Category Archive Musculoskeletal System

Primary Orthostatic Tremor, also known as Orthostatic Tremor (OT), is a progressive neurological movement disorder, characterized by high-frequency tremors, predominantly in the legs when in a standing position, and an immediate sense of instability.

The term “orthostatic tremor” (OT), also known as “shaky legs syndrome”¹ was first coined in 1984 by Heilman,^[rx] although the earlier descriptions of this entity date back to 1970 when Pazzaglia et al.³ reported on three patients with a peculiar disorder only occurring on standing.

Orthostatic tremor (OT) is a rare disorder characterized by tremor and a feeling of unsteadiness while standing that resolves upon walking or sitting. A pathognomonic 13-18 Hz tremor is seen on surface EMG while standing. Though its clinical features have been better defined over time, much of its pathophysiology remains unknown and treatment options are limited. We review here recent developments in both of these areas.

Another Name

• Shaky legs syndrome
• Idiopathic orthostatic tremor

Causes of Primary Orthostatic Tremor

Generally, tremor is caused by a problem in the deep parts of the brain that control movements.  Most types of tremors have no known cause, although there are some forms that appear to be inherited and run in families.

Tremor can occur on its own or be a symptom associated with a number of neurological disorders, including:

• Multiple sclerosis
• Stroke
• Traumatic brain injury
• Neurodegenerative diseases that affect parts of the brain (e.g.,  Parkinson’s disease).
• Neurologic disorders, including multiple sclerosis, Parkinson’s disease, stroke, and traumatic brain injury
• Certain medicines, such as asthma medicines, amphetamines, caffeine, corticosteroids, and medicines used for certain psychiatric and neurological disorders
• Alcohol use disorder or alcohol withdrawal
• Mercury poisoning
• Hyperthyroidism (overactive thyroid)
• Liver or kidney failure
• Anxiety or panic

Some other known causes can include:

• the use of certain medicines (particular asthma medication, amphetamines, caffeine, corticosteroids, and drugs used for certain psychiatric and neurological disorders)
• alcohol abuse or withdrawal
• mercury poisoning
• overactive thyroid
• liver or kidney failure
• anxiety or panic.

Symptoms of Primary Orthostatic Tremor

Symptoms of tremor may include

•  A tremor is involuntary, rhythmic contractions of various muscles. Orthostatic tremor causes feelings of “vibration”, unsteadiness or imbalance in the legs.
• A rhythmic shaking in the hands, arms, head, legs, or torso
• Balance and muscle coordination problem
• Spasticity and muscle spasm with wasting
• Shaky voice
• Difficulty writing or drawing
• Problems holding and controlling utensils, such as a spoon.
• Begin gradually, usually more prominently on one side of the body
• Worsen with movement
• Usually occur in the hands first, affecting one hand or both hands
• Can include a “yes-yes” or “no-no” motion of the head
• It May be aggravated by emotional stress, fatigue, caffeine, or temperature extremes
• Tremors that get worse during emotional stress
• Tremors that get worse when you move on purpose
• Tremors that lessen with rest
• Balance problems (in rare cases)

What we feel in both legs simultaneously is extreme straining, fatigue, unsteadiness, and a fear of falling. The muscles in our legs become hard, our ankles feel weak and our toes curl under as our legs fail to support us. We can stand for only a short period of time, in some cases only seconds. There is a feeling of panic to find a place to sit, or if possible, walk to gain some relief from our symptoms. Some tremors may be triggered by or become worse during times of stress or strong emotion, when an individual is physically exhausted, or when a person is in certain postures or makes certain movements.

Diagnosis of Primary Orthostatic Tremor

Medical history

During the physical evaluation, a doctor will assess the tremor based on:

• whether the tremor occurs when the muscles are at rest or inaction
• the location of the tremor on the body (and if it occurs on one or both sides of the body)
• the appearance of the tremor (tremor frequency and amplitude).

The doctor will also check other neurological findings such as impaired balance, speech abnormalities, or increased muscle stiffness.  Blood or urine tests can rule out metabolic causes such as thyroid malfunction and certain medications that can cause tremors.  These tests may also help to identify contributing causes such as drug interactions, chronic alcoholism, or other conditions or diseases.  Diagnostic imaging may help determine if the tremor is the result of damage to the brain.

Treatment of Primary Orthostatic Tremor

Non-pharmacological

• Physical, speech-language, and occupational therapy – may help to control tremors and meet daily challenges caused by the tremor.  A physical therapist can help people improve their muscle control, functioning, and strength through coordination, balancing, and other exercises.  Some therapists recommend the use of weights, splints, other adaptive equipment, and special plates and utensils for eating.  Speech-language pathologists can evaluate and treat speech, language, communication, and swallowing disorders.  Occupational therapists can teach individuals new ways of performing activities of daily living that may be affected by tremors.
• Eliminating or reducing tremor-inducing substances such as caffeine and other medication – (such as stimulants) can help improve tremor. Though small amounts of alcohol can improve tremors for some people, tremors can become worse once the effects of the alcohol wear off.
• Interventional Therapy – For patients who fail pharmacologic treatment with the above drugs or are unable to tolerate the side effects, surgical options include deep brain stimulation (DBS), focused ultrasound, or radio-surgical gamma knife thalamotomy to treat persistently disabling limb tremor, and botulinum toxin injections to treat persistently disabling head or vocal cord tremor.
• Deep-brain stimulation – This is the most common surgical treatment for essential tremors. Most series report 70% to 90% hand tremor control. In deep-brain stimulation, electrical stimulation is delivered to the brain through an electrode implanted deep into the ventral intermediate nucleus (VIM) of the thalamus. This is typically done by implanting 4 electrodes in the VIM using stereotactic methods. Computerized programming of the pulse generator is most commonly done with a handheld device after the patient leaves the hospital to optimize the electrode montage, voltage, pulse frequency, and pulse width. Deep-brain stimulation can be done unilaterally or bilaterally depending on the patient’s symptoms. There is an increased risk of speech and balance difficulties with bilateral procedures. If the tremor significantly affects both hands, the dominant hand is targeted, bilateral procedures may be considered.
• Focused ultrasound – Approved by the FDA in 2016, magnetic resonance imaging-guided, high-intensity, focused ultrasound thalamotomy is an innovative method for the treatment of essential tremors. Although it is transcranial and does not require an incision, skull penetration, or an implanted device, it is an invasive therapy that produces a permanent thalamic lesion.
• Radio-surgical gamma knife thalamotomy – Gamma-knife thalamotomy fo­cuses high-energy gamma rays on the ventral intermediate resulting in the death of neurons. It is an unproven treatment that has not generally been adopted due to concerns about potential radiation side effects, including a theoretical, long-term risk of secondary tumor formation.
• Ultrasound Therapy – A new treatment for essential tremors uses magnetic resonance images to deliver focused ultrasound to create a lesion in tiny areas of the brain’s thalamus thought to be responsible for causing the tremors.  The treatment is approved only for those individuals with essential tremors who do not respond well to anticonvulsant or beta-blocking drugs.
• Biofeedback – is a mind-body technique that involves using visual or auditory feedback to teach people to recognize the physical signs and symptoms of stress and anxiety, such as increased heart rate, body temperature, and muscle tension.
• Relaxation techniques – can reduce stress symptoms and help you enjoy a better quality of life, especially if you have an illness. Explore relaxation techniques you can do by yourself.
• Learn to relax – Stress and anxiety tend to make tremors worse, and being relaxed may improve tremors. Although you can’t eliminate all stress from your life, you can change how you react to stressful situations using a range of relaxation techniques, such as massage or meditation.
• Noninvasive techniques – Include gait rehabilitation, visually guided techniques, tendon vibration, weighting extremities, positioning techniques, and manual techniques, all of which can be useful for the recovery of functional activities.[rx]
• Invasive techniques – Thalamic deep brain stimulation can alleviate the tremor in MS, providing better functional performance.[rx] Stereotactic radiosurgery thalamotomy at the nucleus ventralis intermedius with a median maximum dose of 140 Gy also provides good functional outcomes in patients with MS.[rx][rx] Radiofrequency thalamotomy had been successfully used in the past but has been replaced with the newer techniques of radiosurgery and deep brain stimulation as they had fewer adverse effects.
• Physical therapy – Physical therapy may help strengthen your muscles and improve your coordination. The use of wrist weights and adaptive devices, such as heavier utensils, may also help relieve tremors.

For example, tremors due to thyroid hyperactivity will improve or even resolve (return to the normal state) with the treatment of thyroid malfunction.  Also, if the tremor is caused by medication, discontinuing the tremor-causing drug may reduce or eliminate this tremor.

Medical Therapy

The therapeutic approach to essential tremors many times follows a trial and error approach, and patients should be challenged by several medications if the first choice is ineffective or associated with debilitating adverse effects. Medical therapy can be divided into first, second, and third-line therapies.

First-line therapy – It is either approved by the FDA or supported by double-blinded, placebo-controlled studies that meet the criteria for the class I evidence. This class of medications includes propranolol and primidone. If both primidone and propranolol are not effective alone, combinations of both may provide relief in selected patients.

Second-line therapy – Second-line therapy is supported by double-blinded, placebo-controlled trials that do not meet other requirements for the class I evidence studies. This includes gabapentin, pregabalin, topiramate, benzodiazepines (clonazepam, alprazolam), beta-blockers (atenolol and metoprolol) and zonisamide.

Third-line therapy – These therapies are based on open-label studies or case series. Drugs in this class include nimodipine and clozapine.

Medication

• Beta-blocking drugs such as propranolol are normally used to treat high blood pressure but they also help treat essential tremors.  Propranolol can also be used in some people with other types of action tremors.  Other beta-blockers that may be used include atenolol, metoprolol, nadolol, and sotalol.
• Anti-seizure medications such as primidone can be effective in people with essential tremors who do not respond to beta-blockers.  Other medications that may be prescribed include gabapentin and topiramate.  However, it is important to note that some anti-seizure medications can cause tremors.
• Tranquilizers (also known as benzodiazepines) such as alprazolam and clonazepam may temporarily help some people with tremors.  However, their use is limited due to unwanted side effects that include sleepiness, poor concentration, and poor coordination.  This can affect the ability of people to perform daily activities such as driving, school, and work.  Also, when taken regularly, tranquilizers can cause physical dependence and when stopped abruptly can cause several withdrawal symptoms.
• Parkinson’s disease medications (levodopa, carbidopa) are used to treat tremors associated with Parkinson’s disease.
• Botulinum toxin – injections can treat almost all types of tremors.  It is especially useful for head tremor, which generally does not respond to medications.  Botulinum toxin is widely used to control dystonic tremors.  Although botulinum toxin injections can improve tremors for roughly three months at a time, they can also cause muscle weakness.  While this treatment is effective and usually well tolerated for head tremors, botulinum toxin treatment in the hands can cause weakness in the fingers.  It can cause a hoarse voice and difficulty swallowing when used to treat voice tremors.

Additional drug therapies that have been used to treat individuals with primary orthostatic tremors include primidone (Mysoline), chlordiazepoxide (Librium), pregabalin (Lyrica), pramipexole (Mirapex), phenobarbital, and valproic acid (Depakote). Drugs commonly used to treat people with Parkinson’s disease (levodopa or pramipexole) may also be prescribed for individuals with primary orthostatic tremors.

Surgery

When people do not respond to drug therapies or have a severe tremor that significantly impacts their daily life, a doctor may recommend surgical interventions such as deep brain stimulation (DBS) or very rarely, thalamotomy.  While DBS is usually well-tolerated, the most common side effects of tremor surgery include dysarthria (trouble speaking) and balance problems.

• Deep brain stimulation (DBS) – is the most common form of surgical treatment of tremors.  This method is preferred because it is effective, has low risk, and treats a broader range of symptoms than thalamotomy.  The treatment uses surgically implanted electrodes to send high-frequency electrical signals to the thalamus, the deep structure of the brain that coordinates and controls some involuntary movements.  A small pulse generating device placed under the skin in the upper chest (similar to a pacemaker) sends electrical stimuli to the brain and temporarily disables the tremor.  DBS is currently used to treat parkinsonian tremors, essential tremors, and dystonia.

• Thalamotomy – is a surgical procedure that involves the precise, permanent destruction of a tiny area in the thalamus.  Currently, surgery is replaced by radiofrequency ablation to treat severe tremors when deep brain surgery is contraindicated—meaning it is unwise as a treatment option or has undesirable side effects.  Radiofrequency ablation uses a radio wave to generate an electric current that heats up a nerve and disrupts its signaling ability for typically six or more months.  It is usually performed on only one side of the brain to improve tremors on the opposite side of the body.  Surgery on both sides is not recommended as it can cause problems with speech.
•  Stereotactic surgical techniques – can be used to create a lesion in the ventral intermediate (VIM) nucleus of the thalamus.

Rehabilitation

Exercise is an important part of healthy living for everyone. For people with tremors, exercise is more than healthy it is a vital component to maintaining balance, mobility, and activities of daily living. Exercise and physical activity can improve many tremors symptoms. These benefits are supported by research.

The tremors show that people with tremors who start exercising earlier and a minimum of 2.5 hours a week, experience a slowed decline in quality of life compared to those who start later. Establishing early exercise habits is essential to overall disease management.

What Type of Exercise Should I Do?

To help manage the symptoms of tremors, be sure your exercise program includes a few key ingredients:

• Aerobic activity
• Strength training
• Balance, agility, and multitasking
• Flexibility

These elements are included in many types of exercise. Biking, running, Tai chi, yoga, Pilates, dance, weight training, non-contact boxing, qi gong, and more — all have positive effects on tremors symptoms.

There is no “exercise prescription” that is right for every person with tremors. The type of exercise you do depends on your symptoms and challenges. For sedentary people, just getting up and moving is beneficial. More active people can build up to the regular, vigorous activity. Many approaches work well to help maintain and improve mobility, flexibility, and balance to ease non-motor tremors symptoms such as depression or constipation.

Researchers in the study did not distinguish between what type of exercise participants did and determined that all types of exercise are beneficial. The most important thing is to do the exercise regularly. We suggest finding an exercise you enjoy and stick with it.

Challenges to Exercising

• People in the early stages of tremors tend to be just as strong and physically fit as healthy individuals of the same age.
• Disease progression can lead to the following physical change:
• Loss of joint flexibility, which can affect balance.
• Decreased muscle strength or deconditioning can affect walking and the ability to stand up from sitting.
• The decline in cardiovascular conditioning, which affects endurance.

Tips for Getting Started

• First, be safe. Before starting an exercise program, consult your neurologist and primary care doctor about concerns and recommendations.
• Ask your doctor or members in your support group to refer to a physical therapist (PT) who knows about tremors. Work together to identify your concerns and limitations. Target exercises to improve them. For most people, a structured exercise program will include aerobic exercise (such as brisk walking) and resistance training (using weights or bands).
• Purchase a pedometer (step-counter) and figure out how many steps you take on average each day, then build up from there. Many smartphones or smartwatches have a built-in pedometer feature or an application that can be downloaded.
• Exercise indoors and outdoors. Change your routine to stay interested and motivated.
• Again, most importantly pick an exercise you enjoy.

What research is being done?

The mission is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

Researchers are working to better understand the underlying brain functions that cause tremors, identify the genetic factors that make individuals more susceptible to the disorder, and develop new and better treatment options.

• Brain functioning – It can be difficult to distinguish between movement disorders such as Parkinson’s disease and essential tremor. These debilitating movement disorders have different prognoses and can respond very differently to available therapies. NINDS researchers are working to identify structural and functional changes in the brain using non-invasive neuroimaging techniques to develop sensitive and specific markers for each of these diseases and then track how they change as each disease progresses. Other researchers are using functional magnetic resonance imaging technology to better understand normal and diseased brain circuit functions and associated motor behaviors.  Scientists hope to design therapies that can restore normal brain circuit function in diseases such as Parkinson’s disease and tremor.
• Genetics – Research has shown that essential tremors may have a strong genetic component affecting multiple generations of families.  NINDS researchers are building on previous genetics work to identify susceptibility genes for familial early-onset (before age 40) essential tremor.  Researchers are focusing on multigenerational, early-onset families to better detect linkages.

Additionally, NINDS scientists are researching the impact of genetic abnormalities on the development of essential tremors.  Previous research that has shown a link between essential tremor and possible genetic variants on chromosome 6 and 11; ongoing research is targeting the impact of other genetic variations in families.

Medications and other treatment methods

While drugs can be effective for some people, approximately 50 percent of individuals do not respond to medication.  In order to develop assistive and rehabilitative tremor-suppressing devices for people with essential tremors, researchers are exploring where and how to minimize or suppress tremors while still allowing for voluntary movements.

Many people with essential tremors respond to ethanol (alcohol); however, it is not clear why or how.  NINDS researchers are studying the impact of ethanol on tremors to determine the correct dosage amount and its physiological impact on the brain and whether other medications without the side effects of ethanol can be effective.

Other NIH researchers hope to identify the source of essential tremors, study the effects of currently available tremor-suppressant drugs on the brain, and develop more targeted and effective therapies.

FAQ

Please answer the following questions to participate in our certified Continuing Medical Education program. Only one answer is possible per question. Please select the answer that is most appropriate.

Question 1

Which of the following constellations of clinical findings is typical of tremor in patients with Parkinson’s disease?

1. bilateral postural tremor

2. unilateral rest tremor and diminished ipsilateral arm swing while walking

3. severe unilateral tremor while holding a cup or glass

4. tremor that only appears when the patient writes

5. postural tremor of both hands and ataxic gait

Question 2

A 25-year-old man has a mild postural tremor of both hands that improves when he drinks alcohol. His mother had the same condition. What can you advise him?

1. He should definitely be evaluated for possible early Parkinson’s disease.

2. He must get treatment now, as otherwise the condition could worsen.

3. If treatment is indicated, propranolol or primidone could be given.

4. Relaxation exercises and physiotherapy are effective treatment options.

5. Genetic testing is needed to confirm the diagnosis of essential tremor.

Question 3

A man who received the diagnosis of multiple sclerosis two years ago presents to you with the new onset of tremor. What constellation of clinical findings is typical of tremor due to multiple sclerosis?

1. rest tremor, only occasionally observable when the patient is excited

2. a tremor that appears sometimes on the left side, sometimes on the right

3. a tremor that is only present in the morning

4. a swaying, broad-based gait and an intention tremor

5. a postural tremor that is easily suppressed by voluntary effort

Question 4

A 55-year-old man with essential tremor says that he can no longer feed himself because of tremor, can dress himself only with great difficulty, and has not had legible handwriting for many years. Drug treatment as recommended in the relevant clinical guidelines brings only slight improvement. What can you advise the patient about the option of surgical treatment?

1. Deep brain stimulation (DBS) might help but is not available in Germany.

2. DBS is an experimental technique that is only performed in clinical trials.

3. DBS is indicated only to treat Parkinson’s disease and plays no role in the treatment of essential tremor.

4. DBS has a high chance of success in this situation; it is now established as a standard treatment for essential tremor.

5. DBS is no more effective than pharmacotherapy for this indication.

Question 5

What information is most important for the diagnostic classification of a tremor syndrome?

1. the clinical findings

2. brain magnetic resonance imaging (MRI) with fine cerebellar sections

3. nuclear-medical visualization of brain perfusion

4. ultrasonography of the basal ganglia

5. measurement of serum drug levels

Question 6

What findings indicate that tremor may be psychogenic?

1. no evidence of essential tremor or Parkinson’s disease on brain MRI

2. a longstanding marital conflict

3. a tremor of inconstant location that diminishes on distraction and is found to be irregular on tremor analysis

4. a clearly identifiable underlying psychological conflict

5. remission after psychotherapy

Question 7

When can tremor be treated surgically?

