What is Charcot-Marie-Tooth Disease?
Charcot-Marie-Tooth (CMT) disease, also known as “progressive muscular atrophy,” is a collection of disorders that you inherit and affects your motor and sensory nerves. These nerves help control your muscles and let you feel things you touch or that touch you. The disease is named after the three doctors who first identified it back in 1886. There’s a lot of variation in how CMT affects different people, what causes it, and how it’s diagnosed.
Originally, doctors classified CMT into two types depending on whether it damaged the protective covering of your nerves (CMT type 1) or the actual nerves themselves (CMT type 2). However, as we’ve gotten better at understanding our genes with newer technologies, we’ve updated the way we classify and diagnose CMT.
CMT is a disorder that typically gets worse over time. It often causes changes to the shape of your feet, a loss of sensation, weakness in the legs, and reduced or missing reflexes. Most people with CMT start showing symptoms during their childhood but may not notice them until they are teenagers or even adults. The weakness tends to start in the legs and then later affects the arms. It’s also worth noting that CMT symptoms can sometimes look like other diseases that cause nerves to deteriorate over time.
What Causes Charcot-Marie-Tooth Disease?
Charcot-Marie-Tooth disease (CMT) and related conditions are decided by our genes, with more than 100 different genes involved. Roughly 80% to 90% of these gene abnormalities are because of changes, or copy number variations (CNVs), in genes like protein 22 (PMP22), GJB1, MPZ, and MFN2. CNVs are a type of genetic variation where the number of copies of a gene differ between people. However, only some families experience these gene mutations, so about 18% to 50% of cases can’t be fully explained yet. This could potentially be because of mutations in DNA sections that don’t code for any protein (“noncoding DNA”) or structural rearrangements in our genome.
Autosomal dominant CMT is the most frequently occurring, followed by X-linked CMT. Autosomal recessive forms of CMT are pretty rare.
About 90% of gene mutations in those with CMT type 1 are due to three main gene defects — duplication of PMP22, point mutations (a specific change in DNA) in GJB1 and MPZ genes. This causes damage to certain nerve cells known as Schwann cells and the protective coating of nerve cells called the myelin sheath. The most common form of CMT, CMT type 1A, is caused by a duplication on chromosome 17p11.2, leading to too much PMP22. This area is quite large, so it often undergoes genomic rearrangements. Changing the amount by either increasing or decreasing PMP22 can lead to CMT due to the responsiveness of nerve tissue to any adjustment in copies of PMP22.
Duplication in one copy of PMP22 causes it to be overexpressed by 1.5 times in Schwann cells, while a duplication in both copies leads to twice as much. This duplication occurs when swopping parts of the genes result in an unequal distribution and is often seen in the paternal line. This overexpression in the lab can overload the cell’s cleaning process, and cause the faulty PMP22 to clump up in cells, activating multiple cellular pathways.
Other mutations in genes like MPZ can lead to the production of flawed proteins that accumulate in nerve cells and trigger a chain of events leading to the death of that cell. Other variations of CMT due to reduced function from different gene mutations or unusually increased function due to toxicity are less common.
Risk Factors and Frequency for Charcot-Marie-Tooth Disease
CMT, or Charcot-Marie-Tooth disease, is a complex nerve disorder that can affect anyone, regardless of their ethnicity. About 1 in 2500 people has this disease. It is more commonly seen in people who visit adult neuropathy clinics than those with inflammatory or paraneoplastic neuropathies. Although it’s difficult to pinpoint the exact number of CMT cases because symptoms and presentations can vary widely, it is estimated to affect between 9.7 out of every 100,000 people in Serbia and 82.3 out of every 100,000 people in Norway.
Past surveys have reported different frequencies of CMT, with reported ranges from 8 per 100,000 in Libya to 28 per 100,000 in northern Spain. The types of CMT, demyelinating (CMT1) and axonal (CMT2), differ in frequency. CMT1 is more frequent, with a range between 37.5% to 84%. CMT2 is less frequent, with a range of 12% to 35.9%. But CMT2 focused studies are less common, which makes finding the affected individuals and families a little more difficult.
