Neuromuscular Disorders 101: The Genetics Behind Charcot-Marie-Tooth Disease

Foreword

Neuromuscular disorders cause major changes in an individual's daily function and independence. Its broad term encompasses a large variety of diseases with different presentations. As healthcare evolves, so does clinical research updating disease diagnostic criteria and treatment options for neuromuscular disorders. This series will discuss neuromuscular disorders from a health science point of view concerning the etiology, pathophysiology, and treatment of neuromuscular disorders. The series will also discuss in depth the types of disorders and their etiology, diagnosis criteria, and medical rehabilitation management.

The series is divided into the following eight chapters:

1. Neuromuscular Disorders 101: Living with Peripheral Neuropathy

2. Neuromuscular Disorders 101: The Progression of Muscular Dystrophy

3. Neuromuscular Disorders 101: The Effects of Amyotrophic Lateral Sclerosis

4. Neuromuscular Disorders 101: The Break Down of Polymyositis

5. Neuromuscular Disorders 101: The Genetics Behind Charcot-Marie-Tooth Disease

6. Neuromuscular Disorders 101: The Dysfunction of Multiple Sclerosis

7. Neuromuscular Disorders 101: In the Face of Myasthenia Gravis

8. Neuromuscular Disorders 101: Infection to Impairment: Guillain-Barre Syndrome

Neuromuscular Disorders 101: The Genetics Behind Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth (CMT) disease is an inherited genetic disorder which causes abnormalities in motor and sensory nerves that supply the feet, legs, hands, and arms (“Charcot-Marie-Tooth Disease”, n.d.). Motor nerves carry signals from the brain to the muscles to initiate and control movement whereas sensory nerves carry sensory information (heat, cold, and/or pain) to the brain (“Charcot-Marie-Tooth Disease”, n.d.). These nerve abnormalities caused by CMT inhibit motor and sensory nerves’ ability to properly send signals to the body and brain, causing loss of nerve function in movement and sensation. CMT typically first appears in teenagers and young adults, with symptoms commonly starting in the feet and legs. Although symptoms vary depending on the individual, common symptoms include muscle weakness, numbness/tingling, and foot deformity. Studies have shown that the prevalence of all CMT cases is 15.7 per 100,000 cases, with a higher prevalence in men (16.6 per 100,000) than females (14.6 per 100,000) (Theadom et al., 2019). Despite the lack of a cure for CMT, the disease is not considered fatal and many individuals are able to remain active with treatment focused on rehabilitation therapy to maintain function and regain strength lost from the disease (“Charcot-Marie-Tooth Disease”, n.d.). In this article we will further discuss the pathophysiology, diagnostics, and medical management for CMT.

Genes are considered the basic unit of physical and functional inheritance (“Genes”, 2023). Genes are passed down to children by their parents which contain information to define a child’s physical and biological traits. Neurons, also referred to as nerve cells, serve as communication lines, receiving and sending messages to and from the body and brain (“What is a neuron?”, n.d.). Neurons are made of three distinct components: Cell body, axon, and the myelin sheath. The CMT Research Foundation (n.d.) describes the function and role of each component:

1. Cell Body: holds the nucleus which contains the majority of a cell’s DNA.

2. Axon: a tube-like structure which is a continuation of the cell body and carries electrical signals to other cells.

3. Myelin Sheath: forms a coating (sheath) around the axon, which makes the electrical signal travel faster.

Figure 1. Parts of a neuron, or nerve cell (“What is CMT?, n.d.)

Disease Pathophysiology

There are several types of CMT, however this article will be focusing on the most common type of CMT, CMT1A (Morena et al., 2019). CMT1A is caused by autosomal dominant inheritance, where a faulty gene is located on a parent’s chromosome (a structure that contains genes) and a single copy of the mutated gene passed down to a child is sufficient enough to cause the disease (“Autosomal Dominant Disorder”, 2023). In autosomal dominant inheritance, a child of a parent that is affected by CMT has a 50% chance of being affected by the condition. Specifically, CMT1A is caused by a duplication of the PMP22 gene, which is responsible for making a protein, peripheral myelin protein 22 (Morena et al., 2019; “PMP22 gene”, n.d.). The PMP22 protein is a part of the myelin sheath of a neuron and is important in protecting nerves from pressure and aids in restoring nerve structure after being compressed (“PMP22 gene”, n.d.). This overexpression in the PMP22 gene by duplication results in demyelination of the nerve cells, or damage to the myelin sheath. This damage in the myelin sheath causes disruption in sending motor and sensory nerve information to and from the body and brain (Morena et al., 2019).

Signs and Symptoms of CMT

CMT is typically caused by genetic mutations that affect the function and structure of peripheral nerves which causes serious affect to the nerves in the arms and legs, causing muscle weakness, muscle atrophy (loss of muscle), and sensory loss (“Charcot-Marie-Tooth Disease”, n.d.). The disease typically presents as foot drop (unable to pick up one’s foot during walking), difficulty walking, and frequent tripping or falling. Individuals with CMT may also experience muscle cramps, numbness or tingling in the hands and feet, and reduced ability to feel temperature and pain sensations. In advanced stages (Nagappa et al., 2022). CMT can cause deformities of the feet, hands, and spine, as well as respiratory and swallowing difficulties. Risk factors for developing CMT include a family history of the disease, certain genetic mutations, and some environmental factors such as exposure to toxins. Having a family history of CMT is a significant risk factor for developing the disease. Genetic mutations that affect the production of proteins involved in nerve function, such as PMP22, are also associated with an increased risk of CMT (“Charcot-Marie-Tooth Disease”, 2023). Some environmental factors, such as exposure to toxins or viral infections, may also contribute to the development of CMT in some cases. Additionally, certain lifestyle factors, such as obesity and lack of physical activity, may exacerbate the symptoms of CMT.