1. When the patient is unwilling to take drugs to treat tremor.

2. When the patient is under 50 years old.

3. When the tremor cannot be adequately suppressed by drugs and there is no contraindication to surgery.

4. When the patient is willing to see a neurosurgeon once a week so that brain stimulation can be performed.

5. When the patient is willing to assume the cost of weekly battery changes.

Question 8

What must be borne in mind with respect to drug treatment for various tremor syndromes?

1. That the treatment is based on the clinical findings and not on the underlying disease causing tremor.

2. That causally directed treatment is generally possible only for drug-induced tremor or tremor due to a metabolic disturbance.

3. That parkinsonian tremor responds best to anticholinergic drugs and does not respond at all to the classic dopamine preparations.

4. That the cerebellar tremor of multiple sclerosis is treated in exactly the same way as essential tremor.

5. That essential tremor is usually medically intractable.

Question 9

What drugs can induce tremor?

1. lithium, valproic acid, cyclosporine A

2. carbamazepine, propranolol, seroxate

3. aspirin, diclofenac, paracetamol

4. penicillin, erythromycin, cephalosporin

5. antilipid drugs, antidiabetic drugs

Question 10

What is the drug, or drug class, of first choice for the treatment of parkinsonian tremor?

1. dopaminergic drugs

2. propanolol

3. primidone

4. gabapentin

5. ondansetron

References

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Orthostatic tremor is also known as idiopathic orthostatic tremor is a rare disorder characterized by rapid muscle contractions in the legs that occur when standing.  People typically experience feelings of unsteadiness or imbalance, causing them to immediately attempt to sit or walk.  Because the tremor has such a high frequency (very fast shaking) it may not visible to the naked eye but can be felt by touching the thighs or calves or can be detected by a doctor examining the muscles with a stethoscope.  In some cases, the tremor can become more severe over time.  The cause of orthostatic tremor is unknown.

Primary Orthostatic Tremor, also known as Orthostatic Tremor (OT), is a progressive neurological movement disorder, characterized by high-frequency tremors, predominantly in the legs when in a standing position, and an immediate sense of instability.

Orthostatic tremor (OT) is a rare disorder characterized by tremor and a feeling of unsteadiness while standing that resolves upon walking or sitting. A pathognomonic 13-18 Hz tremor is seen on surface EMG while standing. Though its clinical features have been better defined over time, much of its pathophysiology remains unknown and treatment options are limited. We review here recent developments in both of these areas.

Another Name

• Shaky legs syndrome
• Idiopathic orthostatic tremor

Causes of Orthostatic Tremor

Generally, tremor is caused by a problem in the deep parts of the brain that control movements.  Most types of tremors have no known cause, although there are some forms that appear to be inherited and run in families.

Tremor can occur on its own or be a symptom associated with a number of neurological disorders, including:

• Multiple sclerosis
• Stroke
• Traumatic brain injury
• Neurodegenerative diseases that affect parts of the brain (e.g.,  Parkinson’s disease).
• Neurologic disorders, including multiple sclerosis, Parkinson’s disease, stroke, and traumatic brain injury
• Certain medicines, such as asthma medicines, amphetamines, caffeine, corticosteroids, and medicines used for certain psychiatric and neurological disorders
• Alcohol use disorder or alcohol withdrawal
• Mercury poisoning
• Hyperthyroidism (overactive thyroid)
• Liver or kidney failure
• Anxiety or panic

Some other known causes can include:

• the use of certain medicines (particular asthma medication, amphetamines, caffeine, corticosteroids, and drugs used for certain psychiatric and neurological disorders)
• alcohol abuse or withdrawal
• mercury poisoning
• overactive thyroid
• liver or kidney failure
• anxiety or panic.

Symptoms of Orthostatic Tremor

Symptoms of tremor may include

•  A tremor is involuntary, rhythmic contractions of various muscles. Orthostatic tremor causes feelings of “vibration”, unsteadiness or imbalance in the legs.
• A rhythmic shaking in the hands, arms, head, legs, or torso
• Balance and muscle coordination problem
• Spasticity and muscle spasm with wasting
• Shaky voice
• Difficulty writing or drawing
• Problems holding and controlling utensils, such as a spoon.
• Begin gradually, usually more prominently on one side of the body
• Worsen with movement
• Usually occur in the hands first, affecting one hand or both hands
• Can include a “yes-yes” or “no-no” motion of the head
• It May be aggravated by emotional stress, fatigue, caffeine, or temperature extremes
• Tremors that get worse during emotional stress
• Tremors that get worse when you move on purpose
• Tremors that lessen with rest
• Balance problems (in rare cases)

What we feel in both legs simultaneously is extreme straining, fatigue, unsteadiness, and a fear of falling. The muscles in our legs become hard, our ankles feel weak and our toes curl under as our legs fail to support us. We can stand for only a short period of time, in some cases only seconds. There is a feeling of panic to find a place to sit, or if possible, walk to gain some relief from our symptoms. Some tremors may be triggered by or become worse during times of stress or strong emotion, when an individual is physically exhausted, or when a person is in certain postures or makes certain movements.

Diagnosis of Orthostatic Tremor

Medical history

During the physical evaluation, a doctor will assess the tremor based on:

• whether the tremor occurs when the muscles are at rest or inaction
• the location of the tremor on the body (and if it occurs on one or both sides of the body)
• the appearance of the tremor (tremor frequency and amplitude).

The doctor will also check other neurological findings such as impaired balance, speech abnormalities, or increased muscle stiffness.  Blood or urine tests can rule out metabolic causes such as thyroid malfunction and certain medications that can cause tremors.  These tests may also help to identify contributing causes such as drug interactions, chronic alcoholism, or other conditions or diseases.  Diagnostic imaging may help determine if the tremor is the result of damage to the brain.

Treatment of Orthostatic Tremor

Non-pharmacological

• Physical, speech-language, and occupational therapy – may help to control tremors and meet daily challenges caused by the tremor.  A physical therapist can help people improve their muscle control, functioning, and strength through coordination, balancing, and other exercises.  Some therapists recommend the use of weights, splints, other adaptive equipment, and special plates and utensils for eating.  Speech-language pathologists can evaluate and treat speech, language, communication, and swallowing disorders.  Occupational therapists can teach individuals new ways of performing activities of daily living that may be affected by tremors.
• Eliminating or reducing tremor-inducing substances such as caffeine and other medication – (such as stimulants) can help improve tremor. Though small amounts of alcohol can improve tremors for some people, tremors can become worse once the effects of the alcohol wear off.
• Interventional Therapy – For patients who fail pharmacologic treatment with the above drugs or are unable to tolerate the side effects, surgical options include deep brain stimulation (DBS), focused ultrasound, or radio-surgical gamma knife thalamotomy to treat persistently disabling limb tremor, and botulinum toxin injections to treat persistently disabling head or vocal cord tremor.
• Deep-brain stimulation – This is the most common surgical treatment for essential tremors. Most series report 70% to 90% hand tremor control. In deep-brain stimulation, electrical stimulation is delivered to the brain through an electrode implanted deep into the ventral intermediate nucleus (VIM) of the thalamus. This is typically done by implanting 4 electrodes in the VIM using stereotactic methods. Computerized programming of the pulse generator is most commonly done with a handheld device after the patient leaves the hospital to optimize the electrode montage, voltage, pulse frequency, and pulse width. Deep-brain stimulation can be done unilaterally or bilaterally depending on the patient’s symptoms. There is an increased risk of speech and balance difficulties with bilateral procedures. If the tremor significantly affects both hands, the dominant hand is targeted, bilateral procedures may be considered.
• Focused ultrasound – Approved by the FDA in 2016, magnetic resonance imaging-guided, high-intensity, focused ultrasound thalamotomy is an innovative method for the treatment of essential tremors. Although it is transcranial and does not require an incision, skull penetration, or an implanted device, it is an invasive therapy that produces a permanent thalamic lesion.
• Radio-surgical gamma knife thalamotomy – Gamma-knife thalamotomy fo­cuses high-energy gamma rays on the ventral intermediate resulting in the death of neurons. It is an unproven treatment that has not generally been adopted due to concerns about potential radiation side effects, including a theoretical, long-term risk of secondary tumor formation.
• Ultrasound Therapy – A new treatment for essential tremors uses magnetic resonance images to deliver focused ultrasound to create a lesion in tiny areas of the brain’s thalamus thought to be responsible for causing the tremors.  The treatment is approved only for those individuals with essential tremors who do not respond well to anticonvulsant or beta-blocking drugs.
• Biofeedback – is a mind-body technique that involves using visual or auditory feedback to teach people to recognize the physical signs and symptoms of stress and anxiety, such as increased heart rate, body temperature, and muscle tension.
• Relaxation techniques – can reduce stress symptoms and help you enjoy a better quality of life, especially if you have an illness. Explore relaxation techniques you can do by yourself.
• Learn to relax – Stress and anxiety tend to make tremors worse, and being relaxed may improve tremors. Although you can’t eliminate all stress from your life, you can change how you react to stressful situations using a range of relaxation techniques, such as massage or meditation.
• Noninvasive techniques – Include gait rehabilitation, visually guided techniques, tendon vibration, weighting extremities, positioning techniques, and manual techniques, all of which can be useful for the recovery of functional activities.[rx]
• Invasive techniques – Thalamic deep brain stimulation can alleviate the tremor in MS, providing better functional performance.[rx] Stereotactic radiosurgery thalamotomy at the nucleus ventralis intermedius with a median maximum dose of 140 Gy also provides good functional outcomes in patients with MS.[rx][rx] Radiofrequency thalamotomy had been successfully used in the past but has been replaced with the newer techniques of radiosurgery and deep brain stimulation as they had fewer adverse effects.
• Physical therapy – Physical therapy may help strengthen your muscles and improve your coordination. The use of wrist weights and adaptive devices, such as heavier utensils, may also help relieve tremors.

For example, tremors due to thyroid hyperactivity will improve or even resolve (return to the normal state) with the treatment of thyroid malfunction.  Also, if the tremor is caused by medication, discontinuing the tremor-causing drug may reduce or eliminate this tremor.

Medical Therapy

The therapeutic approach to essential tremors many times follows a trial and error approach, and patients should be challenged by several medications if the first choice is ineffective or associated with debilitating adverse effects. Medical therapy can be divided into first, second, and third-line therapies.

First-line therapy – It is either approved by the FDA or supported by double-blinded, placebo-controlled studies that meet the criteria for the class I evidence. This class of medications includes propranolol and primidone. If both primidone and propranolol are not effective alone, combinations of both may provide relief in selected patients.

Second-line therapy – Second-line therapy is supported by double-blinded, placebo-controlled trials that do not meet other requirements for the class I evidence studies. This includes gabapentin, pregabalin, topiramate, benzodiazepines (clonazepam, alprazolam), beta-blockers (atenolol and metoprolol) and zonisamide.

Third-line therapy – These therapies are based on open-label studies or case series. Drugs in this class include nimodipine and clozapine.

Medication

• Beta-blocking drugs such as propranolol are normally used to treat high blood pressure but they also help treat essential tremors.  Propranolol can also be used in some people with other types of action tremors.  Other beta-blockers that may be used include atenolol, metoprolol, nadolol, and sotalol.
• Anti-seizure medications such as primidone can be effective in people with essential tremors who do not respond to beta-blockers.  Other medications that may be prescribed include gabapentin and topiramate.  However, it is important to note that some anti-seizure medications can cause tremors.
• Tranquilizers (also known as benzodiazepines) such as alprazolam and clonazepam may temporarily help some people with tremors.  However, their use is limited due to unwanted side effects that include sleepiness, poor concentration, and poor coordination.  This can affect the ability of people to perform daily activities such as driving, school, and work.  Also, when taken regularly, tranquilizers can cause physical dependence and when stopped abruptly can cause several withdrawal symptoms.
• Parkinson’s disease medications (levodopa, carbidopa) are used to treat tremors associated with Parkinson’s disease.
• Botulinum toxin – injections can treat almost all types of tremors.  It is especially useful for head tremor, which generally does not respond to medications.  Botulinum toxin is widely used to control dystonic tremors.  Although botulinum toxin injections can improve tremors for roughly three months at a time, they can also cause muscle weakness.  While this treatment is effective and usually well tolerated for head tremors, botulinum toxin treatment in the hands can cause weakness in the fingers.  It can cause a hoarse voice and difficulty swallowing when used to treat voice tremors.

Additional drug therapies that have been used to treat individuals with primary orthostatic tremors include primidone (Mysoline), chlordiazepoxide (Librium), pregabalin (Lyrica), pramipexole (Mirapex), phenobarbital, and valproic acid (Depakote). Drugs commonly used to treat people with Parkinson’s disease (levodopa or pramipexole) may also be prescribed for individuals with primary orthostatic tremors.

Surgery

When people do not respond to drug therapies or have a severe tremor that significantly impacts their daily life, a doctor may recommend surgical interventions such as deep brain stimulation (DBS) or very rarely, thalamotomy.  While DBS is usually well-tolerated, the most common side effects of tremor surgery include dysarthria (trouble speaking) and balance problems.

• Deep brain stimulation (DBS) – is the most common form of surgical treatment of tremors.  This method is preferred because it is effective, has low risk, and treats a broader range of symptoms than thalamotomy.  The treatment uses surgically implanted electrodes to send high-frequency electrical signals to the thalamus, the deep structure of the brain that coordinates and controls some involuntary movements.  A small pulse generating device placed under the skin in the upper chest (similar to a pacemaker) sends electrical stimuli to the brain and temporarily disables the tremor.  DBS is currently used to treat parkinsonian tremors, essential tremors, and dystonia.

• Thalamotomy – is a surgical procedure that involves the precise, permanent destruction of a tiny area in the thalamus.  Currently, surgery is replaced by radiofrequency ablation to treat severe tremors when deep brain surgery is contraindicated—meaning it is unwise as a treatment option or has undesirable side effects.  Radiofrequency ablation uses a radio wave to generate an electric current that heats up a nerve and disrupts its signaling ability for typically six or more months.  It is usually performed on only one side of the brain to improve tremors on the opposite side of the body.  Surgery on both sides is not recommended as it can cause problems with speech.
•  Stereotactic surgical techniques – can be used to create a lesion in the ventral intermediate (VIM) nucleus of the thalamus.

Rehabilitation

Exercise is an important part of healthy living for everyone. For people with tremors, exercise is more than healthy it is a vital component to maintaining balance, mobility, and activities of daily living. Exercise and physical activity can improve many tremors symptoms. These benefits are supported by research.

The tremors show that people with tremors who start exercising earlier and a minimum of 2.5 hours a week, experience a slowed decline in quality of life compared to those who start later. Establishing early exercise habits is essential to overall disease management.

What Type of Exercise Should I Do?

To help manage the symptoms of tremors, be sure your exercise program includes a few key ingredients:

• Aerobic activity
• Strength training
• Balance, agility, and multitasking
• Flexibility

These elements are included in many types of exercise. Biking, running, Tai chi, yoga, Pilates, dance, weight training, non-contact boxing, qi gong, and more — all have positive effects on tremors symptoms.

There is no “exercise prescription” that is right for every person with tremors. The type of exercise you do depends on your symptoms and challenges. For sedentary people, just getting up and moving is beneficial. More active people can build up to the regular, vigorous activity. Many approaches work well to help maintain and improve mobility, flexibility, and balance to ease non-motor tremors symptoms such as depression or constipation.

Researchers in the study did not distinguish between what type of exercise participants did and determined that all types of exercise are beneficial. The most important thing is to do the exercise regularly. We suggest finding an exercise you enjoy and stick with it.

Challenges to Exercising

• People in the early stages of tremors tend to be just as strong and physically fit as healthy individuals of the same age.
• Disease progression can lead to the following physical change:
• Loss of joint flexibility, which can affect balance.
• Decreased muscle strength or deconditioning can affect walking and the ability to stand up from sitting.
• The decline in cardiovascular conditioning, which affects endurance.

Tips for Getting Started

• First, be safe. Before starting an exercise program, consult your neurologist and primary care doctor about concerns and recommendations.
• Ask your doctor or members in your support group to refer to a physical therapist (PT) who knows about tremors. Work together to identify your concerns and limitations. Target exercises to improve them. For most people, a structured exercise program will include aerobic exercise (such as brisk walking) and resistance training (using weights or bands).
• Purchase a pedometer (step-counter) and figure out how many steps you take on average each day, then build up from there. Many smartphones or smartwatches have a built-in pedometer feature or an application that can be downloaded.
• Exercise indoors and outdoors. Change your routine to stay interested and motivated.
• Again, most importantly pick an exercise you enjoy.

What research is being done?

The mission is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

Researchers are working to better understand the underlying brain functions that cause tremors, identify the genetic factors that make individuals more susceptible to the disorder, and develop new and better treatment options.

• Brain functioning – It can be difficult to distinguish between movement disorders such as Parkinson’s disease and essential tremor. These debilitating movement disorders have different prognoses and can respond very differently to available therapies. NINDS researchers are working to identify structural and functional changes in the brain using non-invasive neuroimaging techniques to develop sensitive and specific markers for each of these diseases and then track how they change as each disease progresses. Other researchers are using functional magnetic resonance imaging technology to better understand normal and diseased brain circuit functions and associated motor behaviors.  Scientists hope to design therapies that can restore normal brain circuit function in diseases such as Parkinson’s disease and tremor.
• Genetics – Research has shown that essential tremors may have a strong genetic component affecting multiple generations of families.  NINDS researchers are building on previous genetics work to identify susceptibility genes for familial early-onset (before age 40) essential tremor.  Researchers are focusing on multigenerational, early-onset families to better detect linkages.

Additionally, NINDS scientists are researching the impact of genetic abnormalities on the development of essential tremors.  Previous research that has shown a link between essential tremor and possible genetic variants on chromosome 6 and 11; ongoing research is targeting the impact of other genetic variations in families.

Medications and other treatment methods

While drugs can be effective for some people, approximately 50 percent of individuals do not respond to medication.  In order to develop assistive and rehabilitative tremor-suppressing devices for people with essential tremors, researchers are exploring where and how to minimize or suppress tremors while still allowing for voluntary movements.

Many people with essential tremors respond to ethanol (alcohol); however, it is not clear why or how.  NINDS researchers are studying the impact of ethanol on tremors to determine the correct dosage amount and its physiological impact on the brain and whether other medications without the side effects of ethanol can be effective.

Other NIH researchers hope to identify the source of essential tremors, study the effects of currently available tremor-suppressant drugs on the brain, and develop more targeted and effective therapies.

FAQ

Please answer the following questions to participate in our certified Continuing Medical Education program. Only one answer is possible per question. Please select the answer that is most appropriate.

Question 1

Which of the following constellations of clinical findings is typical of tremor in patients with Parkinson’s disease?

1. bilateral postural tremor

2. unilateral rest tremor and diminished ipsilateral arm swing while walking

3. severe unilateral tremor while holding a cup or glass

4. tremor that only appears when the patient writes

5. postural tremor of both hands and ataxic gait

Question 2

A 25-year-old man has a mild postural tremor of both hands that improves when he drinks alcohol. His mother had the same condition. What can you advise him?

1. He should definitely be evaluated for possible early Parkinson’s disease.

2. He must get treatment now, as otherwise the condition could worsen.

3. If treatment is indicated, propranolol or primidone could be given.

4. Relaxation exercises and physiotherapy are effective treatment options.

5. Genetic testing is needed to confirm the diagnosis of essential tremor.

Question 3

A man who received the diagnosis of multiple sclerosis two years ago presents to you with the new onset of tremor. What constellation of clinical findings is typical of tremor due to multiple sclerosis?

1. rest tremor, only occasionally observable when the patient is excited

2. a tremor that appears sometimes on the left side, sometimes on the right

3. a tremor that is only present in the morning

4. a swaying, broad-based gait and an intention tremor

5. a postural tremor that is easily suppressed by voluntary effort

Question 4

A 55-year-old man with essential tremor says that he can no longer feed himself because of tremor, can dress himself only with great difficulty, and has not had legible handwriting for many years. Drug treatment as recommended in the relevant clinical guidelines brings only slight improvement. What can you advise the patient about the option of surgical treatment?

