutations in multiple genes that play various roles in the maintenance and function of peripheral nerve axons. These genetic mutations lead to dysfunction in axonal transport, mitochondrial function, and various cellular processes, resulting in the progressive degeneration of the long motor and sensory axons. Over time, this axonal damage leads to muscle weakness, atrophy, and sensory loss, particularly affecting the distal limbs.
Carrier Status: For Charcot-Marie-Tooth Disease Type 2 (CMT2), carrier status concepts are not typically applicable in the same way they are for autosomal recessive conditions. CMT2 is primarily inherited in an autosomal dominant manner, meaning if an individual inherits one mutated gene from an affected parent, they will typically manifest the disease. Unlike autosomal recessive diseases which require both copies of a gene to be mutated (carriers have one normal and one mutated gene), autosomal dominant disorders like CMT2 do not have a "carrier" state because the presence of one mutated gene can lead to the disease.
Mechanism: Charcot-Marie-Tooth disease type 2 (CMT2) is a group of hereditary motor and sensory neuropathies characterized by axonal degeneration. Here are the key points regarding its mechanism and molecular mechanisms:

**Mechanism:**
CMT2 primarily affects the peripheral nervous system, leading to degeneration of the long nerve fibers (axons) that connect the spinal cord to muscles and sensory organs. This axonal degeneration results in muscle weakness and atrophy, particularly in the distal extremities (feet and hands), as well as sensory loss. Unlike CMT type 1, which involves demyelination (damage to the myelin sheath of nerve fibers), CMT2 is predominantly an axonal neuropathy.

**Molecular Mechanisms:**
1. **Genetic Mutations:** CMT2 is caused by mutations in several different genes. These include, but are not limited to, MFN2, GARS, and MPZ. Different gene mutations can result in similar phenotypes but may involve distinct pathways in axonal maintenance and function.

2. **Mitochondrial Dysfunction:** Mutations in the MFN2 gene, which codes for mitofusin 2, play a crucial role in mitochondrial fusion and distribution. Abnormal mitochondrial function disrupts the energy supply needed for axonal maintenance and repair, leading to axonal degeneration.

3. **Defective Protein Synthesis and Transport:** Mutations in genes like GARS (coding for glycyl-tRNA synthetase) disrupt protein synthesis. Impaired proteins can affect axonal transport, which is crucial for maintaining axonal health and function.

4. **Axonal Transport Defects:** The efficient transport of organelles and proteins along axons is essential for neuronal function. Mutations in various genes associated with CMT2 can lead to defects in axonal transport mechanisms, contributing to axonal degeneration.

5. **Cellular Stress and Apoptosis:** Some mutations may lead to increased cellular stress and trigger pathways leading to apoptosis (programmed cell death) of neurons, contributing to the progressive degeneration seen in CMT2.

Understanding these molecular mechanisms is critical for developing potential therapeutic strategies aimed at mitigating the effects of these genetic mutations and improving the quality of life for individuals affected by CMT2.
Treatment: Treatment for Charcot-Marie-Tooth Disease Type 2 (CMT2) focuses on managing symptoms and improving quality of life, as there is no cure. Key aspects of treatment include:

1. **Physical Therapy:** Tailored exercise programs can help maintain muscle strength and flexibility.
2. **Occupational Therapy:** Can assist with daily activities and recommend adaptive devices.
3. **Orthotic Devices:** Braces or custom-made shoes can help with foot drop and improve walking.
4. **Pain Management:** Medications and other therapies can be used for neuropathic pain management.
5. **Surgical Intervention:** In some cases, surgery may be necessary to correct foot deformities.
Compassionate Use Treatment: Charcot-Marie-Tooth disease type 2 (CMT2) is currently an incurable genetic disorder. However, there are ongoing research efforts and experimental treatments aiming to address its symptoms. Compassionate use, off-label, or experimental treatments may include:

1. **Gene Therapy**: Researchers are exploring gene therapy techniques to correct the underlying genetic defects causing CMT2.
2. **Neurotrophic Factors**: These are proteins that support the growth and survival of neurons and are being studied for their potential to slow disease progression.
3. **Repurposing Drugs**: Some existing medications intended for other conditions are being investigated for their potential benefits in CMT2. This includes drugs that might improve nerve function or protect against nerve damage.
4. **Small Molecule Drugs**: Experimental drugs that can modulate specific pathways involved in the disease's pathology are under investigation.
5. **Stem Cell Therapy**: Although still in experimental phases, stem cell therapy is being researched for its potential to regenerate damaged nerves.

