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Charcot-marie-tooth Disease Type 2d

Disease Details

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Description: Charcot-Marie-Tooth disease type 2D (CMT2D) is a genetic disorder characterized by progressive weakness and atrophy of the muscles in the feet, legs, hands, and forearms due to peripheral nerve dysfunction.
Type: Charcot-Marie-Tooth disease type 2D is primarily inherited in an autosomal dominant manner.
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 2D (CMT2D) typically presents onset in late childhood to early adulthood.
Prevalence: The prevalence of Charcot-Marie-Tooth disease type 2D (CMT2D) is not well-defined, but Charcot-Marie-Tooth disease as a whole affects approximately 1 in 2,500 people globally. Specific prevalence data for the CMT2D subtype may vary and is less commonly documented.
Epidemiology: Charcot-Marie-Tooth disease type 2D (CMT2D) is a rare inherited neuropathy. Its exact prevalence is not well-defined but CMT as a whole affects approximately 1 in 2,500 people. CMT2D specifically is a subtype of CMT2, which is less common than CMT1. The condition is caused by mutations in the GARS1 gene.
Intractability: Charcot-Marie-Tooth disease type 2D (CMT2D) is considered intractable in that there is currently no cure. Management focuses on symptomatic treatment, such as physical therapy, orthopedic devices, and pain management. Research is ongoing to find more effective treatments and potential cures.
Disease Severity: Charcot-Marie-Tooth disease type 2D (CMT2D) is a subtype of Charcot-Marie-Tooth disease, a group of inherited neuropathies. CMT2D specifically affects the axons of peripheral nerves. The severity can vary among individuals, but it generally manifests with muscle weakness and atrophy, primarily in the hands, lower legs, and feet, along with sensory loss. The progression is usually gradual, and while it can lead to significant disability, it is not typically life-threatening.
Healthcare Professionals: Disease Ontology ID - DOID:0110164
Pathophysiology: Charcot-Marie-Tooth Disease Type 2D (CMT2D) is a subtype of Charcot-Marie-Tooth disease, a hereditary motor and sensory neuropathy. The pathophysiology of CMT2D primarily involves mutations in the GARS1 gene, which encodes the enzyme glycyl-tRNA synthetase (GARS). This enzyme is vital for protein synthesis, as it attaches glycine to its corresponding tRNA.

Mutations in GARS1 lead to a dysfunctional enzyme that impairs protein synthesis, particularly affecting peripheral neurons. The exact mechanism is not fully understood, but it is hypothesized that the enzyme dysfunction disrupts the maintenance and function of axons, leading to the characteristic demyelination and axonal degeneration seen in the disease. This results in muscle weakness, atrophy, and sensory loss that primarily affects the distal limbs.
Carrier Status: Charcot-Marie-Tooth Disease Type 2D (CMT2D) is an inherited neurological disorder. Carrier status typically refers to an individual who has one copy of a mutated gene but does not exhibit disease symptoms. In the case of CMT2D, it is inherited in an autosomal dominant manner, meaning that only one copy of the mutated gene, usually in the GARS gene, is sufficient to cause the disease. Therefore, the concept of being a "carrier" without symptoms is not applicable in the same way it is for autosomal recessive conditions. People with a single copy of the mutated gene will typically exhibit symptoms of CMT2D.
Mechanism: Charcot-Marie-Tooth disease type 2D (CMT2D) is a hereditary neuropathy. The mechanism involves mutations in the GARS1 gene, which encodes glycyl-tRNA synthetase (GlyRS). This enzyme is essential for protein synthesis as it attaches the amino acid glycine to its corresponding tRNA.

Mutations in GARS1 lead to a gain-of-function effect, causing the mutant GlyRS to abnormally interact with other cellular components. This dysfunction leads to impaired axonal transport and neurodegeneration, particularly affecting peripheral motor and sensory nerves. The erroneous interactions disrupt neuronal function and survival, resulting in the progressive muscle weakness and sensory deficits characteristic of CMT2D.
Treatment: Charcot-Marie-Tooth disease type 2D (CMT2D) primarily involves supportive treatments aimed at managing symptoms and improving quality of life. These may include:

1. **Physical Therapy:** Helps maintain muscle strength and flexibility.
2. **Occupational Therapy:** Assists with daily activities and adapting to physical limitations.
3. **Orthopedic Devices:** Such as braces or orthotic devices to support and stabilize the feet and ankles, improving mobility.
4. **Pain Management:** Medications or therapies to manage pain associated with nerve damage.
5. **Surgical Interventions:** In some cases, surgery may be required to correct severe foot deformities or other orthopedic issues.