1. Deep brain stimulation (DBS) might help but is not available in Germany.

2. DBS is an experimental technique that is only performed in clinical trials.

3. DBS is indicated only to treat Parkinson’s disease and plays no role in the treatment of essential tremor.

4. DBS has a high chance of success in this situation; it is now established as a standard treatment for essential tremor.

5. DBS is no more effective than pharmacotherapy for this indication.

Question 5

What information is most important for the diagnostic classification of a tremor syndrome?

1. the clinical findings

2. brain magnetic resonance imaging (MRI) with fine cerebellar sections

3. nuclear-medical visualization of brain perfusion

4. ultrasonography of the basal ganglia

5. measurement of serum drug levels

Question 6

What findings indicate that tremor may be psychogenic?

1. no evidence of essential tremor or Parkinson’s disease on brain MRI

2. a longstanding marital conflict

3. a tremor of inconstant location that diminishes on distraction and is found to be irregular on tremor analysis

4. a clearly identifiable underlying psychological conflict

5. remission after psychotherapy

Question 7

When can tremor be treated surgically?

1. When the patient is unwilling to take drugs to treat tremor.

2. When the patient is under 50 years old.

3. When the tremor cannot be adequately suppressed by drugs and there is no contraindication to surgery.

4. When the patient is willing to see a neurosurgeon once a week so that brain stimulation can be performed.

5. When the patient is willing to assume the cost of weekly battery changes.

Question 8

What must be borne in mind with respect to drug treatment for various tremor syndromes?

1. That the treatment is based on the clinical findings and not on the underlying disease causing tremor.

2. That causally directed treatment is generally possible only for drug-induced tremor or tremor due to a metabolic disturbance.

3. That parkinsonian tremor responds best to anticholinergic drugs and does not respond at all to the classic dopamine preparations.

4. That the cerebellar tremor of multiple sclerosis is treated in exactly the same way as essential tremor.

5. That essential tremor is usually medically intractable.

Question 9

What drugs can induce tremor?

1. lithium, valproic acid, cyclosporine A

2. carbamazepine, propranolol, seroxate

3. aspirin, diclofenac, paracetamol

4. penicillin, erythromycin, cephalosporin

5. antilipid drugs, antidiabetic drugs

Question 10

What is the drug, or drug class, of first choice for the treatment of parkinsonian tremor?

1. dopaminergic drugs

2. propanolol

3. primidone

4. gabapentin

5. ondansetron

References

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Tremors are rhythmic, oscillatory, involuntary movements with muscle contraction disorders leading to shaking movements in one or more parts of the body.  It is a common movement disorder that most often affects the hands but can also occur in the arms, head, vocal cords, torso, and legs.  Tremor may be intermittent (occurring at separate times, with breaks) or constant.  It can occur sporadically (on its own) or happen as a result of another disorder.

Tremor is most common among middle-aged and older adults, although it can occur at any age.  The disorder generally affects men and women equally. Tremor is not life-threatening.  However, it can be embarrassing and even disabling, making it difficult or even impossible to perform work and daily life tasks.

The Movement Disorders Society diagnostic criteria include:

• Tremor is bilateral, symmetrical and postural
• The tremor involves the forearms and hand
• Is persistent and visible
• May be associated with isolated head tremor

How is tremor classified?

Tremor can be classified into two main categories:

• Resting tremor – occurs when the muscle is relaxed, such as when the hands are resting on the lap.  With this disorder, a person’s hands, arms, or legs may shake even when they are at rest.  Often, the tremor only affects the hand or fingers.  This type of tremor is often seen in people with Parkinson’s disease and is called a “pill-rolling” tremor because the circular finger and hand movements resemble the rolling of small objects or pills in the hand.
• Action tremor – occurs with the voluntary movement of a muscle. Most types of tremors are considered action tremors.  There are several sub-classifications of action tremors, many of which overlap.
• Postural tremor – occurs when a person maintains a position against gravity, such as holding the arms outstretched.
• Kinetic tremor – is associated with any voluntary movement, such as moving the wrists up and down or closing and opening the eyes.
• Intention tremor – is produced with purposeful movement toward a target, such as lifting a finger to touch the nose.  Typically the tremor will become worse as an individual gets closer to their target.
• Task-specific tremor – only appears when performing highly skilled, goal-oriented tasks such as handwriting or speaking.
• Isometric tremor – occurs during a voluntary muscle contraction that is not accompanied by any movement such as holding a heavy book or a dumbbell in the same position.
• Physiologic tremor – Predominantly bilateral, symmetrical action tremor. High frequency (10 to 12 Hz), the presence of known cause (e.g., medications, hyperthyroidism, hypoglycemia)
• Parkinson Disease Tremor – Predominantly at rest, asymmetrical.  Usually does not produce head tremor. Frequency 4 to 6 Hz.
• Orthostatic tremor – Postural tremor in the torso and lower limbs while standing; may also occur in the upper limbs. Suppressed by walking. Tremor is high frequency (14 to 20 Hz) and synchronous among ipsilateral and contralateral muscles.
• Cerebellar tremor – Postural, intention, or action tremor. Relatively low frequency (3 to 4 Hz). Associated with ataxia and dysmetria
• Writing tremor (task-specific) – Not evident in other tasks requiring coordination, only during writing. Is considered a variant of focal hand dystonia (Writer’s cramp).
• Psychogenic tremor – It is not an exclusion diagnosis. Symptoms vary in severity, depending on the subject’s emotional state associated with stressful life events. Several clues are helpful to differentiate the psychogenic nature and include sudden onset and spontaneous remission, larger variations of amplitude and frequency, and less severity. The tremors disappear with distractions such as alternate finger tapping, mental concentration on serial 7s, or the healthcare professional applying a vibrating tuning fork to a patient’s forehead and informing the patient (wrongly) that this can stop the tremor and entrainment. Entrainment is a change in frequency of the tremor in adaptation to voluntary movements such as a regular movement in the contralateral limb.

What are the different categories or types of tremors?

Tremor is most commonly classified by its appearance and cause or origin.  There are more than 20 types of tremors.  Some of the most common forms of tremor include:

Essential tremor

Essential tremor (previously also called benign essential tremor or familial tremor) is one of the most common movement disorders.  The exact cause of essential tremors is unknown.  For some people, this tremor is mild and remains stable for many years.  The tremor usually appears on both sides of the body but is often noticed more in the dominant hand because it is an action tremor.

The key feature of essential tremor is a tremor in both hands and arms, which is present during action and when standing still.  Additional symptoms may include head tremor (e.g., a “yes” or “no” motion) without abnormal posturing of the head and a shaking or quivering sound to the voice if the tremor affects the voice box.  The action tremor in both hands in essential tremor can lead to problems with writing, drawing, drinking from a cup, or using tools or a computer.

Tremor frequency (how “fast” the tremor shakes) may decrease as the person ages, but the severity may increase, affecting the person’s ability to perform certain tasks or activities of daily living.  Heightened emotion, stress, fever, physical exhaustion, or low blood sugar may trigger tremors and/or increase its severity.  Though the tremor can start at any age, it most often appears for the first time during adolescence or in middle age (between ages 40 and 50).  Small amounts of alcohol may help decrease essential tremors, but the mechanism behind this is unknown.

About 50 percent of the cases of essential tremors are thought to be caused by a genetic risk factor (referred to as familial tremors).  Children of a parent who has familial tremors have a greater risk of inheriting the condition.  Familial forms of essential tremors often appear early in life.

For many years essential tremor was not associated with any known disease.  However, some scientists think essential tremor is accompanied by a mild degeneration of certain areas of the brain that control movement.  This is an ongoing debate in the research field.

Dystonic tremor

Dystonic tremor occurs in people who are affected by dystonia—a movement disorder where incorrect messages from the brain cause muscles to be overactive, resulting in abnormal postures or sustained, unwanted movements.  Dystonic tremor usually appears in young or middle-aged adults and can affect any muscle in the body.  Symptoms may sometimes be relieved by complete relaxation.

Although some of the symptoms are similar, dystonic tremor differs from essential tremor in some ways.  The dystonic tremor:

• is associated with abnormal body postures due to forceful muscle spasms or cramps
• can affect the same parts of the body as essential tremor, but also—and more often than essential tremor—the head, without any other movement in the hands or arms
• can also mimic resting tremors, such as the ones seen in Parkinson’s disease.
• Also, the severity of dystonic tremors may be reduced by touching the affected body part or muscle, and tremor movements are “jerky” or irregular instead of rhythmic.

Cerebellar tremor

Cerebellar tremor is typically a slow, high-amplitude (easily visible) tremor of the extremities (e.g., arm, leg) that occurs at the end of a purposeful movement such as trying to press a button.  It is caused by damage to the cerebellum and its pathways to other brain regions resulting from a stroke or tumor.  Damage also may be caused by diseases such as multiple sclerosis or an inherited degenerative disorder such as ataxia (in which people lose muscle control in the arms and legs) and Fragile X syndrome (a disorder marked by a range of intellectual and developmental problems).  It can also result from chronic damage to the cerebellum due to alcoholism.

Psychogenic tremor

Psychogenic tremor (also called functional tremor) can appear as any form of tremor.  It symptoms may vary but often start abruptly and may affect all body parts.  The tremor increases in times of stress and decreases or disappears when distracted.  Many individuals with psychogenic tremors have an underlying psychiatric disorder such as depression or post-traumatic stress disorder (PTSD).

Physiologic tremor

Physiologic tremor occurs in all healthy individuals.  It is rarely visible to the eye and typically involves a fine shaking of both of the hands and also the fingers.  It is not considered a disease but is a normal human phenomenon that is the result of physical properties in the body (for example, rhythmical activities such as heartbeat and muscle activation).

Enhanced physiologic tremor

Enhanced physiological tremor is a more noticeable case of physiologic tremor that can be easily seen.  It is generally not caused by a neurological disease but by the reaction to certain drugs, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia.  It is usually reversible once the cause is corrected.

Parkinsonian tremor

Parkinsonian tremor is a common symptom of Parkinson’s disease, although not all people with Parkinson’s disease have tremors.  Generally, symptoms include shaking in one or both hands at rest.  It may also affect the chin, lips, face, and legs.  The tremor may initially appear in only one limb or on just one side of the body.  As the disease progresses, it may spread to both sides of the body.  The tremor is often made worse by stress or strong emotions.  More than 25 percent of people with Parkinson’s disease also have an associated action tremor.

Orthostatic tremor

Orthostatic tremor is a rare disorder characterized by rapid muscle contractions in the legs that occur when standing.  People typically experience feelings of unsteadiness or imbalance, causing them to immediately attempt to sit or walk.  Because the tremor has such a high frequency (very fast shaking) it may not visible to the naked eye but can be felt by touching the thighs or calves or can be detected by a doctor examining the muscles with a stethoscope.  In some cases, the tremor can become more severe over time.  The cause of orthostatic tremor is unknown.

What causes tremors?

Generally, tremor is caused by a problem in the deep parts of the brain that control movements.  Most types of tremors have no known cause, although there are some forms that appear to be inherited and run in families.

Tremor can occur on its own or be a symptom associated with a number of neurological disorders, including:

• Multiple sclerosis
• Stroke
• Traumatic brain injury
• Neurodegenerative diseases that affect parts of the brain (e.g.,  Parkinson’s disease).
• Neurologic disorders, including multiple sclerosis, Parkinson’s disease, stroke, and traumatic brain injury
• Certain medicines, such as asthma medicines, amphetamines, caffeine, corticosteroids, and medicines used for certain psychiatric and neurological disorders
• Alcohol use disorder or alcohol withdrawal
• Mercury poisoning
• Hyperthyroidism (overactive thyroid)
• Liver or kidney failure
• Anxiety or panic

Some other known causes can include:

• the use of certain medicines (particular asthma medication, amphetamines, caffeine, corticosteroids, and drugs used for certain psychiatric and neurological disorders)
• alcohol abuse or withdrawal
• mercury poisoning
• overactive thyroid
• liver or kidney failure
• anxiety or panic.

What Are The Symptoms of Tremor?

Symptoms of tremor may include:

• A rhythmic shaking in the hands, arms, head, legs, or torso
• Balance and muscle coordination problem
• Spasticity and muscle spasm with wasting
• Shaky voice
• Difficulty writing or drawing
• Problems holding and controlling utensils, such as a spoon.
• Begin gradually, usually more prominently on one side of the body
• Worsen with movement
• Usually occur in the hands first, affecting one hand or both hands
• Can include a “yes-yes” or “no-no” motion of the head
• It May be aggravated by emotional stress, fatigue, caffeine, or temperature extremes
• Tremors that get worse during emotional stress
• Tremors that get worse when you move on purpose
• Tremors that lessen with rest
• Balance problems (in rare cases)

Some tremors may be triggered by or become worse during times of stress or strong emotion, when an individual is physically exhausted, or when a person is in certain postures or makes certain movements.

How is Tremor Diagnosed?

Medical history

During the physical evaluation, a doctor will assess the tremor based on:

• whether the tremor occurs when the muscles are at rest or inaction
• the location of the tremor on the body (and if it occurs on one or both sides of the body)
• the appearance of the tremor (tremor frequency and amplitude).

The doctor will also check other neurological findings such as impaired balance, speech abnormalities, or increased muscle stiffness.  Blood or urine tests can rule out metabolic causes such as thyroid malfunction and certain medications that can cause tremors.  These tests may also help to identify contributing causes such as drug interactions, chronic alcoholism, or other conditions or diseases.  Diagnostic imaging may help determine if the tremor is the result of damage in the brain.

How is Tremor Treated?

Non-pharmacological

• Physical, speech-language, and occupational therapy – may help to control tremors and meet daily challenges caused by the tremor.  A physical therapist can help people improve their muscle control, functioning, and strength through coordination, balancing, and other exercises.  Some therapists recommend the use of weights, splints, other adaptive equipment, and special plates and utensils for eating.  Speech-language pathologists can evaluate and treat speech, language, communication, and swallowing disorders.  Occupational therapists can teach individuals new ways of performing activities of daily living that may be affected by tremors.
• Eliminating or reducing tremor-inducing substances such as caffeine and other medication – (such as stimulants) can help improve tremor. Though small amounts of alcohol can improve tremors for some people, tremors can become worse once the effects of the alcohol wear off.
• Interventional Therapy – For patients who fail pharmacologic treatment with the above drugs or are unable to tolerate the side effects, surgical options include deep brain stimulation (DBS), focused ultrasound, or radio-surgical gamma knife thalamotomy to treat persistently disabling limb tremor, and botulinum toxin injections to treat persistently disabling head or vocal cord tremor.
• Deep-brain stimulation – This is the most common surgical treatment for essential tremors. Most series report 70% to 90% hand tremor control. In deep-brain stimulation, electrical stimulation is delivered to the brain through an electrode implanted deep into the ventral intermediate nucleus (VIM) of the thalamus. This is typically done by implanting 4 electrodes in the VIM using stereotactic methods. Computerized programming of the pulse generator is most commonly done with a handheld device after the patient leaves the hospital to optimize the electrode montage, voltage, pulse frequency, and pulse width. Deep-brain stimulation can be done unilaterally or bilaterally depending on the patient’s symptoms. There is an increased risk of speech and balance difficulties with bilateral procedures. If the tremor significantly affects both hands, the dominant hand is targeted, bilateral procedures may be considered.
• Focused ultrasound – Approved by the FDA in 2016, magnetic resonance imaging-guided, high-intensity, focused ultrasound thalamotomy is an innovative method for the treatment of essential tremors. Although it is transcranial and does not require an incision, skull penetration, or an implanted device, it is an invasive therapy that produces a permanent thalamic lesion.
• Radio-surgical gamma knife thalamotomy – Gamma-knife thalamotomy fo­cuses high-energy gamma rays on the ventral intermediate resulting in the death of neurons. It is an unproven treatment that has not generally been adopted due to concerns about potential radiation side effects, including a theoretical, long-term risk of secondary tumor formation.
• Ultrasound Therapy – A new treatment for essential tremors uses magnetic resonance images to deliver focused ultrasound to create a lesion in tiny areas of the brain’s thalamus thought to be responsible for causing the tremors.  The treatment is approved only for those individuals with essential tremors who do not respond well to anticonvulsant or beta-blocking drugs.
• Biofeedback – is a mind-body technique that involves using visual or auditory feedback to teach people to recognize the physical signs and symptoms of stress and anxiety, such as increased heart rate, body temperature, and muscle tension.
• Relaxation techniques – can reduce stress symptoms and help you enjoy a better quality of life, especially if you have an illness. Explore relaxation techniques you can do by yourself.
• Learn to relax – Stress and anxiety tend to make tremors worse, and being relaxed may improve tremors. Although you can’t eliminate all stress from your life, you can change how you react to stressful situations using a range of relaxation techniques, such as massage or meditation.
• Noninvasive techniques – Include gait rehabilitation, visually guided techniques, tendon vibration, weighting extremities, positioning techniques, and manual techniques, all of which can be useful for the recovery of functional activities.[rx]
• Invasive techniques – Thalamic deep brain stimulation can alleviate the tremor in MS, providing better functional performance.[rx] Stereotactic radiosurgery thalamotomy at the nucleus ventralis intermedius with a median maximum dose of 140 Gy also provides good functional outcomes in patients with MS.[rx][rx] Radiofrequency thalamotomy had been successfully used in the past but has been replaced with the newer techniques of radiosurgery and deep brain stimulation as they had fewer adverse effects.
• Physical therapy – Physical therapy may help strengthen your muscles and improve your coordination. The use of wrist weights and adaptive devices, such as heavier utensils, may also help relieve tremors.

For example, tremors due to thyroid hyperactivity will improve or even resolve (return to the normal state) with the treatment of thyroid malfunction.  Also, if the tremor is caused by medication, discontinuing the tremor-causing drug may reduce or eliminate this tremor.

Medical Therapy

The therapeutic approach to essential tremors many times follows a trial and error approach, and patients should be challenged by several medications if the first choice is ineffective or associated with debilitating adverse effects. Medical therapy can be divided into first, second, and third-line therapies.

First-line therapy – It is either approved by the FDA or supported by double-blinded, placebo-controlled studies that meet the criteria for the class I evidence. This class of medications includes propranolol and primidone. If both primidone and propranolol are not effective alone, combinations of both may provide relief in selected patients.

Second-line therapy – Second-line therapy is supported by double-blinded, placebo-controlled trials that do not meet other requirements for the class I evidence studies. This includes gabapentin, pregabalin, topiramate, benzodiazepines (clonazepam, alprazolam), beta-blockers (atenolol and metoprolol) and zonisamide.

Third-line therapy – These therapies are based on open-label studies or case series. Drugs in this class include nimodipine and clozapine.

Medication

• Beta-blocking drugs such as propranolol are normally used to treat high blood pressure but they also help treat essential tremors.  Propranolol can also be used in some people with other types of action tremors.  Other beta-blockers that may be used include atenolol, metoprolol, nadolol, and sotalol.
• Anti-seizure medications such as primidone can be effective in people with essential tremors who do not respond to beta-blockers.  Other medications that may be prescribed include gabapentin and topiramate.  However, it is important to note that some anti-seizure medications can cause tremors.
• Tranquilizers (also known as benzodiazepines) such as alprazolam and clonazepam may temporarily help some people with tremors.  However, their use is limited due to unwanted side effects that include sleepiness, poor concentration, and poor coordination.  This can affect the ability of people to perform daily activities such as driving, school, and work.  Also, when taken regularly, tranquilizers can cause physical dependence and when stopped abruptly can cause several withdrawal symptoms.
• Parkinson’s disease medications (levodopa, carbidopa) are used to treat tremors associated with Parkinson’s disease.
• Botulinum toxin – injections can treat almost all types of tremors.  It is especially useful for head tremor, which generally does not respond to medications.  Botulinum toxin is widely used to control dystonic tremors.  Although botulinum toxin injections can improve tremors for roughly three months at a time, they can also cause muscle weakness.  While this treatment is effective and usually well tolerated for head tremors, botulinum toxin treatment in the hands can cause weakness in the fingers.  It can cause a hoarse voice and difficulty swallowing when used to treat voice tremors.