Figure 2. Foot deformity in CMT (“Charcot-Marie-Tooth disorder”, n.d.)

Diagnosis of CMT

The diagnosis of CMT involves a combination of clinical evaluation, genetic testing, nerve conduction studies, and electromyography (EMG) (“Charcot-Marie-Tooth Disease”, n.d.; Nagappa et al., 2022). During the clinical evaluation, a health provider will review the patient's medical history, perform a physical examination, and assess their symptoms, such as muscle weakness, atrophy, and sensory loss. A health provider may also ask about the patient's family history of neurological disorders. Genetic testing is often used to confirm a diagnosis of CMT, especially in cases with a family history of the disease (“Diagnosing CMT”, n.d.). The tests can identify mutations in genes associated with CMT, such as PMP22. Nerve conduction studies and EMG are also used to assess the function of the patient's peripheral nerves and muscles. Nerve conduction studies measure the speed and strength of electrical impulses as they travel along the nerves, while EMG assesses the electrical activity of muscles (Nagappa et al., 2022). These tests can help to differentiate CMT from other neuromuscular disorders and can also provide information about the severity of the disease. Additional tests, such as imaging studies and sensory testing, may be performed to further evaluate the extent and location of nerve damage in some cases. The combination of these diagnostic tools can help to confirm a diagnosis of CMT and provide information about the type and severity of the disease, which is important for developing an appropriate treatment plan.

Medical Management of CMT

Treatment of CMT is mostly rehabilitation focused and focused on one’s symptoms as there is not a definite disease-modifying treatment effective for the disease. (“Charcot-Marie-Tooth Disease'', n.d.; Nagappa et al., 2022). Medical management options for CMT typically include physical therapy, orthopedic devices, pain management, and surgery. Physical therapy is a cornerstone of treatment and aims to improve strength, flexibility, and balance to maintain mobility and prevent falls. Orthopedic devices, such as braces, splints, and orthotics, can provide support and stability to the affected limbs and prevent deformities (Nagappa et al., 2022). Pain management may involve over-the-counter or prescription medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), depending on the severity of the pain. Surgery may be recommended in some cases to correct deformities or address nerve compression (“Charcot-Marie-Tooth disease, 2022). Conservative management options for CMT include lifestyle modifications, such as regular low-impact exercise, a healthy diet, and avoiding harmful substances such as alcohol and tobacco, which can exacerbate symptoms (“Charcot-Marie-Tooth Disease”, n.d.). Assistive devices such as canes, crutches, or walkers can also help with mobility and reduce the risk of falls. Overall, the management of CMT requires a multidisciplinary approach, with various healthcare professionals working together to provide individualized care for each patient. The goal of treatment is to maximize function and quality of life, reduce pain and disability, and prevent complications associated with the disease.

Figure 3. Genetic pattern of CMT1A (“Charcot Marie Tooth” , n.d.)

CMT Case Study

A case report by Albuquerque et al. (2023) describes the patient case of a 52-year-old male who was diagnosed with CMT1A after experiencing several years of symptoms. The patient initially presented with weakness and numbness in the feet and legs, which gradually progressed over time. The patient also experienced difficulty with balance and coordination. Upon examination, the patient exhibited foot deformities consistent with a CMT1A diagnosis, such as high arches, hammertoes, and muscle wasting in the lower legs. To confirm the diagnosis, the patient underwent various tests, including nerve conduction studies, electromyography, and genetic testing. The nerve conduction studies showed a significant reduction in the conduction velocities of the motor and sensory nerves in the patient's legs, which is a hallmark sign of CMT1A. The electromyography revealed signs of chronic denervation in the lower leg muscles, further supporting the CMT1A diagnosis. Lastly, genetic testing confirmed the presence of a mutation in the patient's PMP22 gene, which is associated with CMT1A. The patient was able to receive physical therapy and adaptive equipment to aid in mobility. Overall, the combination of clinical presentation, physical examination findings, and diagnostic tests led to a confirmed diagnosis of CMT1A in the patient The report highlights the importance of early diagnosis and genetic testing in CMT1A patients to prevent progression of the disease and improve quality of life. This report also emphasizes the need for increased awareness and education about CMT, as well as the importance of timely diagnosis and management.

Conclusion

In conclusion, Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies that affect the nerves in the arms and legs, causing muscle weakness, wasting, and sensory loss ((“Charcot-Marie-Tooth Disease'', n.d.; Nagappa et al., 2022). CMT is typically caused by genetic mutations that affect the function and structure of peripheral nerves, with risk factors including a family history of the disease, certain genetic mutations, and some environmental factors. The diagnosis of CMT involves a combination of clinical evaluation, genetic testing, nerve conduction studies, and electromyography (Nagappa et al., 2022). While there is currently no cure for CMT, treatment options are focused on managing the symptoms and improving the patient's quality of life through medical and conservative management options. A multidisciplinary approach involving various healthcare professionals is essential for providing individualized care to each patient, with the goal of maximizing function and quality of life, reducing pain and disability, and preventing complications associated with the disease.

Bibliographical References

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Visual Sources