It's important for patients to consult with their healthcare providers regarding participation in clinical trials or the use of off-label treatments to ensure safety and suitability for their specific case.
Lifestyle Recommendations: For Charcot-Marie-Tooth Disease Type 2 (CMT2), here are some lifestyle recommendations:

1. **Exercise Regularly**: Engage in low-impact exercises like swimming, cycling, or walking to maintain muscle strength and flexibility without causing undue stress on your joints.

2. **Physical Therapy**: Work with a physical therapist to develop a personalized exercise plan. This can help with muscle strength, coordination, and flexibility.

3. **Occupational Therapy**: An occupational therapist can assist in making daily activities easier and suggest adaptive devices if needed.

4. **Maintain a Healthy Weight**: Managing weight can reduce stress on the feet and ankles.

5. **Foot Care**: Regularly check your feet for any injuries or sores, as reduced sensation can make you unaware of these issues. Use orthotic devices or custom shoes as recommended by your healthcare provider.

6. **Avoid Alcohol and Tobacco**: These can potentially exacerbate nerve damage or interfere with your overall health.

7. **Balanced Diet**: Eat a balanced diet rich in vitamins and nutrients to support overall health and possibly improve nerve function.

8. **Ergonomic Adjustments**: Make ergonomic adjustments in your home and workplace to reduce strain during activities.

9. **Regular Medical Check-Ups**: Regular visits to your healthcare provider can help monitor the progression of the disease and adjust care plans as needed.
Medication: There is no specific medication to cure Charcot-Marie-Tooth disease type 2 (CMT2); however, treatments focus on managing symptoms and improving quality of life. These can include:

1. **Pain Management:** Over-the-counter pain relievers like acetaminophen or ibuprofen, and in some cases, prescription medications.
2. **Physical Therapy:** To maintain muscle strength and flexibility.
3. **Occupational Therapy:** To assist with daily activities and to recommend adaptive devices.
4. **Orthopedic Devices:** Braces, orthopedic shoes, or other aids to assist with mobility.
5. **Surgical Interventions:** In some cases, surgery may be necessary to correct foot deformities or other orthopedic issues.

Regular follow-ups with a healthcare provider familiar with CMT2 are important for managing the condition effectively.
Repurposable Drugs: Repurposable drugs for Charcot-Marie-Tooth Disease Type 2 (CMT2) include certain previously approved medications that have shown potential benefits in managing symptoms or slowing disease progression. Although there's no cure for CMT2, some drugs under investigation for repurposing include:

1. **Metformin**: Originally used for type 2 diabetes, it has shown potential in animal models to improve mitochondrial function and peripheral neuropathy.
2. **N-acetylcysteine (NAC)**: An antioxidant that helps in reducing oxidative stress, which is thought to play a role in peripheral nerve damage.
3. **Pioglitazone**: Used for diabetes, it may enhance mitochondrial function and has shown potential in neuromuscular diseases.
4. **Acetyl-L-carnitine**: A dietary supplement that may support mitochondrial function and has been suggested to help with nerve regeneration and pain.
5. **Gabapentin and Pregabalin**: Although primarily for neuropathic pain management, they can offer symptomatic relief.

These drugs hold promise, but more research and clinical trials are needed to establish their efficacy and safety for CMT2 specifically. Always consult with health professionals before considering these options.
Metabolites: Charcot-Marie-Tooth disease type 2 (CMT2) is a subtype of Charcot-Marie-Tooth disease characterized by axonal neuropathy. While there is extensive research on the genetic mutations and neuropathological features of CMT2, specific metabolites consistently altered in CMT2 are not well-defined in the literature. Metabolomic studies may potentially reveal biomarkers in the future, but currently, no standardized set of metabolites is associated with this condition.
Nutraceuticals: There is limited evidence to suggest that nutraceuticals have a significant impact on Charcot-Marie-Tooth Disease Type 2 (CMT2). CMT2 is a hereditary neuropathy characterized by axonal degeneration. While some patients might use supplements such as alpha-lipoic acid, omega-3 fatty acids, or vitamin B12, the efficacy of these nutraceuticals specifically for CMT2 is not well-established through rigorous clinical trials. It is always recommended to consult with a healthcare provider before starting any supplement regimen.
Peptides: Charcot-Marie-Tooth Disease Type 2 (CMT2) primarily involves mutations in genes that affect the axons of peripheral nerves. These mutations result in axonal degeneration and subsequent muscle weakness and atrophy, as well as sensory loss. Peptides, which are short chains of amino acids, have not been standardly utilized in the treatment of CMT2. Research is ongoing to understand more about potential therapeutic strategies, but as of now, peptides are not a recognized treatment for this condition.