Surgery

When people do not respond to drug therapies or have a severe tremor that significantly impacts their daily life, a doctor may recommend surgical interventions such as deep brain stimulation (DBS) or very rarely, thalamotomy.  While DBS is usually well-tolerated, the most common side effects of tremor surgery include dysarthria (trouble speaking) and balance problems.

• Deep brain stimulation (DBS) – is the most common form of surgical treatment of tremors.  This method is preferred because it is effective, has low risk, and treats a broader range of symptoms than thalamotomy.  The treatment uses surgically implanted electrodes to send high-frequency electrical signals to the thalamus, the deep structure of the brain that coordinates and controls some involuntary movements.  A small pulse generating device placed under the skin in the upper chest (similar to a pacemaker) sends electrical stimuli to the brain and temporarily disables the tremor.  DBS is currently used to treat parkinsonian tremors, essential tremors, and dystonia.

• Thalamotomy – is a surgical procedure that involves the precise, permanent destruction of a tiny area in the thalamus.  Currently, surgery is replaced by radiofrequency ablation to treat severe tremors when deep brain surgery is contraindicated—meaning it is unwise as a treatment option or has undesirable side effects.  Radiofrequency ablation uses a radio wave to generate an electric current that heats up a nerve and disrupts its signaling ability for typically six or more months.  It is usually performed on only one side of the brain to improve tremors on the opposite side of the body.  Surgery on both sides is not recommended as it can cause problems with speech.
•  Stereotactic surgical techniques – can be used to create a lesion in the ventral intermediate (VIM) nucleus of the thalamus.

What is the prognosis?

Tremor is not considered a life-threatening condition.  Although many cases of tremors are mild, tremors can be very disabling for other people.  It can be difficult for individuals with tremors to perform normal daily activities such as working, bathing, dressing, and eating.  Tremor can also cause “social disability.”   People may limit their physical activity, travel, and social engagements to avoid embarrassment or other consequences.

The symptoms of essential tremors usually worsen with age.  Additionally, there is some evidence that people with essential tremor are more likely than average to develop other neurodegenerative conditions such as Parkinson’s disease or Alzheimer’s disease, especially in individuals whose tremor first appears after age 65.

Unlike essential tremors, the symptoms of physiologic and drug-induced tremors do not generally worsen over time and can often be improved or eliminated once the underlying causes are treated.

Rehabilitation

Exercise is an important part of healthy living for everyone. For people with Parkinson’s disease (PD), exercise is more than healthy it is a vital component to maintaining balance, mobility and activities of daily living. Exercise and physical activity can improve many PD symptoms. These benefits are supported by research.

The Parkinson’s Outcomes Project shows that people with PD who start exercising earlier and a minimum of 2.5 hours a week, experience a slowed decline in quality of life compared to those who start later. Establishing early exercise habits is essential to overall disease management.

What Type of Exercise Should I Do?

To help manage the symptoms of PD, be sure your exercise program includes a few key ingredients:

• Aerobic activity
• Strength training
• Balance, agility, and multitasking
• Flexibility

These elements are included in many types of exercise. Biking, running, Tai chi, yoga, Pilates, dance, weight training, non-contact boxing, qi gong, and more — all have positive effects on PD symptoms.

There is no “exercise prescription” that is right for every person with PD. The type of exercise you do depends on your symptoms and challenges. For sedentary people, just getting up and moving is beneficial. More active people can build up to the regular, vigorous activity. Many approaches work well to help maintain and improve mobility, flexibility and balance to ease non-motor PD symptoms such as depression or constipation.

Researchers in the study did not distinguish between what type of exercise participants did and determined that all types of exercise are beneficial. The most important thing is to do the exercise regularly. We suggest finding an exercise you enjoy and stick with it.

Challenges to Exercising

• People in the early stages of PD tend to be just as strong and physically fit as healthy individuals of the same age.
• Disease progression can lead to the following physical change:
• Loss of joint flexibility, which can affect balance.
• Decreased muscle strength or deconditioning can affect walking and the ability to stand up from sitting.
• The decline in cardiovascular conditioning, which affects endurance.

Tips for Getting Started

• First, be safe. Before starting an exercise program, consult your neurologist and primary care doctor about concerns and recommendations.
• Ask your doctor or members in your support group to refer to a physical therapist (PT) who knows about PD. Work together to identify your concerns and limitations. Target exercises to improve them. For most people, a structured exercise program will include aerobic exercise (such as brisk walking) and resistance training (using weights or bands).
• Purchase a pedometer (step-counter) and figure out how many steps you take on average each day, then build up from there. Many smartphones or smartwatches have a built-in pedometer feature or an application that can be downloaded.
• Exercise indoors and outdoors. Change your routine to stay interested and motivated.
• Again, most importantly pick an exercise you enjoy.

What research is being done?

The mission is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

Researchers are working to better understand the underlying brain functions that cause tremors, identify the genetic factors that make individuals more susceptible to the disorder, and develop new and better treatment options.

Brain functioning
It can be difficult to distinguish between movement disorders such as Parkinson’s disease and essential tremor. These debilitating movement disorders have different prognoses and can respond very differently to available therapies. NINDS researchers are working to identify structural and functional changes in the brain using non-invasive neuroimaging techniques to develop sensitive and specific markers for each of these diseases and then track how they change as each disease progresses.

Other researchers are using functional magnetic resonance imaging technology to better understand normal and diseased brain circuit functions and associated motor behaviors.  Scientists hope to design therapies that can restore normal brain circuit function in diseases such as Parkinson’s disease and tremor.

Genetics
Research has shown that essential tremors may have a strong genetic component affecting multiple generations of families.  NINDS researchers are building on previous genetics work to identify susceptibility genes for familial early-onset (before age 40) essential tremor.  Researchers are focusing on multigenerational, early-onset families to better detect linkages.

Additionally, NINDS scientists are researching the impact of genetic abnormalities on the development of essential tremors.  Previous research that has shown a link between essential tremor and possible genetic variants on chromosome 6 and 11; ongoing research is targeting the impact of other genetic variations in families.

Medications and other treatment methods

While drugs can be effective for some people, approximately 50 percent of individuals do not respond to medication.  In order to develop assistive and rehabilitative tremor-suppressing devices for people with essential tremors, researchers are exploring where and how to minimize or suppress tremors while still allowing for voluntary movements.

Many people with essential tremors respond to ethanol (alcohol); however, it is not clear why or how.  NINDS researchers are studying the impact of ethanol on tremors to determine the correct dosage amount and its physiological impact on the brain and whether other medications without the side effects of ethanol can be effective.

Other NIH researchers hope to identify the source of essential tremors, study the effects of currently available tremor-suppressant drugs on the brain, and develop more targeted and effective therapies.

FAQ

Please answer the following questions to participate in our certified Continuing Medical Education program. Only one answer is possible per question. Please select the answer that is most appropriate.

Question 1

Which of the following constellations of clinical findings is typical of tremor in patients with Parkinson’s disease?

1. bilateral postural tremor

2. unilateral rest tremor and diminished ipsilateral arm swing while walking

3. severe unilateral tremor while holding a cup or glass

4. tremor that only appears when the patient writes

5. postural tremor of both hands and ataxic gait

Question 2

A 25-year-old man has a mild postural tremor of both hands that improves when he drinks alcohol. His mother had the same condition. What can you advise him?

1. He should definitely be evaluated for possible early Parkinson’s disease.

2. He must get treatment now, as otherwise the condition could worsen.

3. If treatment is indicated, propranolol or primidone could be given.

4. Relaxation exercises and physiotherapy are effective treatment options.

5. Genetic testing is needed to confirm the diagnosis of essential tremor.

Question 3

A man who received the diagnosis of multiple sclerosis two years ago presents to you with the new onset of tremor. What constellation of clinical findings is typical of tremor due to multiple sclerosis?

1. rest tremor, only occasionally observable when the patient is excited

2. a tremor that appears sometimes on the left side, sometimes on the right

3. a tremor that is only present in the morning

4. a swaying, broad-based gait and an intention tremor

5. a postural tremor that is easily suppressed by voluntary effort

Question 4

A 55-year-old man with essential tremor says that he can no longer feed himself because of tremor, can dress himself only with great difficulty, and has not had legible handwriting for many years. Drug treatment as recommended in the relevant clinical guidelines brings only slight improvement. What can you advise the patient about the option of surgical treatment?

1. Deep brain stimulation (DBS) might help but is not available in Germany.

2. DBS is an experimental technique that is only performed in clinical trials.

3. DBS is indicated only to treat Parkinson’s disease and plays no role in the treatment of essential tremor.

4. DBS has a high chance of success in this situation; it is now established as a standard treatment for essential tremor.

5. DBS is no more effective than pharmacotherapy for this indication.

Question 5

What information is most important for the diagnostic classification of a tremor syndrome?

1. the clinical findings

2. brain magnetic resonance imaging (MRI) with fine cerebellar sections

3. nuclear-medical visualization of brain perfusion

4. ultrasonography of the basal ganglia

5. measurement of serum drug levels

Question 6

What findings indicate that tremor may be psychogenic?

1. no evidence of essential tremor or Parkinson’s disease on brain MRI

2. a longstanding marital conflict

3. a tremor of inconstant location that diminishes on distraction and is found to be irregular on tremor analysis

4. a clearly identifiable underlying psychological conflict

5. remission after psychotherapy

Question 7

When can tremor be treated surgically?

1. When the patient is unwilling to take drugs to treat tremor.

2. When the patient is under 50 years old.

3. When the tremor cannot be adequately suppressed by drugs and there is no contraindication to surgery.

4. When the patient is willing to see a neurosurgeon once a week so that brain stimulation can be performed.

5. When the patient is willing to assume the cost of weekly battery changes.

Question 8

What must be borne in mind with respect to drug treatment for various tremor syndromes?

1. That the treatment is based on the clinical findings and not on the underlying disease causing tremor.

2. That causally directed treatment is generally possible only for drug-induced tremor or tremor due to a metabolic disturbance.

3. That parkinsonian tremor responds best to anticholinergic drugs and does not respond at all to the classic dopamine preparations.

4. That the cerebellar tremor of multiple sclerosis is treated in exactly the same way as essential tremor.

5. That essential tremor is usually medically intractable.

Question 9

What drugs can induce tremor?

1. lithium, valproic acid, cyclosporine A

2. carbamazepine, propranolol, seroxate

3. aspirin, diclofenac, paracetamol

4. penicillin, erythromycin, cephalosporin

5. antilipid drugs, antidiabetic drugs

Question 10

What is the drug, or drug class, of first choice for the treatment of parkinsonian tremor?

1. dopaminergic drugs

2. propanolol

3. primidone

4. gabapentin

5. ondansetron

References

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Muscular dystrophy (MD) refers to a group of more than 30 genetic diseases that cause progressive weakness and degeneration of skeletal muscles used during voluntary movement. The word dystrophy is derived from the Greek dys, which means “difficult” or “faulty,” and troph, or “nourish.” These disorders vary in age of onset, severity, and pattern of affected muscles. All forms of MD grow worse as muscles progressively degenerate and weaken. Many individuals eventually lose the ability to walk.

The term “muscular dystrophy” incorporates an assortment of hereditary disorders that lead to progressive, generalized disease of the muscle prompted by inadequate or missing glycoproteins in the muscle cell plasma membrane. This activity outlines the evaluation and treatment of muscular dystrophy and highlights the role of the healthcare team in managing patients with this condition.

Some types of MD also affect the heart, gastrointestinal system, endocrine glands, spine, eyes, brain, and other organs. Respiratory and cardiac diseases may occur, and some people may develop a swallowing disorder. MD is not contagious and cannot be brought on by injury or activity.

What causes MD?

All of the muscular dystrophies are inherited and involve a mutation in one of the thousands of genes that program proteins critical to muscle integrity. The body’s cells don’t work properly when a protein is altered or produced in insufficient quantity (or sometimes missing completely). Many cases of MD occur from spontaneous mutations that are not found in the genes of either parent, and this defect can be passed to the next generation.

Genes are like blueprints: they contain coded messages that determine a person’s characteristics or traits. They are arranged along 23 rod-like pairs of chromosomes,  with one half of each pair being inherited from each parent. Each half of a chromosome pair is similar to the other, except for one pair, which determines the sex of the individual. Muscular dystrophies can be inherited in three ways:

• Autosomal dominant inheritance occurs when a child receives a normal gene from one parent and a defective gene from the other parent. Autosomal means the genetic mutation can occur on any of the 22 non-sex chromosomes in each of the body’s cells. Dominant means only one parent needs to pass along the abnormal gene in order to produce the disorder. In families where one parent carries a defective gene, each child has a 50 percent chance of inheriting the gene and therefore the disorder. Males and females are equally at risk and the severity of the disorder can differ from person to person.
• Autosomal recessive inheritance means that both parents must carry and pass on the faulty gene. The parents each have one defective gene but are not affected by the disorder. Children in these families have a 25 percent chance of inheriting both copies of the defective gene and a 50 percent chance of inheriting one gene and therefore becoming a carrier, able to pass along the defect to their children. Children of either sex can be affected by this pattern of inheritance.
• X-linked (or sex-linked) recessive inheritance occurs when a mother carries the affected gene on one of her two X chromosomes and passes it to her son (males always inherit an X chromosome from their mother and a Y chromosome from their father, while daughters inherit an X chromosome from each parent). Sons of carrier mothers have a 50 percent chance of inheriting the disorder. Daughters also have a 50 percent chance of inheriting the defective gene but usually are not affected, since the healthy X chromosome they receive from their father can offset the faulty one received from their mother. Affected fathers cannot pass an X-linked disorder to their sons but their daughters will be carriers of that disorder. Carrier females occasionally can exhibit milder symptoms of MD.

Muscular dystrophy most often results from defective or absent glycoproteins in the muscle membrane.[rx] Each type of muscular dystrophy results from different gene deletions or mutations, causing various enzymatic or metabolic defects. [rx] The dystrophin gene is the largest in the human genome, with 79 exons.[rx] The dystrophin gene is subject to a high rate of spontaneous mutations because of its enormous size (>2 × 106 bases).[rx]

Effect

Modes of Inheritance  

• Autosomal Dominant, Autosomal Recessive: Limb-Girdle (Dysferlinopathy, Erb), Pelvifemoral, Scapulohumeral
• Autosomal Dominant: Facioscapulohumeral (Landouzy-Dejerine), Late-Onset Distal (>40 Years old), Myotonic, Oculopharyngeal, Scapuloperoneal
• Autosomal Recessive: Congenital, Early Onset Distal (<40 years old)
• X-Linked: Becker (Benign Pseudohypertrophic), Duchenne (pseudohypertrophic)

Autosomal Dominant, Autosomal Recessive, X-Linked Inheritance

• Emery-Dreifuss (EDMD)

Emery-Dreifuss Muscular Dystrophy: Caused by an X-linked recessive defect in nuclear protein emerin at the Xq27-28 position.[rx] This variant can also result from an autosomal recessive or autosomal dominant defect in inner nuclear lamina proteins lamin A/C on chromosome 1.[rx]

Autosomal Dominant, Autosomal Recessive Inheritance

• Limb-Girdle (Erb)
• Pelvifemoral *
• Scapulohumeral *

Limb-Girdle (Erb) Muscular Dystrophy: The majority are autosomal recessive but can be autosomal dominant.[rx] The age of onset is variable with the distribution of involved muscles to include limbs and trunk. May display a heterogeneous phenotype.[rx] The recessive form of the disease tends to have an earlier onset and progresses more quickly, whereas the dominant form follows a slower and more variable course.[rx] Several different genes have been implicated in this disease—this type of muscular dystrophy correlates with deficiencies identified in multiple proteins. Sarcoglycan, calpain, dystroglycan, and dysferlin may be most common.[rx] Also may involve telethon in, lamin A/C, myotilin, and caveolin-3.[rx] LGMB 1A: is caused by myotilin gene deletion.[rx]

LGMB 1B results from by lamin A/C gene deletion.[rx] LGMD 1C is the result of a caveolin 3 gene deletion.[rx] A calpain gene mutation causes LGMD 2A.[rx] LGMD 2B is caused by dysferlin gene deletion.[rx] LGMD 2C is caused by sarcoglycan gene deletion.[rx] LGMD 2D is caused by sarcoglycan gene deletion.[rx] LGMD 2E is caused by sarcoglycan gene deletion.[rx] LGMD 2F is caused by sarcoglycan gene deletion.[rx] LGMD 2G results from telethon in gene mutation.[rx] LGMD 2H is caused by a TRIM32 (tripartite motif-containing) gene 32 mutations.[rx] LGMD 2I is the result of a fukutin-related protein gene deletion.[rx]

Autosomal Dominant Inheritance

• Facioscapulohumeral (Landouzy-Dejerine)
• Late-Onset Distal (>40 Years old) *
• Myotonic
• Oculopharyngeal
• Scapuloperoneal 

Facioscapulohumeral (FSHD) Muscular Dystrophy: Caused by an autosomal dominant deletion of 3.3 kb repeat on chromosome 4.[rx] Approximately 95% of cases are due to a mutation in the D4Z4 region in FSHD1.[rx] Other areas, such as the SMCHD1 region in FSHD2, can also cause this disease.[rx] The age of onset is approximately 10 to 30 years old, with the distribution of affected muscles involved to be face, neck, and shoulders.[rx]

Myotonic Muscular Dystrophy: Myotonic muscular dystrophy (or simply Myotonic dystrophy) results from the impaired expression of the Dystrophia Myotonica Protein Kinase (DMPK).[rx] Caused by an autosomal dominant abnormally expanded CTG trinucleotide repeat sequence located in the 3′ untranslated region of the Dystrophia Myotonica Protein Kinase (DMPK) gene.[rx] Because this mechanism involves the expansion of trinucleotide repeat sequences (CTG), the phenomenon of amplification and anticipation occurs (i.e., family members get the disease at earlier and earlier ages throughout the generations).[rx]

Clinical severity increases as the number of nucleotides repeat increases; some cases can be in the thousands.[rx] Age of onset is approximately 10 to 15 years old with the distribution of involved muscles to include face and extremities. Some cases can be in the thousands.[rx] This defect is classically associated with chromosome 19; however, a second form can occur on chromosome 3q.[rx][rx]

Oculopharyngeal Muscular Dystrophy: Age of onset is approximately 30 to 40 years of age. The distribution of involved muscles includes the extraocular and pharyngeal muscles. Caused by an autosomal dominant GCG trinucleotide repeat resulting in deficient mRNA transfer from the nucleus.[rx]

Autosomal Recessive Inheritance

• Congenital
• Early Onset Distal (<40 years old) 

Congenital Muscular Dystrophy: Caused by a mutation of the sarcolemmal protein Merosin gene, deficiencies or mutations in laminin-alpha 2, collagen type VI, integrin-alpha 7, and glycosyltransferases.[rx]

X-Linked Inheritance

• Becker (benign pseudohypertrophic)
• Duchenne (pseudohypertrophic)

Becker Muscular Dystrophy: Caused by a mutation of muscle protein dystrophin gene, which codes for the protein dystrophin, with 79 exons, by far the largest gene known in humans.[rx] This gene transmitted in an X-linked re­cessive manner.[rx] Its location is on the small arm (p) of the X chromosome at the Xp21 locus position.[rx] Without dystrophin, muscle cells deteriorate or die. The age of onset is 10 to 20 years old, with the distribution of involved muscles to be generalized.[rx]

Duchenne Muscular Dystrophy: Caused by a mutation of the dystrophin gene, located on the small arm (p) of the X chromosome at the Xp21 position.[rx] A spontaneous mutation occurs in a third of cases.[rx][rx] X-linked recessive maternal-fetal transmission occurs in the other two-thirds of cases.[rx] The effect is resulting in a non-functional dystrophin protein, which causes similar effects as to that seen in Becker muscular dystrophy. Age of onset is approximately 3 to 5 years of age, with the distribution of involved muscles to be generalized.[rx]

How does MD affect muscles?