Signs and Symptoms of Charcot-Marie-Tooth Disease
The condition in discussion is Charcot-Marie-Tooth disease (CMT), an inherited disorder that affects nerves. Typical signs and symptoms include slow-progressing and varying degrees of difficulty with walking or running, frequent tripping and falls, clumsiness, sprained ankles, and muscle cramps. In young patients, there may be late achievement of motor skills, such as learning to walk.
This condition’s onset can be tricky to pinpoint, as it tends to start subtly and progress over a long period. Some observed characteristics in patients include foot deformities, delayed motor skills development, difficulty walking, and reduced sensation. Additional issues may arise if the patient has other conditions, such as hypothyroidism, diabetes, obesity, or exposure to toxins. More severe symptoms tend to be seen with early onset, particularly in infants.
- Pain
- Weakness
- Loss of sensation
- Foot deformities
- Delays in achieving motor skills
- Experiencing difficulty with walking or running
The appearance of CMT can differ even between family members sharing the exact genetic abnormalities. Therefore, it’s crucial to ask about any signs of neuropathy in the family’s medical history. This variability also leads to differing severity levels of CMT, ranging from minimally symptomatic to severe.
Physical assessment is critical in diagnosing the condition. Typical signs across all variations of CMT include weakness in the feet and legs, shrinking weak muscles, loss or reduction of tendon reflexes, and skeletal deformities. As the disease advances, patients might develop a high-stepping gait due to foot drop. Upper limb onset with proximal muscle weakness is rare.
Among the uncommon features, patients with specific genetic variations may exhibit abnormal pupil function, and eye conditions like ptosis, early cataracts, and age-related macular degeneration have been reported in some cases. Additionally, telltale signs of dysautonomia like urinary urgency, low blood pressure upon standing, and excessive sweating could be present.
By paying attention to these detailed signs and symptoms, doctors can better diagnose and treat this slow-progressing neuropathic condition.
Testing for Charcot-Marie-Tooth Disease
The way doctors evaluate Charcot-Marie-Tooth disease (CMT) has become more advanced with modern tests. However, these tests are not always available everywhere and might be expensive. In the past, the diagnosis was based only on the patient’s symptoms. Now, doctors diagnose CMT using a combination of your symptoms, some special tests that check how your nerves are working, and genetic testing. Most experts recommend taking a step-by-step approach when testing for CMT, starting with nerve conduction studies, which are tests that measure the speed of the electrical activity in your nerves.
Electromyography (EMG) and nerve conduction velocity (NCV) tests are important for confirming the diagnosis of a nerve disease and differentiating between types of CMT. These tests are minimally invasive, provide quick results, and help rule out other causes of nerve disease. They also help to check family members of patients who might not have symptoms yet.
These tests measure the following key parameters: how long it takes for the nerves to respond, the strength of these responses, and the speed of nerve transmission. Slower nerve transmission speed can represent potential problems with the protective sheath around the nerve fibers (myelin). Reduced strength of the muscle response with normal nerve transmission speed could indicate damage to the nerve fibers (axon). In some cases, both types of neuropathies may exist.
Genetic testing is the gold standard that can give a definite diagnosis. Genetic testing is also important in providing medical counseling, helping with reproductive planning, and choosing the right patients for clinical trials and research. If a patient is suspected of having CMT, they should have a detailed examination of their symptoms, a thorough investigation of their family medical history, and proper counseling before genetic testing.
If there is a family history of CMT with a known genetic variant, that variant is usually assessed first. If it’s negative and genetic testing is available and affordable, a larger genetic test for CMT should be done. If that’s not affordable, a step-by-step genetic test based on the nerve conduction studies can be done next.