Currently, there is no cure for CMT2D, and treatment focuses on symptom management and maintaining patient mobility and independence.
Compassionate Use Treatment: Charcot-Marie-Tooth disease type 2D (CMT2D) is a hereditary motor and sensory neuropathy primarily affecting peripheral nerves. In terms of compassionate use and off-label or experimental treatments for CMT2D:

1. **Compassionate Use Treatment**:
- Compassionate use programs allow patients with serious or life-threatening conditions access to investigational drugs outside clinical trials.
- Specific programs may vary, but patients must usually meet certain criteria, and the treating physician must justify the need for experimental intervention.
- Contacting the manufacturer or relevant regulatory body (e.g., FDA in the United States) may provide access to specific investigational therapies for CMT2D.

2. **Off-Label Treatments**:
- These involve using approved medications for conditions other than their primary indication.
- For CMT2D, off-label treatments might include drugs aimed at alleviating symptoms or improving nerve function.
- Examples could include gabapentin or pregabalin for neuropathic pain, though these don't address the underlying genetic cause.

3. **Experimental Treatments**:
- Gene therapy and other advanced molecular techniques are being researched for CMT and other genetic disorders.
- Small molecule drugs, gene editing (like CRISPR), and antisense oligonucleotides are promising areas of study.
- Clinical trials are a primary means by which these treatments are tested. Patients might consider enrolling in clinical trials specifically targeting CMT2D.

It's crucial for patients to discuss any treatment options thoroughly with their healthcare provider to understand potential risks and benefits.
Lifestyle Recommendations: Lifestyle recommendations for Charcot-Marie-Tooth disease type 2D (CMT2D) include:

1. **Physical Therapy**: Engaging in regular physical therapy to maintain muscle strength, flexibility, and mobility. A physical therapist can tailor exercises to individual needs.

2. **Occupational Therapy**: Consulting an occupational therapist to learn adaptive techniques for daily activities and to use assistive devices effectively.

3. **Low-Impact Exercise**: Participating in low-impact exercises like swimming, cycling, or yoga to enhance cardiovascular health and muscle strength without excessive strain.

4. **Healthy Diet**: Maintaining a balanced diet to support overall health and prevent obesity, which can place additional stress on weakened muscles.

5. **Foot Care**: Paying special attention to foot care, wearing well-fitting shoes and custom orthotics to prevent injuries and alleviate foot deformities.

6. **Regular Check-Ups**: Keeping regular medical appointments to monitor the progression of the disease and adjust treatments as necessary.

7. **Avoiding Alcohol and Smoking**: Reducing or eliminating alcohol and avoiding smoking to improve overall health and prevent exacerbating symptoms.

8. **Energy Conservation**: Learning energy conservation techniques to manage fatigue, which is common in individuals with CMT.

These recommendations aim to improve quality of life and manage the symptoms associated with CMT2D.
Medication: Currently, there are no specific medications approved to treat Charcot-Marie-Tooth disease type 2D (CMT2D). Management mainly focuses on supportive treatments such as physical therapy, occupational therapy, orthopedic devices, and pain management to maintain mobility and improve quality of life. It's essential for patients to work closely with a healthcare team specializing in neuromuscular disorders to develop a personalized care plan.
Repurposable Drugs: Charcot-Marie-Tooth Disease Type 2D (CMT2D) is a peripheral neuropathy primarily caused by mutations in the GARS gene. Potentially repurposable drugs that have shown promise in research settings include:

1. **N-Acetylcysteine (NAC)**: An antioxidant that may help reduce oxidative stress in neuronal cells.
2. **P38 MAPK Inhibitors**: These inhibitors could potentially reduce inflammation and neuronal damage.

Other compounds being investigated include neurotrophic factors and agents targeting mitochondrial function. However, clinical validation and regulatory approval are essential before these can be considered standard treatment options.
Metabolites: Charcot-Marie-Tooth disease type 2D (CMT2D) is linked to mutations in the GARS1 gene that encodes glycyl-tRNA synthetase. As a neuropathy, it does not have specific metabolites used for diagnosis or monitoring. Instead, diagnosis typically relies on genetic testing, clinical evaluation, electromyography (EMG), and nerve conduction studies. Metabolite profiling is not a standard diagnostic tool for CMT2D.
Nutraceuticals: Charcot-Marie-Tooth Disease Type 2D (CMT2D) is a hereditary motor and sensory neuropathy caused by mutations in the GARS1 gene. However, no specific nutraceuticals have been definitively proven to treat or manage CMT2D effectively. The management primarily focuses on physical therapy, occupational therapy, and orthopedic interventions to manage symptoms and maintain quality of life. Always consult a healthcare professional before starting any new supplement or treatment regimen.
Peptides: Charcot-Marie-Tooth disease type 2D (CMT2D) involves mutations in the GARS1 gene, which encodes the enzyme glycyl-tRNA synthetase. The role of peptides in CMT2D research could involve developing therapeutic peptides to modulate the activity of this enzyme or ameliorate disease symptoms. However, as of now, peptide-based treatments for CMT2D are not established. Nanotechnology approaches (referred to as "nan") are being explored more broadly in neurological diseases for targeted drug delivery, but their specific application to CMT2D is still in the experimental stages.