Muscles are made up of thousands of muscle fibers. Each fiber is actually a number of individual cells that have joined together during development and are encased by an outer membrane. Muscle fibers that make up individual muscles are bound together by connective tissue.

Muscles are activated when an impulse, or signal, is sent from the brain through the spinal cord and peripheral nerves (nerves that connect the central nervous system to sensory organs and muscles) to the neuromuscular junction (the space between the nerve fiber and the muscle it activates). There, a release of the chemical acetylcholine triggers a series of events that cause the muscle to contract.

The muscle fiber membrane contains a group of proteins—called the dystrophin-glycoprotein complex—which prevents damage as muscle fibers contract and relax. When this protective membrane is damaged, muscle fibers begin to leak the protein creatine kinase (needed for the chemical reactions that produce energy for muscle contractions) and take on excess calcium, which causes further harm. Affected muscle fibers eventually die from this damage, leading to progressive muscle degeneration.

Although MD can affect several body tissues and organs, it most prominently affects the integrity of muscle fibers. The disease causes muscle degeneration, progressive weakness, fiber death, fiber branching and splitting, phagocytosis (in which muscle fiber material is broken down and destroyed by scavenger cells), and, in some cases, chronic or permanent shortening of tendons and muscles. Also, overall muscle strength and tendon reflexes are usually lessened or lost due to the replacement of muscle by connective tissue and fat.

Are there other MD-like conditions?

There are many other heritable diseases that affect the muscles, the nerves, or the neuromuscular junction. Such diseases as inflammatory myopathy, progressive muscle weakness, and cardiomyopathy (heart muscle weakness that interferes with pumping ability) may produce symptoms that are very similar to those found in some forms of MD), but they are caused by different genetic defects. The differential diagnosis for people with similar symptoms includes congenital myopathy, spinal muscular atrophy, and congenital myasthenic syndromes. The sharing of symptoms among multiple neuromuscular diseases, and the prevalence of sporadic cases in families not previously affected by MD, often makes it difficult for people with MD to obtain a quick diagnosis. Gene testing can provide a definitive diagnosis for many types of MD, but not all genes have been discovered that are responsible for some types of MD. Some individuals may have signs of MD, but carry none of the currently recognized genetic mutations. Studies of other related muscle diseases may, however, contribute to what we know about MD.

How do the muscular dystrophies differ?

There are nine major groups of the muscular dystrophies. The disorders are classified by the extent and distribution of muscle weakness, age of onset, rate of progression, severity of symptoms, and family history (including any pattern of inheritance). Although some forms of MD become apparent in infancy or childhood, others may not appear until middle age or later. Overall, incidence rates and severity vary, but each of the dystrophies causes progressive skeletal muscle deterioration, and some types affect cardiac muscle.

Duchenne MD is the most common childhood form of MD, as well as the most common of the muscular dystrophies overall, accounting for approximately 50 percent of all cases. Because inheritance is X-linked recessive (caused by a mutation on the X, or sex, chromosome), Duchenne MD primarily affects boys, although girls and women who carry the defective gene may show some symptoms. About one-third of the cases reflect new mutations and the rest run in families. Sisters of boys with Duchenne MD have a 50 percent chance of carrying the defective gene.

Duchenne MD usually becomes apparent during the toddler years, sometimes soon after an affected child begins to walk. Progressive weakness and muscle wasting (a decrease in muscle strength and size) caused by degenerating muscle fibers begins in the upper legs and pelvis before spreading into the upper arms. Other symptoms include loss of some reflexes, a waddling gait, frequent falls and clumsiness (especially when running), difficulty when rising from a sitting or lying position or when climbing stairs, changes to overall posture, impaired breathing, lung weakness, and cardiomyopathy. Many children are unable to run or jump. The wasting muscles, in particular the calf muscles (and, less commonly, muscles in the buttocks, shoulders, and arms), may be enlarged by an accumulation of fat and connective tissue, causing them to look larger and healthier than they actually are (called pseudohypertrophy). As the disease progresses, the muscles in the diaphragm that assist in breathing and coughing may weaken. Affected individuals may experience breathing difficulties, respiratory infections, and swallowing problems. Bone thinning and scoliosis (curving of the spine) are common. Some affected children have varying degrees of cognitive and behavioral impairments. Between ages 3 and 6, children may show brief periods of physical improvement followed later on by progressive muscle degeneration. Children with Duchenne MD typically lose the ability to walk by early adolescence. Without aggressive care, they usually die in their late teens or early twenties from progressive weakness of the heart muscle, respiratory complications, or infection. However, improvements in multidisciplinary care have extended the life expectancy and improved the quality of life significantly for these children; numerous individuals with Duchenne muscular dystrophy now survive into their 30s, and some even into their 40s.

Duchenne MD results from an absence of the muscle protein dystrophin. Dystrophin is a protein found in muscle that helps muscles stay healthy and strong. Blood tests of children with Duchenne MD show an abnormally high level of creatine kinase; this finding is apparent from birth.

Becker MD is less severe than but closely related to Duchenne MD. People with Becker MD have partial but insufficient function of the protein dystrophin. There is greater variability in the clinical course of Becker MD compared to Duchenne MD. The disorder usually appears around age 11 but may occur as late as age 25, and affected individuals generally live into middle age or later. The rate of progressive, symmetric (on both sides of the body) muscle atrophy and weakness varies greatly among affected individuals. Many individuals are able to walk until they are in their mid-thirties or later, while others are unable to walk past their teens. Some affected individuals never need to use a wheelchair. As in Duchenne MD, muscle weakness in Becker MD is typically noticed first in the upper arms and shoulders, upper legs, and pelvis.

Early symptoms of Becker MD include walking on one’s toes, frequent falls, and difficulty rising from the floor. Calf muscles may appear large and healthy as deteriorating muscle fibers are replaced by fat, and muscle activity may cause cramps in some people. Cardiac complications are not as consistently present in Becker MD compared to Duchenne MD, but may be as severe in some cases. Cognitive and behavioral impairments are not as common or severe as in Duchenne MD, but they do occur.

Congenital MD refers to a group of autosomal recessive muscular dystrophies that are either present at birth or become evident before age 2. They affect both boys and girls. The degree and progression of muscle weakness and degeneration vary with the type of disorder. Weakness may be first noted when children fail to meet landmarks in motor function and muscle control. Muscle degeneration may be mild or severe and is restricted primarily to skeletal muscle. The majority of individuals are unable to sit or stand without support, and some affected children may never learn to walk. There are three groups of congenital MD:

• merosin-negative disorders, where the protein merosin (found in the connective tissue that surrounds muscle fibers) is missing;
• merosin-positive disorders, in which merosin is present but other needed proteins are missing; and
• neuronal migration disorders, in which very early in the development of the fetal nervous system the migration of nerve cells (neurons) to their proper location is disrupted.

Defects in the protein merosin cause nearly half of all cases of congenital MD.

People with congenital MD may develop contractures (chronic shortening of muscles or tendons around joints, which prevents the joints from moving freely), scoliosis, respiratory and swallowing difficulties, and foot deformities. Some individuals have normal intellectual development while others become severely impaired. Weakness in diaphragm muscles may lead to respiratory failure. Congenital MD may also affect the central nervous system, causing vision and speech problems, seizures, and structural changes in the brain. Some children with the disorders die in infancy while others may live into adulthood with only minimal disability.

Distal MD, also called distal myopathy, describes a group of at least six specific muscle diseases that primarily affect distal muscles (those furthest away from the shoulders and hips) in the forearms, hands, lower legs, and feet. Distal dystrophies are typically less severe, progress more slowly, and involve fewer muscles than other forms of MD, although they can spread to other muscles, including the proximal ones later in the course of the disease. Distal MD can affect the heart and respiratory muscles, and individuals may eventually require the use of a ventilator. Affected individuals may not be able to perform fine hand movements and have difficulty extending the fingers. As leg muscles become affected, walking and climbing stairs become difficult and some people may be unable to hop or stand on their heels. The onset of distal MD, which affects both men and women, is typically between the ages of 40 and 60 years. In one form of distal MD, a muscle membrane protein complex called dysferlin is known to be lacking.

Although distal MD is primarily an autosomal dominant disorder, autosomal recessive forms have been reported in young adults. Symptoms are similar to those of Duchenne MD but with a different pattern of muscle damage. An infantile-onset form of autosomal recessive distal MD has also been reported. Slow but progressive weakness is often first noticed around age 1, when the child begins to walk and continues to progress very slowly throughout adult life.

Emery-Dreifuss MD primarily affects boys. The disorder has two forms: one is X-linked recessive and the other is autosomal dominant.

The onset of Emery-Dreifuss MD is usually apparent by age 10, but symptoms can appear as late as the mid-twenties. This disease causes slow but progressive wasting of the upper arm and lower leg muscles and symmetric weakness. Contractures in the spine, ankles, knees, elbows, and back of the neck usually precede significant muscle weakness, which is less severe than in Duchenne MD. Contractures may cause elbows to become locked in a flexed position. The entire spine may become rigid as the disease progresses. Other symptoms include shoulder deterioration, toe-walking, and mild facial weakness. Serum creatine kinase levels may be moderately elevated. Nearly all people with Emery-Dreifuss MD have some form of heart problem by age 30, often requiring a pacemaker or other assistive device. Female carriers of the disorder often have cardiac complications without muscle weakness. Affected individuals often die in mid-adulthood from progressive pulmonary or cardiac failure. In some cases, the cardiac symptoms may be the earliest and most significant symptom of the disease and may appear years before muscle weakness does.

Facioscapulohumeral MD (FSHD) initially affects muscles of the face (facio), shoulders (scapula), and upper arms (humeral) with progressive weakness. Also known as Landouzy-Dejerine disease, this third most common form of MD is an autosomal dominant disorder. Most individuals have a normal life span, but some individuals become severely disabled. Disease progression is typically very slow, with intermittent spurts of rapid muscle deterioration. Onset is usually in the teenage years but may occur as early as childhood or as late as age 40. One hallmark of FSHD is that it commonly causes asymmetric weakness.  Muscles around the eyes and mouth are often affected first, followed by weakness around the shoulders, chest, and upper arms. A particular pattern of muscle wasting causes the shoulders to appear to be slanted and the shoulder blades to appear winged. Muscles in the lower extremities may also become weakened. Reflexes are diminished, typically in the same distribution as the weakness. Changes in facial appearance may include the development of a crooked smile, a pouting look, flattened facial features, or a mask-like appearance. Some individuals cannot pucker their lips or whistle and may have difficulty swallowing, chewing, or speaking. In some individuals, muscle weakness can spread to the diaphragm, causing respiratory problems. Other symptoms may include hearing loss (particularly at high frequencies) and lordosis, an abnormal swayback curve in the spine. Contractures are rare. Some people with FSHD feel severe pain in the affected limb. Cardiac muscles are not usually affected, and significant weakness of the pelvic girdle is less common than in other forms of MD. An infant-onset form of FSHD can also cause retinal disease and some hearing loss.

Limb-girdle MD (LGMD) refers to more than 20 inherited conditions marked by progressive loss of muscle bulk and symmetrical weakening of voluntary muscles, primarily those in the shoulders and around the hips. At least 5 forms of autosomal dominant limb-girdle MD (known as type 1) and 17 forms of autosomal recessive limb-girdle MD (known as type 2) have been identified. Some autosomal recessive forms of the disorder are now known to be due to a deficiency of any of four dystrophin-glycoprotein complex proteins called the sarcoglycans. Deficiencies in dystroglycan, classically associated with congenital muscular dystrophies, may also cause LGMD.

The recessive LGMDs occur more frequently than the dominant forms, usually begin in childhood or the teenage years, and show dramatically increased levels of serum creatine kinase. The dominant LGMDs usually begin in adulthood. In general, the earlier the clinical signs appear, the more rapid the rate of disease progression. Limb-girdle MD affects both males and females. Some forms of the disease progress rapidly, resulting in serious muscle damage and loss of the ability to walk, while others advance very slowly over many years and cause minimal disability, allowing a normal life expectancy. In some cases, the disorder appears to halt temporarily, but progression then resumes.

The pattern of muscle weakness is similar to that of Duchenne MD and Becker MD.  Weakness is typically noticed first around the hips before spreading to the shoulders, legs, and neck. Individuals develop a waddling gait and have difficulty when rising from chairs, climbing stairs, or carrying heavy objects. They fall frequently and are unable to run. Contractures at the elbows and knees are rare but individuals may develop contractures in the back muscles, which gives them the appearance of a rigid spine. Proximal reflexes (closest to the center of the body) are often impaired. Some individuals also experience cardiomyopathy and respiratory complications, depending in part on the specific subtype. Intelligence remains normal in most cases, though exceptions do occur. Many individuals with limb-girdle MD become severely disabled within 20 years of disease onset.

Myotonic dystrophy (DM1), also known as Steinert’s disease and dystrophia myotonica, is another common form of MD. Myotonia, or an inability to relax muscles following a sudden contraction, is found only in this form of MD, but is also found in other non-dystrophic muscle diseases. People with DM1 can live a long life, with variable but slowly progressive disability. Typical disease onset is between ages 20 and 30, but childhood-onset and congenital onset are well-documented. Muscles in the face and the front of the neck are usually first to show weakness and may produce a haggard, “hatchet” face and a thin, swan-like neck. Wasting and weakness noticeably affect forearm muscles. DM1 affects the central nervous system and other body systems, including the heart, adrenal glands and thyroid, eyes, and gastrointestinal tract. Other symptoms include cardiac complications, difficulty swallowing, droopy eyelids (called ptosis), cataracts, poor vision, early frontal baldness, weight loss, impotence, testicular atrophy, mild mental impairment, and increased sweating. Individuals may also feel drowsy and have an excessive need to sleep. There is a second form of the disease that is similar to the classic form but usually affects proximal muscles more significantly. This form is known as myotonic dystrophy type 2 (DM2).

This autosomal dominant disease affects both men and women. Females may have irregular menstrual periods and are sometimes infertile. The disease may occur earlier and be more severe in successive generations. A childhood-onset form of myotonic MD may become apparent between ages 5 and 10. Symptoms include general muscle weakness (particularly in the face and distal muscles), lack of muscle tone, and mental impairment.

A woman with DM1 can give birth to an infant with a rare congenital form of the disorder. Symptoms at birth may include difficulty swallowing or sucking, impaired breathing, absence of reflexes, skeletal deformities and contractures (such as club feet), and muscle weakness, especially in the face. Children with congenital myotonic MD may also experience mental impairment and delayed motor development. This severe infantile form of myotonic MD occurs almost exclusively in children who have inherited the defective gene from their mother, whose symptoms may be so mild that she is sometimes not aware that she has the disease until she has an affected child.

The inherited gene defect that causes DM1 is an abnormally long repetition of a three-letter “word” in the genetic code. In unaffected people, the word is repeated a number of times, but in people with DM1, it is repeated many more times. This triplet repeat gets longer with each successive generation. The triplet repeat mechanism has now been implicated in at least 15 other disorders, including Huntington’s disease and the spinocerebellar ataxias.

Oculopharyngeal MD (OPMD) generally begins in a person’s forties or fifties and affects both men and women. In the United States, the disease is most common in families of French-Canadian descent and among Hispanic residents of northern New Mexico. People first report drooping eyelids, followed by weakness in the facial muscles and pharyngeal muscles in the throat, causing difficulty swallowing. The tongue may atrophy and changes to the voice may occur. Eyelids may droop so dramatically that some individuals compensate by tilting back their heads. Affected individuals may have double vision and problems with upper gaze, and others may have retinitis pigmentosa (progressive degeneration of the retina that affects night vision and peripheral vision) and cardiac irregularities. Muscle weakness and wasting in the neck and shoulder region is common. Limb muscles may also be affected. Persons with OPMD may find it difficult to walk, climb stairs, kneel, or bend. Those persons most severely affected will eventually lose the ability to walk.

How are the muscular dystrophies diagnosed?

Both the individual’s medical history and complete family history should be thoroughly reviewed to determine if the muscle disease is secondary to a disease affecting other tissues or organs or is an inherited condition. It is also important to rule out any muscle weakness resulting from prior surgery, exposure to toxins, or current medications that may affect the person’s functional status or rule out many acquired muscle diseases. Thorough clinical and neurological exams can rule out disorders of the central and/or peripheral nervous systems, identify any patterns of muscle weakness and atrophy, test reflex responses and coordination, and look for contractions.

Various laboratory tests may be used to confirm the diagnosis of MD.

Blood and urine tests can detect defective genes and help identify specific neuromuscular disorders. For example:

• Creatine kinase is an enzyme that leaks out of the damaged muscle. Elevated creatine kinase levels may indicate muscle damage, including some forms of MD before physical symptoms become apparent. Levels are significantly increased in the early stages of Duchenne and Becker MD. Testing can also determine if a young woman is a carrier of the disorder.
• The level of serum aldolase, an enzyme involved in the breakdown of glucose, is measured to confirm a diagnosis of skeletal muscle disease. High levels of the enzyme, which is present in most body tissues, are noted in people with MD and some forms of myopathy.
• Myoglobin is measured when injury or disease in skeletal muscle is suspected. Myoglobin is an oxygen-binding protein found in cardiac and skeletal muscle cells. High blood levels of myoglobin are found in people with MD.
• Polymerase chain reaction (PCR) can detect some mutations in the dystrophin gene. Also known as molecular diagnosis or genetic testing, PCR is a method for generating and analyzing multiple copies of a fragment of DNA.
• Serum electrophoresis is a test to determine quantities of various proteins in a person’s DNA. A blood sample is placed on specially treated paper and exposed to an electric current. The charge forces the different proteins to form bands that indicate the relative proportion of each protein fragment.

Exercise tests can detect elevated rates of certain chemicals following exercise and are used to determine the nature of the MD or other muscle disorders. Some exercise tests can be performed bedside while others are done at clinics or other sites using sophisticated equipment. These tests also assess muscle strength. They are performed when the person is relaxed and in the proper position to allow technicians to measure muscle function against gravity and detect even slight muscle weakness. If weakness in respiratory muscles is suspected, respiratory capacity may be measured by having the person take a deep breath and count slowly while exhaling.

Genetic testing looks for genes known to either cause or be associated with inherited muscle disease. DNA analysis and enzyme assays can confirm the diagnosis of certain neuromuscular diseases, including MD. Genetic linkage studies can identify whether a specific genetic marker on a chromosome and a disease are inherited together. They are particularly useful in studying families with members in different generations who are affected. An exact molecular diagnosis is necessary for some of the treatment strategies that are currently being developed. Advances in genetic testing include whole-exome and whole-genome sequencing, which will enable people to have all of their genes screened at once for disease-causing mutations, rather than have just one gene or several genes tested at a time. Exome sequencing looks at the part of the individual’s genetic material, or genome, that “code for” (or translate) into proteins.

Genetic counseling can help parents who have a family history of MD determine if they are carrying one of the mutated genes that cause the disorder. Two tests can be used to help expectant parents find out if their child is affected.