Advanced imaging, like nerve ultrasound and magnetic resonance neurography, are increasingly used to evaluate nerve diseases. In CMT, there is usually a broad enlargement of nerves, including roots, nerve networks, and peripheral nerves. The enlargement is usually more significant in the upper limbs and in CMT1A compared to other forms of CMT.
In children and adolescents with CMT, a type of advanced imaging called Magnetic Resonance Imaging (MRI) can be used to assess the relationship between muscle volume and the amount of fat inside the muscles in the lower legs, and how this relates to walking difficulties, weakness and disability.
Patients with CMT should also be evaluated for other illnesses that could affect peripheral nerve function such as diabetes, thyroid dysfunction and nutritional deficiencies. They may also need eye examination for cataracts or glaucoma, laryngoscopy for vocal cord mobility, and hearing tests. In addition, tests for lung function and sleep disorders may be needed. If the CMT is related to a mutation in the INF2 gene, urinary tests might be necessary to check for kidney problems since in these patients the kidney function can deteriorate quickly and requiring a kidney transplant.
Treatment Options for Charcot-Marie-Tooth Disease
The treatment for Charcot-Marie-Tooth disease (CMT), a group of inherited disorders that cause nerve damage, focuses primarily on symptom management and rehabilitation, since there aren’t currently any treatments that can slow or stop the progression of the disease. The healthcare team for managing CMT typically includes neurologists, physiatrists (doctors specializing in physical medicine and rehabilitation), orthopedic surgeons, podiatrists (foot and ankle specialists), and physical and occupational therapists.
Pharmaceutical treatments may provide some relief from CMT symptoms. Simple pain relievers or anti-inflammatory drugs may help with joint and muscle pain, and specific medications like antidepressants and gabapentin can alleviate neuropathic pain – a complex, chronic pain state usually caused by nerve damage. For fatigue, a medication called modafinil can help. However, most current drug treatments rest on our understanding of CMT’s genetic and physiological basis.
Although some medications have shown potential for targeting the problems caused by the specific genetic mutations in CMT, success in human trials has been limited. For instance, PXT3003 – a combination of three drugs – has shown potential for reducing the harmful effects of one specific genetic issue in CMT but has not yet led to improvement in human studies. Curcumin, a substance found in turmeric, has also shown potential in laboratory studies.
Despite these developments, the cornerstone of CMT treatment remains rehabilitation. This largely involves physical therapy exercises designed to maintain and improve muscle strength, keep joints flexible, relieve fatigue and pain, correct walking and balance problems, and prevent stiffness or deformities. But the care plan for each individual will depend on their specific symptoms. In some cases, they may require special shoes and assistive devices, like canes or braces, to walk. Occupational therapy can also provide help with everyday tasks and activities. Debate continues over the concept of “overuse weakness,” the idea that excessive exercise might worsen muscle loss and weakness in CMT patients.
Other treatment measures vary depending on the individual’s symptoms. Fatigue, depression, pain, and restless leg syndrome are managed similarly to other nerve disorders. Some may need surgery or other treatments for foot deformities, scoliosis (a sideways curvature of the spine), and hip dysplasia (a hip joint that doesn’t fit together correctly). Problems with the lungs, sleep, and voice may also need specific interventions.
In children with CMT, health experts recommend various exercises – like resistance exercises, joint stretching, and balance training – to improve muscle strength and slow down the progression of weakness. If necessary, they may need a referral to a specialist for treatment of foot and ankle issues, hip dysplasia, and scoliosis. They may also need specially adapted equipment to help with their daily activities. Any respiratory issues should be addressed, and if a child has recurrent lung infections or has difficulty sleeping, referral to a lung or sleep specialist is advised.
What else can Charcot-Marie-Tooth Disease be?
Charcot-Marie-Tooth disease (CMT) symptoms like muscle weakness, wastage, foot deformities, and progressive weakness are similar to several other conditions. For an accurate diagnosis, it’s important to tell it apart from these diseases. This may include differentiating it from conditions like dysimmune neuropathies that were acquired later in life.