• Amniocentesis, done usually at 14-16 weeks of pregnancy, tests a sample of the amniotic fluid in the womb for genetic defects (the fluid and the fetus have the same DNA). Under local anesthesia, a thin needle is inserted through the woman’s abdomen and into the womb. About 20 milliliters of fluid (roughly 4 teaspoons) is withdrawn and sent to a lab for evaluation. Test results often take 1-2 weeks.
• Chorionic villus sampling, or CVS, involves the removal and testing of a very small sample of the placenta during early pregnancy. The sample, which contains the same DNA as the fetus, is removed by catheter or a fine needle inserted through the cervix or by a fine needle inserted through the abdomen. The tissue is tested for genetic changes identified in an affected family member. Results are usually available within 2 weeks.

Diagnostic imaging can help determine the specific nature of a disease or condition. One such type of imaging, called magnetic resonance imaging (MRI), is used to examine muscle quality, any atrophy or abnormalities in size, and fatty replacement of muscle tissue, as well as to monitor disease progression. MRI scanning equipment creates a strong magnetic field around the body. Radio waves are then passed through the body to trigger a resonance signal that can be detected at different angles within the body. A computer processes this resonance into either a three-dimensional picture or a two-dimensional “slice” of the tissue being scanned. MRI is a non-invasive, painless procedure. Other forms of diagnostic imaging for MD include phosphorus magnetic resonance spectroscopy, which measures cellular response to exercise and the amount of energy available to the muscle fiber, and ultrasound imaging (also known as sonography), which uses high-frequency sound waves to obtain images inside the body. The sound wave echoes are recorded and displayed on a computer screen as a real-time visual image. Ultrasound may be used to measure muscle bulk. MRI scans of the brain may be useful in diagnosing certain forms of congenital muscular dystrophy where structural brain abnormalities are typically present.

Muscle biopsies are used for diagnostic purposes, and in research settings, to monitor the course of disease and treatment effectiveness. Using local or general anesthesia, a physician or surgeon can remove a small sample of muscle for analysis. The sample may be gathered either surgically, through a slit made in the skin, or by needle biopsy, in which a thin hollow needle is inserted through the skin and into the muscle. A small piece of muscle remains in the hollow needle when it is removed from the body. The muscle specimen is stained and examined to determine whether the person has muscle disease, nerve disease (neuropathy), inflammation, or another myopathy. Muscle biopsies can sometimes also assist in carrier testing. With the advent of accurate molecular techniques, muscle biopsy is less frequently needed to diagnose muscular dystrophies. Muscle biopsy is still necessary to make the diagnosis in most of the acquired muscle diseases.

Immunofluorescence testing can detect specific proteins such as dystrophin within muscle fibers. Following biopsy, fluorescent markers are used to stain the sample that has the protein of interest.

Electron microscopy can identify changes in subcellular components of muscle fibers. Electron microscopy can also identify changes that characterize cell death, mutations in muscle cell mitochondria, and an increase in connective tissue seen in muscle diseases such as MD. Changes in muscle fibers that are evident in a rare form of distal MD can be seen using an electron microscope.

Chromosomal Analysis – DNA testing for common mutations and chromosomal analysis can now rule out Down syndrome, myotonic dystrophy, and other disorders. In both Becker and Duchenne dystrophies, the DNA deletion size does not predict clinical severity.[rx] DNA deletion, however, does not change the translational read frame of the messenger RNA in approximately 95 percent of patients suffering from Becker dystrophy. Such “in-frame” mutations allow for the development of dystrophin, which explains the existence of dystrophin on Western blot examination.[rx]

Immunocytochemistry – A definitive diagnosis of muscular dystrophy can be established based on dystrophin deficiency in a biopsy of muscle tissue.[rx] Also, staining of muscle with dystrophin antibodies can demonstrate the absence or deficiency of dystrophin localizing to the sarcolemmal membrane.[rx] Disease carriers may demonstrate a mosaic pattern, but dystrophin analysis of muscle biopsy specimens for carrier detection is not reliable.[rx] Immunohistochemistry reveals the absence of emerin staining of myonuclei in X-linked Emery-Dreifuss due to emerin mutations.[rx]

Alanine Aminotransferase (ALT, SGPT) – The normal range in males is 10 to 40 U/L. The normal range in females is 8 to 35 U/L; it is elevated in muscular dystrophy.[rx]

Aldolase (Serum) – The normal range is 0 to 6 U/L. It is elevated in muscular dystrophy but decreases in later stages of muscular dystrophy.[rx]

Arterial Blood Gases (ABG) – Normal ranges: PO2 is 75 to 100 mmHg; PCO2 is 35 to 45 mm Hg; HCO3- is 24 to 28 mEq/L; pH is 7.35 to 7.45. Respiratory acidosis can develop if there are defects in muscles involved in respiration.[rx]

Aspartate Aminotransferase (AST) – Normal ranges from 0 to 35 U/L. Elevated in muscular dystrophy.[rx]

Polysomnogram – Excessive daytime somnolence with or without sleep apnea is not uncommon. Sleep studies, noninvasive respiratory support (biphasic positive airway pressure [BiPAP]), and treatment with modafinil may be beneficial.[rx]

Slit Lamp – An examination for cataracts that may be present in patients with muscular dystrophy.[rx]

Western Blot – A diagnosis of Duchenne dystrophy can also be made by Western blot analysis of muscle biopsy specimens, revealing abnormalities in the quantity and molecular weight of dystrophin protein. On Western blot, Becker muscular dystrophy individuals dystrophin levels will appear normal, although the protein itself is abnormal; this is in comparison to Duchenne muscular dystrophy affected individuals who have a significantly decreased dystrophin on Western blot.[rx]

Neurophysiology studies can identify physical and/or chemical changes in the nervous system.

• Nerve conduction velocity studies measure the speed and strength with which an electrical signal travels along a nerve. A small surface electrode stimulates a nerve, and a recording electrode detects the resulting electrical signal either elsewhere on the same nerve or on a muscle controlled by that nerve. The response can be assessed to determine whether nerve damage is present.
• Repetitive stimulation studies involve electrically stimulating a motor nerve several times in a row to assess the function of the neuromuscular junction. The recording electrode is placed on a muscle controlled by the stimulated nerve, as is done for a routine motor nerve conduction study.
• Electromyography (EMG) can record muscle fiber and motor unit activity. A tiny needle containing an electrode is inserted through the skin into the muscle. The electrical activity detected in the muscle can be displayed on a monitor, and can also be heard when played through a speaker. Results may reveal electrical activity characteristics of MD or other neuromuscular disorders.

How are the muscular dystrophies treated?

All forms of MD are genetic and cannot be prevented at this time, aside from the use of prenatal screening interventions. However, available treatments are aimed at keeping the person independent for as long as possible and prevent complications that result from weakness, reduced mobility, and cardiac and respiratory difficulties. Treatment may involve a combination of approaches, including physical therapy, drug therapy, and surgery.  The available treatments are sometimes quite effective and can have a significant impact on life expectancy and quality of life.

• Anti-Arrhythmics – The pharmacological treatment of patients with a prevalent involvement of the cardiac tissue conduction relies on the use of ACE inhibitors and appropriate antiarrhythmic drugs. In the case of atrial arrhythmias, the preference is for drugs such as antiarrhythmics (flecainide, propafenone) and beta-blockers. Amiodarone should be limited to patients who do not respond to the previous drugs, taking in mind that these are young patients, long-term therapy, and a high risk of adverse effects on the thyroid and pulmonary function.[rx]
• Anti-Epileptics – Children need to be followed closely by neurologists. Management of epilepsy is necessary for some patients.[rx]
• Anti-Myotonics – The pain associated with muscle rigidity is greatly alarming in the patient.[rx] When myotonia is disabling, treatment with a sodium channel blocker such as phenytoin (100 mg orally three times daily), procainamide (0.5–1 g orally four times daily), or mexiletine (150 to 200 mg orally three times daily) may prove helpful, but the associated side effects, particularly for antiarrhythmic medications, are often limiting.[rx] The preferred drug for a symptomatic patient requiring anti-myotonia medication is phenytoin and mexiletine; other medications, especially quinine and procainamide, can cause an increase in the risk of cardiovascular complications.[rx]
• Assisted ventilation – is often needed to treat respiratory muscle weakness that accompanies many forms of MD, especially in the later stages. Air that includes supplemental oxygen is fed through a flexible mask (or, in some cases, a tube inserted through the esophagus and into the lungs) to help the lungs inflate fully. Since respiratory difficulty may be most extreme at night, some individuals may need overnight ventilation. Many people prefer non-invasive ventilation, in which a mask worn over the face is connected by a tube to a machine that generates intermittent bursts of forced air that may include supplemental oxygen. Some people with Duchenne MD, especially those who are overweight, may develop obstructive sleep apnea and require nighttime ventilation. Individuals on a ventilator may also require the use of a gastric feeding tube.
• Drug therapy – may be prescribed to delay muscle degeneration. The U.S. Food and Drug Administration (FDA) has approved injections of the drugs golodirsen and viltolarsen to treat Duchenne muscular dystrophy (DMD) patients who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping. It is estimated that about 8 percent of patients with DMD have this mutation. The FDA has approved the injection of the drug casimersen to treat patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping.  The FDA also approved three applications of fingolimod (Gilenya) to treat the relapsing form of MS in adults. Corticosteroids such as prednisone can slow the rate of muscle deterioration in Duchenne MD and help children retain strength and prolong independent walking by as much as several years. However, these medicines have side effects such as weight gain, facial changes, loss of linear (height) growth, and bone fragility that can be especially troubling in children. Immunosuppressive drugs such as cyclosporine and azathioprine can delay some damage to dying muscle cells. Drugs that may provide short-term relief from myotonia (muscle spasms and weakness) include mexiletine; phenytoin; baclofen, which blocks signals sent from the spinal cord to contract the muscles; dantrolene, which interferes with the process of muscle contraction; and quinine.  The Food and Drug Administration has granted accelerated approval of the drug Exondys 51 to treat individuals who have a confirmed mutation of the dystrophin gene amenable to exon 15 skipping.  The accelerated approval means the drug can be administered to selected individuals who meet the rare disease criteria while the company works on additional trials to learn more about the effectiveness of the drug.  (Drugs for myotonia may not be effective in myotonic MD but work well for myotonia congenita, a genetic neuromuscular disorder characterized by the slow relaxation of the muscles.) Respiratory infections may be treated with antibiotics.
• Glucocorticoid Therapy – Glucocorticoid therapy decreases the rate of apoptosis of myotubes and can decelerate myofiber necrosis. Prednisone is used in patients four years and older in whom muscle function is declining or plateauing. Prednisone is recommended at a dosage of (0.75 mg/kg per day or 10 mg/kg per week is given over two weekend days). Deflazacort, an oxazoline derivative of prednisone, is sometimes preferred over prednisone as it has a better side effect profile and has an estimated dosage equivalency of 1:1.3 compared with prednisone. The recommended dosage is 0.9 mg/kg/day. Studies have shown that glucocorticoid treatment is associated with improved pulmonary function, delayed development of scoliosis reduces incidence and progression of cardiomyopathy, and overall improved mortality.
• Golodirsen (SRP-4053): This drug is an antisense therapy used for the treatment of Duchenne muscular dystrophy. Patients need to have a confirmed mutation of the dystrophin gene to facilitate exon 53 skipping. It is FDA approved, but the evidence to support its use is not yet well established.[rx][rx]
• Cardiomyopathy – Treatment with angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers is recommended. Early studies suggest that early treatment with ACE inhibitors may slow the progression of the disease and prevent the onset of heart failure. Overt heart failure is treated with digoxins and diuretics as in other patients with cardiomyopathy. Surveillance consists of a cardiology assessment with ECG and echocardiogram. This should be performed at the time of diagnosis or by the age of 6 years. Routine surveillance should be performed once every two years until the age of 10 and then yearly after that. If evidence of cardiomyopathy is present, surveillance every six months is indicated.
• Pulmonary Interventions – The pulmonary function must be tested prior to the exclusive use of a wheelchair. This should be repeated twice a year once the patient reaches 12 years of age, must use a wheelchair, or vital capacity is found to be less than 80% of predicted.
• Orthopedic Interventions – Physiotherapy to prevent contractures is the mainstay of orthopedic interventions. Based upon patient requirements, passive stretching exercises, plastic ankle-foot orthosis during sleep, long leg braces to assist in ambulation may be used. Surgery to release contractures may be required for advanced disease. Surgery to correct scoliosis may improve pulmonary function.
• Nutrition – Patients are at risk for malnutrition, including obesity. Calcium and vitamin D should be supplemented to prevent osteoporosis secondary to chronic steroid use. DEXA scanning should be obtained at age three and then repeated yearly.
• Exercise – Guidelines recommend all patients participate in a gentle exercise to avoid disuse atrophy. A combination of swimming pool and recreation-based exercises is recommended. Activity should be reduced if myoglobinuria is noted or significant muscle pain develops.

Physical therapy

It can help prevent deformities, improve movement, and keep muscles as flexible and strong as possible. Options include passive stretching, postural correction, and exercise. A program is developed to meet the individual’s needs. Therapy should begin as soon as possible following diagnosis before there is joint or muscle tightness.

• Passive stretching can increase joint flexibility and prevent contractures that restrict movement and cause loss of function. When done correctly, passive stretching is not painful. The therapist or other trained health professional slowly moves the joint as far as possible and maintains the position for about 30 seconds. The movement is repeated several times during the session. Passive stretching on children may be easier following a warm bath or shower.
• Regular, moderate exercise can help people with MD maintain range of motion and muscle strength, prevent muscle atrophy, and delay the development of contractures. Individuals with a weakened diaphragm can learn coughing and deep breathing exercises that are designed to keep the lungs fully expanded.
• Postural correction is used to counter the muscle weakness, contractures, and spinal irregularities that force individuals with MD into uncomfortable positions. When possible, individuals should sit upright, with feet at a 90-degree angle to the floor. Pillows and foam wedges can help keep the person upright, distribute weight evenly, and cause the legs to straighten. Armrests should be at the proper height to provide support and prevent leaning.
• Support aids such as wheelchairs, splints and braces, other orthopedic appliances, and overhead bed bars (trapezes) can help maintain mobility. Braces are used to help stretch muscles and provide support while keeping the person ambulatory. Spinal supports can help delay scoliosis. Night splints, when used in conjunction with passive stretching, can delay contractures. Orthotic devices such as standing frames and swivel walkers help people remain standing or walking for as long as possible, which promotes better circulation and improves calcium retention in bones.
• Repeated low-frequency bursts of electrical stimulation to the thigh muscles may produce a slight increase in strength in some boys with Duchenne MD, though this therapy has not been proven to be effective.

Occupational therapy may help some people deal with progressive weakness and loss of mobility. Some individuals may need to learn new job skills or new ways to perform tasks while other persons may need to change jobs. Assistive technology may include modifications to home and workplace settings and the use of motorized wheelchairs, wheelchair accessories, and adaptive utensils.

Speech therapy – may help individuals whose facial and throat muscles have weakened. Individuals can learn to use special communication devices, such as a computer with a voice synthesizer

Dietary changes – have not been shown to slow the progression of MD. Proper nutrition is essential, however, for overall health. Limited mobility or inactivity resulting from muscle weakness can contribute to obesity, dehydration, and constipation. A high-fiber, high-protein, low-calorie diet combined with recommended fluid intake may help. Feeding techniques can help people with MD who have a swallowing disorder and find it difficult to pass from or liquid from the mouth to the stomach.

Supportive Bracing – This helps to maintain normal function as long as possible  Proper wheelchair seating is essential. Molded ankle-foot orthoses help stabilize gait in patients with foot drop.[rx] Lightweight plastic ankle-foot orthoses (AFOs) for footdrop are extremely helpful. Footdrop is easily treatable with AFOs.[rx] Individuals with scapuloperoneal muscular dystrophy remain ambulatory for 40 or more years.[rx]  Occasionally, walking may become hampered by paraspinal muscle contractures; in that case, a wheelchair may assist the individual when it is necessary to cover long distances.[rx] Bracing may be performed for function; for example, dorsiflexion of the feet with ankle-foot orthotics to prevent tripping or to provide support and comfort.[rx]

Supportive Counseling – Some forms of muscular dystrophy may be arrested for prolonged periods, and most patients remain active with a normal life expectancy.[rx] Thus, vocational training and supportive counseling are important to provide the information necessary to plan their future.

Corrective surgery is often performed to ease complications from MD.

• Tendon or muscle-release surgery is recommended when a contracture becomes severe enough to lock a joint or greatly impair movement. The procedure, which involves lengthening a tendon or muscle to free movement, is usually performed under general anesthesia. Rehabilitation includes the use of braces and physical therapy to strengthen muscles and maintain the restored range of motion.  A period of immobility is often needed after these orthopedic procedures, thus the benefits of the procedure should be weighed against the risk of this period of immobility, as the latter may lead to a setback.
• Individuals with either Emery-Dreifuss or myotonic dystrophy may require a pacemaker at some point to treat cardiac problems.
• Surgery to reduce the pain and postural imbalance caused by scoliosis may help some individuals. Scoliosis occurs when the muscles that support the spine begin to weaken and can no longer keep the spine straight. The spinal curve, if too great, can interfere with breathing and posture, causing pain. One or more metal rods may need to be attached to the spine to increase strength and improve posture. Another option is spinal fusion, in which bone is inserted between the vertebrae in the spine and allowed to grow, fusing the vertebrae together to increase spinal stability.
• People with myotonic dystrophy often develop cataracts, a clouding of the lens of the eye that blocks light. Cataract surgery involves removing the cloudy lens to improve the person’s ability to see.

What research is being done?

The NIH supports a broad range of basic, translational, and clinical research in the MDs.  Advances in basic research are essential to the basic understanding of each type of MD. While many genes that cause muscular dystrophy still remain to be identified, advances in gene sequencing have aided the identification of genes that may be involved in most types of muscular dystrophy.  In turn, new knowledge of specific disease mechanisms is identifying potential targets for therapy development.  In recent years, research into the underlying disease mechanisms has created new opportunities for therapy development in nearly all types of MD. For example,  advances in targeted therapy have led to promising efforts in myotonic dystrophy and facioscapulohumeral muscular dystrophy.

Federal funding, through the NIH and other agencies, as well as the venture philanthropy programs supported by patient advocacy groups, have attracted biotechnology and pharmaceutical firm investments into therapies for the MDs.

Currently, a variety of strategies are employed in developing a new drug and biologic therapies for the range of MDs. Strategies being explored are either specific to a particular type of MD or may address disease progression that may apply to multiple types of MD.

Gene replacement therapy – Gene therapy has the potential for directly addressing the primary cause of MD by providing for the production of the missing protein.  Hurdles to be overcome include determining the timing of the therapy (to possibly overcome the genetic defect), avoiding or easing potential immune responses to the replacement gene, and, in the case of Duchenne MD, the large size of the gene to be replaced.  For those MDs with central nervous system consequences (congenital muscular dystrophy and myotonic dystrophy), researchers are developing and fine-tuning gene therapy vectors (a way to deliver genetic materials to cells) that can cross the protective blood-brain barrier.

Recent progress in the delivery of replacement genes in MD includes considerable refinement of the viral vector types that improve the targeting to skeletal muscle and vascular approaches to deliver replacement genes to most or all skeletal muscles. Approaches that work for skeletal muscles may or may not work for cardiac muscle; this is a challenge that must be met since many MDs cause cardiomyopathy. The strategies for assessing potential immune responses to the proteins encoded by replacement genes and for managing those responses also have received considerable attention in animal model studies and in human clinical trials. Finally, for some MDs, early detection of the disease-causing mutations, through newborn screening, may be necessary for gene replacement therapy to be used early enough to mitigate the progression of the disease.

Clinical testing of gene therapy strategies in MD has been underway for Duchenne and limb-girdle muscular dystrophy. Injections of gene therapy vectors into single muscles of participants were done as a first step to establishing the safety of the approach. With the support of extensive studies in animal models, clinical trials are now moving toward testing of gene therapy of all muscles of entire limbs, using an isolated vascular delivery approach. If isolated limb delivery approaches prove safe and effective, research will move to systemic delivery of gene therapy vectors so all muscles can be treated simultaneously.