One key condition to rule out when diagnosing CMT is Infantile Spinal Muscular Atrophy with Respiratory Distress type 1 (SMARD1) due to mutations in the IGHMBP2 gene. While this condition also results in very low motor nerve conduction velocities, unlike CMT, patients with SMARD1 have normal sensory nerve action potentials.
Other conditions like Distal myopathies could also present with foot drop – a common symptom in CMT. However, doctors can tell them apart from CMT using a pattern of weakness and electrophysiological studies. In children, telling apart CMT from Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) might be particularly challenging. Genetic tests, as well as clinical and electrophysiological examinations of asymptomatic family members, and nerve biopsies could be useful in arriving at an accurate diagnosis.
Other potential diagnoses to consider are:
- Neuropathies acquired due to diabetes
- Nutritional deficiencies
- Vasculitis
- Heavy metal poisoning
There are also inherited conditions where CMT-like symptoms are part of a multisystem disorder. These include:
- Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
- Friedreich’s ataxia
- Metachromatic leukodystrophy
- Syndrome of neurogenic weakness, ataxia, and retinitis pigmentosa (NARP)
- Refsum’s disease
What to expect with Charcot-Marie-Tooth Disease
CMT, or Charcot-Marie-Tooth disease, is a set of disorders that slowly worsen over time. These conditions cause increasing weakness and thinning of the arms and legs, making daily activities and movement difficult. The speed at which the condition worsens can vary depending on the specific type of CMT.
Usually, CMT doesn’t affect a person’s expected lifespan, but it can be severe if it starts showing symptoms early in life. Regular check-ups and treatments from a team of various health professionals are crucial to help maintain independence and safely carry out daily tasks.
Possible Complications When Diagnosed with Charcot-Marie-Tooth Disease
In simple terms, foot deformities can cause significant issues for people with Charcot-Marie-Tooth disease (CMT). Over time, these deformities worsen even with consistent physical therapy and use of braces or supports. Operating early to correct muscle imbalances and adjust foot placement can help prevent continued deformity and lessen the need for future joint fusion surgeries. Frequent pressure points can lead to the formation of corns and calluses, which may later develop into skin ulcers.
More serious complications can arise, like respiratory insufficiency, which stems from severe neuropathy (nerve damage), weakened diaphragmatic (breathing muscle) function, or any concurrent spinal deformities.
Pregnancy can exacerbate CMT symptoms, leading to potential childbirth complications. These might include incorrect fetal positioning, post-delivery bleeding, or the need for emergency interventions during childbirth. To mitigate these risks, regular prenatal check-ups for both the mother and the baby are advised. There are other factors that could worsen the neuropathy associated with CMT, like neurotoxic drugs, chemotherapy drugs, and other concurrent neuropathic (nerve-related) diseases.
Common Issues from Charcot-Marie-Tooth disease:
- Foot deformities
- Corns and calluses leading to skin ulcers
- Respiratory insufficiency
Potential Pregnancy-related Complications:
- Worsening of CMT symptoms
- Inadequate fetal positioning
- Postpartum bleeding
- Emergency interventions during delivery
Exacerbating Factors for Neuropathy:
- Neurotoxic drugs
- Chemotherapy drugs
- Other concurrent neuropathic diseases
Preventing Charcot-Marie-Tooth Disease
People who have CMT (Charcot-Marie-Tooth disease) and their families should be informed about the condition and its symptoms, which include muscle weakness and foot problems. They should also be given more information about the treatments available and how the condition typically progresses. When we talk about the ‘mode of inheritance’, we mean how CMT can be passed down through generations. This is explained based on the family’s health history and genetic testing results.
It’s encouraged for people with CMT to stay active, maintain a healthy weight, regularly check in with their healthcare team, and avoid harmful substances and medications that could make their nerve damage worse. If anyone has questions or concerns about how CMT could affect family planning, referral to genetic counseling can help address these concerns. Genetic counseling can provide information on how likely it is for the condition to be passed onto future generations.