Utrophin is a protein that is closely related to dystrophin and is not affected in the gene mutations that cause Duchenne MD. Targeting increased expression of utrophin may prove a useful approach in treating Duchenne MD. NIH supports both gene therapy and small molecule drug development programs to increase the muscle production of utrophin.

Finally, modifier genes—genes with activities that act to reduce the severity of MD—have been discovered by NIH-funded teams. These genes, including latent TGF binding protein 4 and osteopontin, represent new therapeutic targets to potentially reduce the severity of several types of muscular dystrophy.

Genetic modification therapy to bypass inherited mutations – Most individuals with Duchenne have mutations in the dystrophin gene that cause it to function improperly and stop producing the dystrophin protein. By manipulating the protein synthesis process, the production of a gene that either “reads through” or “skips” the genetic mutation can result in at least partial functional dystrophin.

Two strategies are currently under study to bypass dystrophin mutations, one of which is drugs that cause the protein synthesis machinery to ignore the premature stop signal and produce functional dystrophin. This strategy, which is potentially useful in about 15 percent of individuals with Duchenne MD, is currently in clinical trials. Second, a more recent approach uses antisense oligonucleotides (short strands of nucleic acid designed to block the transfer of some genetic information into protein production) to alter splicing and produce nearly a full-length dystrophin gene, potentially converting an individual with Duchenne to a much milder Becker MD.  Two biotechnology companies are currently testing oligonucleotide drugs in advanced clinical trials for people who require skipping of exon 51 of dystrophin.  (An exon is a coding sequence in a gene for a protein). NINDS and NIAMS are supporting preclinical work on oligonucleotide drugs for individuals with Duchenne MD  who require skipping of exon 45. While the exon-skipping approach requires ‘personalized medicines’ for subsets of people having Duchenne who need skipping of specific exons, as many as 80 percent of affected individuals could benefit from this new technology.

Antisense oligonucleotide technology is also being evaluated for use in myotonic dystrophy, but by a different mechanism than in Duchenne MD. In myotonic dystrophy, long duplications of repetitive DNA sequences lead to the production of a toxic RNA that sequesters a splicing regulator, Muscleblind, causing mis-splicing of many genes in muscle and brain. An NINDS and NIAMS-supported project is advancing an oligonucleotide therapeutic designed to degrade the toxic RNA and mitigate the splicing defects. This approach, in partnership with academic investigators and biotechnology and pharmaceutical companies, has the potential to address all people having myotonic dystrophy and is planned to be in clinical trials within the next few years.

Drug-based therapy to delay muscle wasting by promoting muscle growth or mitigating damage due to inflammation
Progressive loss of muscle mass is primarily responsible for reduced quality and length of life in MD. Drug treatment strategies designed to slow this muscle degeneration can have substantial impact on quality of life. Similarly, skeletal muscle has the ability to repair itself, but its regeneration and repair mechanisms are progressively depleted during the course of several types of MD. Understanding the repair mechanisms may provide new therapies to slow, and possibly stabilize, muscle degeneration.

Corticosteroids are known to extend the ability of people with Duchenne MD to walk by up to 2 years, but steroids have substantial side effects and their mechanism of action is unknown. Since several corticosteroid protocols are used, an NINDS-funded study is evaluating drugs and their efficacy and tolerability at different doses in order to determine optimal clinical practice for their use in Duchenne MD. In addition, a biotechnology company supported by the NIH’s National Center for Advancing Translational Sciences is developing a modified steroid to increase its efficacy in Duchenne while reducing the side effects that often limit individuals from using corticosteroid therapy.

Preclinical drug development efforts supported by NINDS and NIAMS are developing a peptide therapeutic that has, in animal models, dual activity in mitigating muscle damage due to inflammation and also enhancing muscle regeneration. Efforts to preserve muscle mass through inhibition of a negative regulator of muscle growth, myostatin, have encountered some roadblocks, including failed clinical trials, but are still under study.

Cell-based therapy
The muscle cells of people with MD often lack a critical protein, such as dystrophin in Duchenne MD or sarcoglycan in some of the limb-girdle MDs. Scientists are exploring the possibility that the missing protein can be replaced by introducing muscle stem cells capable of making the missing protein in new muscle cells. Such new cells would be protected from the progressive degeneration characteristic of MD and potentially restore muscle function in affected persons.

The natural regenerative capacity of muscle provides possibilities for treatment of MD. Researchers have shown that stem cells can be used to deliver a functional dystrophin gene to skeletal muscles of dystrophic mice and dogs.  The focus of research has been on identifying the cell types with the highest potential for engraftment and growth of muscle and on strategies to deliver these muscle precursor cells to human skeletal muscles. Overall, cell-based therapeutic approaches are under consideration for multiple types of MD.

Moving forward with research in MD
Until recently, most therapy development programs in MD were focused on Duchenne.  With the dramatic advances in understanding disease mechanisms, significant therapy development efforts are now being launched in many types of MD. NINDS funding supports teams working on the disease mechanisms in facioscapulohumeral muscular dystrophy, central nervous system involvement in myotonic dystrophy, and on the role of fibrosis in Duchenne MD. Similarly,  NIAMS-supported projects are identifying novel therapy development targets that are attracting interest from biotechnology and pharmaceutical companies and will help move toward therapy development programs for all types of MD.

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Peroneal Muscular Atrophy/Hereditary Motor and Sensory Neuropathy/Charcot-Marie-Tooth disease (CMT) is slowly progressive neurodegenerative hereditary chronic motor and sensory neuropathy disease and one of a group of disorders that cause damage to the peripheral nerves, the nerves that transmit information and signals from the brain and spinal cord to and from the rest of the body, as well as sensory information such as touch back to the spinal cord and brain.  CMT can also directly affect the nerves that control the muscles.  Progressive muscle weakness typically becomes noticeable in adolescence or early adulthood, but the onset of disease can occur at any age.  Because longer nerves are affected first, symptoms usually begin in the feet and lower legs and then can affect the fingers, hands, and arms.  Most individuals with CMT have some amount of physical disability, although some people may never know they have the disease.

CMT, also known as hereditary motor and sensory neuropathy, slowly progressive inherited neurological disorders distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands is one of the most common neuropathy affecting an estimated. It is possible to have two or more types of CMT, which happens when the person has mutations in two or more genes, each of which causes a form of the disease.  CMT is a heterogeneous genetic disease, meaning mutations in different genes can produce similar clinical symptoms.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves. During the last decade over two dozen genes have been identified in which mutations cause CMT. The disease illustrates a multitude of genetic principles, including diverse mutational mechanisms from point mutations to copy number variation (CNV), allelic heterogeneity, age-dependent penetrance and variable expressivity.

Types of Charcot-Marie-Tooth Disease

There are many different types of CMT disease, which may share some symptoms but vary by pattern of inheritance, age of onset, and whether the axon or myelin sheath is involved.

In general the three autosomal dominant neuropathy types based on NCV (normal >40-45 meters/second) were the following [Stojkovic 2016]:

• Demyelinating (CMT1) defined as NCV <35 m/s. The clinical findings of distal muscle weakness and atrophy and sensory loss were usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually became symptomatic between ages five and 25 years. Fewer than 5% of individuals became wheelchair dependent. Life span was not shortened.
• Axonal (non-demyelinating) (CMT 2) defined as NCV >45m/s. The clinical findings were distal muscle weakness and atrophy. Although axonal peripheral neuropathy shows extensive clinical overlap with demyelinating peripheral neuropathy, in general individuals with axonal neuropathy tended to be less disabled and have less sensory loss than individuals with demyelinating neuropathy.
• Dominant intermediate CMT (DI-CMT) defined as NCV 35-45 m/s. The clinical findings are a relatively typical CMT phenotype. NCVs are so variable that within a family some affected individuals fall in the demyelinating neuropathy range, whereas others fall in the axonal neuropathy range.

CMT1 – is caused by abnormalities in the myelin sheath.  The autosomal dominant disorder has six main subtypes.

• CMT1A – results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP22).  The PMP22 protein is a critical component of the myelin sheath.  Overexpression of this gene causes the abnormal structure and function of the myelin sheath.  CMT1A is usually slowly progressive.  Individuals experience weakness and atrophy of the muscles of the lower legs beginning in childhood; later they experience hand weakness, sensory loss, and foot and leg problems.  A different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP22 genes.  In this case, abnormally low levels of the PMP22 gene result in episodic, recurrent demyelinating neuropathy.
• CMT1B – is caused by mutations in the gene that carries the instructions for manufacturing the myelin protein zero (MPZ, also called P0), which is another critical component of the myelin sheath.  Most of these mutations are point mutations, meaning a mistake occurs in only one letter of the DNA genetic code.  To date, scientists have identified more than 120 different point mutations in the P0 gene.  CMT1B produces symptoms similar to those found in CMT1A.
• Other less common causes of CMT1 result from mutations within the SIMPLE (also called LITAF), EGR2, PMP22, and NEFL genes, respectively.

CMT2

• Results from abnormalities in the axon of the peripheral nerve cell, rather than the myelin sheath, and is less common than CMT1.  This autosomal dominant disorder has more than a dozen subtypes (some of which have their own variants), with each subtype being associated with mutations in a specific gene.  Symptoms are similar to those seen in CMT1, but people with CMT2 often have less disability and sensory loss than individuals with CMT1.  The onset of CMT2 is usually in childhood or adolescence.  Some types of CMT2 may have vocal cord or phrenic nerve involvement, causing speech or breathing problems.

CMT3, or Dejerine-Sottas disease

• It is a particularly severe demyelinating neuropathy that begins in infancy.  Infants have severe muscle atrophy, weakness, delayed motor skills development, and sensory problems.  Symptoms may progress to severe disability, loss of sensation, and curvature of the spine.  This rare disorder can be caused by mutations in multiple genes, including PMP22, MPZ, and EGR2, and can be inherited either dominantly or recessively.

CMT4

• It comprises several different subtypes of demyelinating and axonal and motor neuropathies that are inherited autosomal recessively.   Each neuropathy subtype is caused by a mutation in a different gene (several genes have been identified in CMT4).  The mutations may affect a particular ethnic population and produce distinct physiologic or clinical characteristics.  People with CMT4 generally develop symptoms of leg weakness in childhood and by adolescence they may not be able to walk.  CMT4 is rare in the United States.

CMTX1 (also called CMT X, Type 1)

• It is the second most common form of CMT.  This X-linked disease is caused by mutations in a gene that provides instructions for making the protein connexin-32.  The connexin-32 protein is found in myelinating Schwann cells—cells that wrap around nerve axons and make up the myelin sheath.  Males who inherit the mutated gene show moderate to severe symptoms of the disease beginning in late childhood or adolescence.  Females who inherit a mutated gene often develop milder symptoms than males or do not show symptoms.

Disease phenotypes

• Charcot–Marie–Tooth Disease  – As CMT1 and CMT2 present with similar clinical features, distinction on the basis of the neurological exam is often impossible. The onset of clinical symptoms is in the first or second decade of life. Weakness starts distally in the feet and progresses proximally in an ascending pattern. Neuropathic bony deformities develop including pes cavus (high-arched feet) and hammer toes. With further progression the hands become weak. Muscle stretch reflexes disappear early in the ankles and later in the patella and upper limbs. Mild sensory loss to pain, temperature or vibration sensation in the legs is consistent with the phenotype. Patients also complain of numbness and tingling in their feet and hands, but paresthesias are not as common as in acquired neuropathies. Restless leg syndrome occurs in nearly 40% of patients with the axonal form.^[rx]
• Hereditary neuropathy with liability to pressure palsies (MIM 162500) – The clinical phenotype is characterized by recurrent nerve dysfunction at compression sites. Asymmetric palsies occur after relatively minor compression or trauma. Repeated attacks result in the inability of full reversal. Thus with ageing the patients with hereditary neuropathy with liability to pressure palsies (HNPP) can have significant clinical overlap with CMT1. Electrophysiological findings include mildly slowed NCV, increased distal motor latencies and conduction blocks.^[rx] The neuropathological hallmark is sausage-like thickening of myelin sheaths (tomacula).
• Dejerine–Sottas neuropathy (MIM 145900) – Dejerine–Sottas neuropathy (DSN) is a clinically distinct entity defined by delayed motor milestones. Signs of lower motor neuron-type lesion accompany the delayed motor milestones. Neurophysiological studies reveal severe slowing of NCV (<10 m/s). Neuropathology reveals pronounced demyelination, and a greater number of onion bulbs are present compared to CMT. Cerebrospinal fluid proteins may be elevated. Most patients have significant disability.
• Congentital hypomyelinating neuropathy (MIM 605253) – Congentital hypomyelinating neuropathy (CHN) is usually present at birth, although frequently the delayed motor development draws the first attention to the peripheral neuropathy. The distinction between DSN and CHN is often difficult by clinical examination as they both may present as a hypotonic infant. The differentiation of CHN and DSN is based on pathology: the presence of onion bulbs suggest DSN whereas their absence indicate CHN. CHN may present as arthrogryposis multiplex congenita.^[rx]
• Roussy–Levy syndrome (MIM 180800) – Roussy–Levy syndrome (RLS) was originally described as demyelinating CMT associated with sensory ataxia and tremor. As molecular data became available, it was shown that these patients have the same molecular abnormalities as observed in patients clinically classified as demyelinating CMT. RLS represents the spectrum of CMT.

Causes Charcot-Marie-Tooth Disease

A nerve cell communicates information to distant targets by sending electrical signals down a long, thin part of the cell called the axon.  The axon is surrounded by myelin, a covering that acts like the insulation on an electrical wire and aids the high-speed transmission of electrical signals.  Without an intact axon and myelin sheath, signals that run along the nerve and axon are either slow or have a weak signal, meaning that the peripheral nerve cells become unable to activate muscles or relay sensory information from the limbs back to the spinal cord and the brain.

CMT is caused by mutations in genes that support or produce proteins involved in the structure and function of either the peripheral nerve axon or the myelin sheath. More than 40 genes have been identified in CMT, with each gene linked to one or more types of the disease.  In addition, multiple genes can be linked to one type of CMT.  More than half of all cases of CMT are caused by a duplication of the PMP22 gene on chromosome 17.

Although different proteins are abnormal in different forms of CMT disease, all of the mutations mainly affect the normal function of the peripheral nerves.  Gene defects in myelin cause dysfunction of the coating, which distorts or blocks nerve signals, while other mutations limit axon function and cause axonal loss.

CMTs may occur due to any one of the following molecular and cellular mechanisms

• Myelin assembly – genes involved in myelin compaction (MPZ), gap junctions formation (GJB1), the interaction of Schwann cells with the extracellular matrix as well as in regulating cell spreading, cell migration and apoptosis (PMP22)
• Cytoskeletal structure – genes involved in actin polymerization (INF2), membrane-protein interactions to stabilize the myelin sheath (PRX), intermediate filaments (NEFL), cell signaling (FGD4), axonal transport (DYNC1H1)
• Endosomal sorting and cell signaling – genes regulating vesicular transport, membrane trafficking, transport of intracellular organelles and cell signaling (LITAF, MTMR2, SBF1, SBF2, SH3TC2, NDRG1, FIG4, RAB7A, TFG, DNM2, SIMPLE)
• Proteasome and protein aggregation – genes regulating microtubules (HSPB1, HSPB8), cell adhesion (LRSAM1), ubiquitin ligase (TRIM2)
• Mitochondria – genes regulating mitochondrial dynamics, structure, and the function of the respiratory chain (MFN2, GDAP1, MT-ATP6, PDK3)
• Others – genes regulating cell fusion-fission apparatus (DNM2), calcium homeostasis (TRPV4) glucose metabolism (HK1), transcription (EGR2, HINT1, PRPS1, AARS, GARS, MARS, KARS, YARS)

Because of the close functional interaction, demyelinating neuropathies eventually lead to functional axonopathies and clinically manifest secondary axonal degeneration.[rx][rx] Thus common secondary phenomena in CMTs include axonal loss, secondary Schwann cell proliferation, and acceleration of pathology due to immune-mediated mechanisms.[rx]

Symptoms of Charcot-Marie-Tooth Disease

CMT affects both sensory and motor nerves (nerves that trigger an impulse for a muscle to contract) in the arms, hands, legs, and feet.  The affected nerves slowly degenerate and lose the ability to communicate with their distant targets.  Motor nerve degeneration results in muscle weakness and a decrease in muscle bulk (atrophy) in the arms, legs, hands, or feet.

Typical early features include weakness or paralysis of the foot and lower leg muscles, which can cause difficulty lifting the foot (foot drop) and a high-stepped gait with frequent tripping or falling.  Individuals also may notice balance problems.  Foot deformities, such as high arches and curled toes (hammertoes), are also common in CMT.  The lower legs may take on an “inverted champagne bottle” shape due to the loss of muscle bulk.  As the disease progresses, weakness and atrophy may occur in the hands, causing difficulty with fine motor skills.  Degeneration of sensory nerve axons may result in a reduced ability to feel heat, cold, and touch.  The senses of vibration and position (proprioception) are often decreased in individuals with CMT.  The disease also can cause curvature of the spine (scoliosis) and hip displacement.  Many people with CMT develop contractures—chronic shortening of muscles or tendons around joints, which prevents the joints from moving freely.  Muscle cramping is common.  Nerve pain can range from mild to severe, and some individuals may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Some people with CMT experience tremors and vision and hearing can also be affected. In rare cases, breathing difficulties may occur if the nerves that control the muscles of the diaphragm are affected.

The severity of symptoms can vary greatly among individuals and even among family members with the disease and gene mutation.  Progression of symptoms is gradual.

Signs and symptoms of Charcot-Marie-Tooth disease may include

• Weakness in your legs, ankles and feet
• Loss of muscle bulk in your legs and feet
• High foot arches
• Curled toes (hammertoes)
• Decreased ability to run
• Difficulty lifting your foot at the ankle (footdrop)
• Awkward or higher than normal step (gait)
• Frequent tripping or falling
• Decreased sensation or a loss of feeling in your legs and feet

As Charcot-Marie-Tooth disease progresses, symptoms may spread from the feet and legs to the hands and arms. The severity of symptoms can vary greatly from person to person, even among family members.

Diagnosis of Charcot-Marie-Tooth disease

Diagnosis of CMT begins with a detailed medical history, family history, and neurological examination.

Family History

• A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records, including the results of molecular genetic testing and EMG and NCV studies.

Physical Exam

Treatment of Charcot-Marie-Tooth

Non Pharmacological

There is no cure for CMT, but physical and occupational therapies, braces and other orthopedic devices, and orthopedic surgery can help people cope with the disabling symptoms of the disease.  In addition, pain-relief drugs can be prescribed for individuals who have severe nerve pain.

• Maintaining mobility, flexibility, and muscle strength – Beginning a treatment program early may delay or reduce nerve degeneration and muscle weakness before it progresses to the point of disability.  Physical therapy includes muscle strength training, muscle and ligament stretching, and moderate aerobic exercise.  A specialized exercise program approved by the person’s physician can help build stamina, increase endurance, and maintain overall health.
• Braces – Many individuals with CMT require ankle braces and other orthopedic devices to maintain everyday mobility and prevent injury.  Braces can help prevent ankle sprains by providing support and stability during activities such as walking or climbing stairs.  High-top shoes or boots also can give the person support for weak ankles.  Thumb splints can help with hand weakness and loss of fine motor skills.  Assistive devices should be used before disability sets in because the devices may prevent muscle strain and reduce muscle weakening. Some people with CMT may decide to have orthopedic surgery to treat severe foot and joint deformities, improve the ability to walk, and lessen pain.
• Occupational therapy –  involves learning new ways to cope with the activities of daily living.  For example, individuals with weakness in their arms and hands may learn to use Velcro closures or clasps instead of buttons on their clothes, or new ways of feeding themselves using assistive technology.
• Genetic counseling – Because CMT follows the principles of Mendelian inheritance, genetic counseling for recurrence of CMT1 and CMT2 is relatively straightforward if the family history for an affected individual is defined. Because of intrafamilial variability in disease expression, definition of parental disease status requires either testing for a mutation defined in the propositus or, if the mutation is not identifiable, a thorough neurological exam with objective NCS.

Medications

Symptomatic treatment may have a substantial impact on the quality of life.

• NSAIDs – Nonsteroidal anti-inflammatory drugs may help to relieve lower back or leg pain.
• Antiepileptic drugs – Neuropathic pain can be treated with antiepileptic drugs (gabapentin, pregabalin, topiramate) or tricyclic antidepressants (amitriptyline).^{[rx, rx]}
• Beta-blockers – The tremor may respond to β-blockers or primidone.^[rx] Caffeine and nicotine can aggravate the fine intentional tremor, thus avoidance of these substances is recommended.
• Neurotoxic drugs – excessive alcohol should be avoided. A small dose of vincristine can produce a devastating effect in patients with CMT, thus early detection of HMSN can avoid life-threatening vincristine neurotoxicity.^[rx]
• Vitamin C – Potential therapeutic approaches aiming at normalizing dosage by small molecules in the CMT1A duplication models include vitamin C and onapristone, a progesterone antagonist.^{[rx, rx, rx]} An alternate molecular mechanism, point mutations in Pmp22 in the Trembler and Trembler J mouse models cause peripheral neuropathy; the disease was modified by the administration of curcumin likely by alleviating the unfolded protein response.^[rx]
• Systemic biology-based modeling – anti-sense oligonucleotides, adenoviral vector-based drug delivery, and RNA interference technology. In CMT1A, agents target PMP22 overexpression such as ascorbic acid, onapristone, geldanamycin, and rapamycin have been beneficial in animal models and cell lines with improved muscle mass and weakness. However, these agents were not useful in human clinical trials.[rx] PXT3003 (a combination of baclofen, naltrexone, and d-sorbitol) has shown a reduction in the toxic effects of PMP22 over-expression in mice and humans. A significant number of subjects who received PXT3003 showed non-deterioration or improvement in CMT Neuropathy score(CMTNS), Overall Neuropathy Limitations Scale (ONLS), 10-meter walk test, and conduction velocities as compared to placebo. PXT3003 was well tolerated and safe.[rx] Curcumin reduces endoplasmic reticulum stress and improves MPZ associated neuropathy in mice.[rx]

Lifestyle and home remedies

Some habits may prevent complications caused by Charcot-Marie-Tooth disease and help you manage its effects.

Started early and followed regularly, at-home activities can provide protection and relief:

• Stretch regularly – Stretching can help improve or maintain the range of motion of your joints and reduce the risk of injury. It’s also helpful in improving your flexibility, balance and coordination. If you have Charcot-Marie-Tooth disease, regular stretching can prevent or reduce joint deformities that may result from uneven pulling of muscle on your bones.
• Exercise daily – Regular exercise keeps your bones and muscles strong. Low-impact exercises, such as biking and swimming, are less stressful on fragile muscles and joints. By strengthening your muscles and bones, you can improve your balance and coordination, reducing your risk of falls.
• Improve your stability – Muscle weakness associated with Charcot-Marie-Tooth disease may cause you to be unsteady on your feet, resulting in falls and serious injury. Walking with a cane or a walker can increase your stability. Good lighting at night can help you avoid stumbling and falling.

Here are some important points of which to take note

• CMTs are common inherited neuromuscular disorders characterized by progressive weakness, wasting, and skeletal deformities.
• Electrophysiological tests are useful to confirm the diagnosis of neuropathy and exclude alternative conditions that present with foot drop and/or foot deformities such as distal myopathies, muscular dystrophies, and idiopathic pes cavus, among others.
• Electrophysiological tests are useful to screen other family members for asymptomatic neuropathy.
• Patients of demyelinating CMTs have slowed conduction velocities within the first few years of life. Clinical manifestations of weakness, wasting, and deformities arise from axonal loss over the years.
• There is striking phenotypic variability suggesting the potential role for modifier genes and epigenetic factors.
• A detailed pedigree chart covering three or four generations is essential to find the pattern of inheritance. This is necessary before carrying out genetic studies.
• All patients should have genetic counseling before genetic testing.
• In the case of demyelinating neuropathies, the patient should first undergo testing for PMP22 duplication since it is the commonest genetic abnormality. After excluding copy number variations in PMP22, they need targeted gene sequencing or whole-exome sequencing.
• In the case of axonal neuropathies, the patient is first tested for mutations in MFN2. Alternately, the patient can directly undergo target gene sequencing or whole-exome sequencing.
• Establishing the genetic diagnosis is crucial for genetic counseling, reproductive planning, and considering the patient for potential upcoming therapies.
• Patients need to undergo specific tests to detect subclinical involvement of other organs/ systems to recommend timely prophylactic measures.
• Patients should avoid using drugs that worsen neuropathy.
• Patient education and counseling, regular follow-up, emphasis on rehabilitation measures, and consideration for therapeutic trials by a multi-disciplinary team are very important.

What research is being done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

Ongoing research on CMT includes efforts to identify more of the mutant genes and proteins that cause the various disease subtypes, discover the mechanisms of nerve degeneration and muscle atrophy with the goal of developing interventions to stop or slow down these debilitating processes, and develop therapies to reverse nerve degeneration and muscle atrophy.

The NINDS supports the NIH’s Rare Diseases Clinical Research Network, which is made up of different research consortia aimed at improving the availability of rare diseases information, clinical studies, and clinical research information.  The Network’s Inherited Neuropathies Consortium conducts studies that include a natural history analysis of CMT, the search for new genes and those that modify an individual’s symptoms, therapy development, and training programs to educate future investigators for the inherited neuropathies.  For more information on the Rare Diseases Clinical Research Network and its consortia, see Rare Diseases Info.

Scientists are studying PMP22 gene regulation to design and validate assays that measure the presence, amount, or activity of a target object.  Other studies examine the effects of small molecules on the biological system in order to develop novel treatments.  High-throughput screens (a way to quickly assess the biological activity of large numbers of compounds) may identify candidate medications that reduce PMP22 levels. Additional research focuses on how the mitochondria, the cell’s power plant, may play a role in the axonal degeneration seen in CMT, as well as other diseases.

An NIH longitudinal collaborative study hopes to determine the natural history of CMT and how the presence of a certain gene mutation may result in disease types and symptoms.  Also, a two-part study is looking for new genes that cause the disease as well as genes that do not cause the disease but may modify a person’s symptoms.  Other NIH-funded scientists are using next-generation sequencing (which can quickly identify the structure of millions of small fragments of DNA at the same time) to identify novel CMT genes.

Gene therapy is another promising area of research.  Experiments involving cell cultures and animal models of the disease have shown that it is possible to deliver genes to Schwann cells and muscles.  Other studies show trophic factors or nerve growth factors, such as the hormone androgen that prevent nerve degeneration.

References

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Hereditary Motor and Sensory Neuropathy/Charcot-Marie-Tooth disease (CMT) is slowly progressive neurodegenerative hereditary chronic motor and sensory neuropathy disease and one of a group of disorders that cause damage to the peripheral nerves, the nerves that transmit information and signals from the brain and spinal cord to and from the rest of the body, as well as sensory information such as touch back to the spinal cord and brain.  CMT can also directly affect the nerves that control the muscles.  Progressive muscle weakness typically becomes noticeable in adolescence or early adulthood, but the onset of disease can occur at any age.  Because longer nerves are affected first, symptoms usually begin in the feet and lower legs and then can affect the fingers, hands, and arms.  Most individuals with CMT have some amount of physical disability, although some people may never know they have the disease.

CMT, also known as hereditary motor and sensory neuropathy, slowly progressive inherited neurological disorders distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands is one of the most common neuropathy affecting an estimated. It is possible to have two or more types of CMT, which happens when the person has mutations in two or more genes, each of which causes a form of the disease.  CMT is a heterogeneous genetic disease, meaning mutations in different genes can produce similar clinical symptoms.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves. During the last decade over two dozen genes have been identified in which mutations cause CMT. The disease illustrates a multitude of genetic principles, including diverse mutational mechanisms from point mutations to copy number variation (CNV), allelic heterogeneity, age-dependent penetrance and variable expressivity.

Types of Charcot-Marie-Tooth Disease

There are many different types of CMT disease, which may share some symptoms but vary by pattern of inheritance, age of onset, and whether the axon or myelin sheath is involved.

In general the three autosomal dominant neuropathy types based on NCV (normal >40-45 meters/second) were the following [Stojkovic 2016]:

• Demyelinating (CMT1) defined as NCV <35 m/s. The clinical findings of distal muscle weakness and atrophy and sensory loss were usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually became symptomatic between ages five and 25 years. Fewer than 5% of individuals became wheelchair dependent. Life span was not shortened.
• Axonal (non-demyelinating) (CMT 2) defined as NCV >45m/s. The clinical findings were distal muscle weakness and atrophy. Although axonal peripheral neuropathy shows extensive clinical overlap with demyelinating peripheral neuropathy, in general individuals with axonal neuropathy tended to be less disabled and have less sensory loss than individuals with demyelinating neuropathy.
• Dominant intermediate CMT (DI-CMT) defined as NCV 35-45 m/s. The clinical findings are a relatively typical CMT phenotype. NCVs are so variable that within a family some affected individuals fall in the demyelinating neuropathy range, whereas others fall in the axonal neuropathy range.

CMT1 – is caused by abnormalities in the myelin sheath.  The autosomal dominant disorder has six main subtypes.

• CMT1A – results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP22).  The PMP22 protein is a critical component of the myelin sheath.  Overexpression of this gene causes the abnormal structure and function of the myelin sheath.  CMT1A is usually slowly progressive.  Individuals experience weakness and atrophy of the muscles of the lower legs beginning in childhood; later they experience hand weakness, sensory loss, and foot and leg problems.  A different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP22 genes.  In this case, abnormally low levels of the PMP22 gene result in episodic, recurrent demyelinating neuropathy.
• CMT1B – is caused by mutations in the gene that carries the instructions for manufacturing the myelin protein zero (MPZ, also called P0), which is another critical component of the myelin sheath.  Most of these mutations are point mutations, meaning a mistake occurs in only one letter of the DNA genetic code.  To date, scientists have identified more than 120 different point mutations in the P0 gene.  CMT1B produces symptoms similar to those found in CMT1A.
• Other less common causes of CMT1 result from mutations within the SIMPLE (also called LITAF), EGR2, PMP22, and NEFL genes, respectively.

CMT2

• Results from abnormalities in the axon of the peripheral nerve cell, rather than the myelin sheath, and is less common than CMT1.  This autosomal dominant disorder has more than a dozen subtypes (some of which have their own variants), with each subtype being associated with mutations in a specific gene.  Symptoms are similar to those seen in CMT1, but people with CMT2 often have less disability and sensory loss than individuals with CMT1.  The onset of CMT2 is usually in childhood or adolescence.  Some types of CMT2 may have vocal cord or phrenic nerve involvement, causing speech or breathing problems.

CMT3, or Dejerine-Sottas disease

• It is a particularly severe demyelinating neuropathy that begins in infancy.  Infants have severe muscle atrophy, weakness, delayed motor skills development, and sensory problems.  Symptoms may progress to severe disability, loss of sensation, and curvature of the spine.  This rare disorder can be caused by mutations in multiple genes, including PMP22, MPZ, and EGR2, and can be inherited either dominantly or recessively.

CMT4

• It comprises several different subtypes of demyelinating and axonal and motor neuropathies that are inherited autosomal recessively.   Each neuropathy subtype is caused by a mutation in a different gene (several genes have been identified in CMT4).  The mutations may affect a particular ethnic population and produce distinct physiologic or clinical characteristics.  People with CMT4 generally develop symptoms of leg weakness in childhood and by adolescence they may not be able to walk.  CMT4 is rare in the United States.

CMTX1 (also called CMT X, Type 1)

• It is the second most common form of CMT.  This X-linked disease is caused by mutations in a gene that provides instructions for making the protein connexin-32.  The connexin-32 protein is found in myelinating Schwann cells—cells that wrap around nerve axons and make up the myelin sheath.  Males who inherit the mutated gene show moderate to severe symptoms of the disease beginning in late childhood or adolescence.  Females who inherit a mutated gene often develop milder symptoms than males or do not show symptoms.

Disease phenotypes

• Charcot–Marie–Tooth Disease  – As CMT1 and CMT2 present with similar clinical features, distinction on the basis of the neurological exam is often impossible. The onset of clinical symptoms is in the first or second decade of life. Weakness starts distally in the feet and progresses proximally in an ascending pattern. Neuropathic bony deformities develop including pes cavus (high-arched feet) and hammer toes. With further progression the hands become weak. Muscle stretch reflexes disappear early in the ankles and later in the patella and upper limbs. Mild sensory loss to pain, temperature or vibration sensation in the legs is consistent with the phenotype. Patients also complain of numbness and tingling in their feet and hands, but paresthesias are not as common as in acquired neuropathies. Restless leg syndrome occurs in nearly 40% of patients with the axonal form.^[rx]
• Hereditary neuropathy with liability to pressure palsies (MIM 162500) – The clinical phenotype is characterized by recurrent nerve dysfunction at compression sites. Asymmetric palsies occur after relatively minor compression or trauma. Repeated attacks result in the inability of full reversal. Thus with ageing the patients with hereditary neuropathy with liability to pressure palsies (HNPP) can have significant clinical overlap with CMT1. Electrophysiological findings include mildly slowed NCV, increased distal motor latencies and conduction blocks.^[rx] The neuropathological hallmark is sausage-like thickening of myelin sheaths (tomacula).
• Dejerine–Sottas neuropathy (MIM 145900) – Dejerine–Sottas neuropathy (DSN) is a clinically distinct entity defined by delayed motor milestones. Signs of lower motor neuron-type lesion accompany the delayed motor milestones. Neurophysiological studies reveal severe slowing of NCV (<10 m/s). Neuropathology reveals pronounced demyelination, and a greater number of onion bulbs are present compared to CMT. Cerebrospinal fluid proteins may be elevated. Most patients have significant disability.
• Congentital hypomyelinating neuropathy (MIM 605253) – Congentital hypomyelinating neuropathy (CHN) is usually present at birth, although frequently the delayed motor development draws the first attention to the peripheral neuropathy. The distinction between DSN and CHN is often difficult by clinical examination as they both may present as a hypotonic infant. The differentiation of CHN and DSN is based on pathology: the presence of onion bulbs suggest DSN whereas their absence indicate CHN. CHN may present as arthrogryposis multiplex congenita.^[rx]
• Roussy–Levy syndrome (MIM 180800) – Roussy–Levy syndrome (RLS) was originally described as demyelinating CMT associated with sensory ataxia and tremor. As molecular data became available, it was shown that these patients have the same molecular abnormalities as observed in patients clinically classified as demyelinating CMT. RLS represents the spectrum of CMT.

Causes Charcot-Marie-Tooth Disease

A nerve cell communicates information to distant targets by sending electrical signals down a long, thin part of the cell called the axon.  The axon is surrounded by myelin, a covering that acts like the insulation on an electrical wire and aids the high-speed transmission of electrical signals.  Without an intact axon and myelin sheath, signals that run along the nerve and axon are either slow or have a weak signal, meaning that the peripheral nerve cells become unable to activate muscles or relay sensory information from the limbs back to the spinal cord and the brain.

CMT is caused by mutations in genes that support or produce proteins involved in the structure and function of either the peripheral nerve axon or the myelin sheath. More than 40 genes have been identified in CMT, with each gene linked to one or more types of the disease.  In addition, multiple genes can be linked to one type of CMT.  More than half of all cases of CMT are caused by a duplication of the PMP22 gene on chromosome 17.

Although different proteins are abnormal in different forms of CMT disease, all of the mutations mainly affect the normal function of the peripheral nerves.  Gene defects in myelin cause dysfunction of the coating, which distorts or blocks nerve signals, while other mutations limit axon function and cause axonal loss.

CMTs may occur due to any one of the following molecular and cellular mechanisms

• Myelin assembly – genes involved in myelin compaction (MPZ), gap junctions formation (GJB1), the interaction of Schwann cells with the extracellular matrix as well as in regulating cell spreading, cell migration and apoptosis (PMP22)
• Cytoskeletal structure – genes involved in actin polymerization (INF2), membrane-protein interactions to stabilize the myelin sheath (PRX), intermediate filaments (NEFL), cell signaling (FGD4), axonal transport (DYNC1H1)
• Endosomal sorting and cell signaling – genes regulating vesicular transport, membrane trafficking, transport of intracellular organelles and cell signaling (LITAF, MTMR2, SBF1, SBF2, SH3TC2, NDRG1, FIG4, RAB7A, TFG, DNM2, SIMPLE)
• Proteasome and protein aggregation – genes regulating microtubules (HSPB1, HSPB8), cell adhesion (LRSAM1), ubiquitin ligase (TRIM2)
• Mitochondria – genes regulating mitochondrial dynamics, structure, and the function of the respiratory chain (MFN2, GDAP1, MT-ATP6, PDK3)
• Others – genes regulating cell fusion-fission apparatus (DNM2), calcium homeostasis (TRPV4) glucose metabolism (HK1), transcription (EGR2, HINT1, PRPS1, AARS, GARS, MARS, KARS, YARS)

Because of the close functional interaction, demyelinating neuropathies eventually lead to functional axonopathies and clinically manifest secondary axonal degeneration.[rx][rx] Thus common secondary phenomena in CMTs include axonal loss, secondary Schwann cell proliferation, and acceleration of pathology due to immune-mediated mechanisms.[rx]

Symptoms of Charcot-Marie-Tooth Disease

CMT affects both sensory and motor nerves (nerves that trigger an impulse for a muscle to contract) in the arms, hands, legs, and feet.  The affected nerves slowly degenerate and lose the ability to communicate with their distant targets.  Motor nerve degeneration results in muscle weakness and a decrease in muscle bulk (atrophy) in the arms, legs, hands, or feet.

Typical early features include weakness or paralysis of the foot and lower leg muscles, which can cause difficulty lifting the foot (foot drop) and a high-stepped gait with frequent tripping or falling.  Individuals also may notice balance problems.  Foot deformities, such as high arches and curled toes (hammertoes), are also common in CMT.  The lower legs may take on an “inverted champagne bottle” shape due to the loss of muscle bulk.  As the disease progresses, weakness and atrophy may occur in the hands, causing difficulty with fine motor skills.  Degeneration of sensory nerve axons may result in a reduced ability to feel heat, cold, and touch.  The senses of vibration and position (proprioception) are often decreased in individuals with CMT.  The disease also can cause curvature of the spine (scoliosis) and hip displacement.  Many people with CMT develop contractures—chronic shortening of muscles or tendons around joints, which prevents the joints from moving freely.  Muscle cramping is common.  Nerve pain can range from mild to severe, and some individuals may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Some people with CMT experience tremors and vision and hearing can also be affected. In rare cases, breathing difficulties may occur if the nerves that control the muscles of the diaphragm are affected.

The severity of symptoms can vary greatly among individuals and even among family members with the disease and gene mutation.  Progression of symptoms is gradual.

Signs and symptoms of Charcot-Marie-Tooth disease may include

• Weakness in your legs, ankles and feet
• Loss of muscle bulk in your legs and feet
• High foot arches
• Curled toes (hammertoes)
• Decreased ability to run
• Difficulty lifting your foot at the ankle (footdrop)
• Awkward or higher than normal step (gait)
• Frequent tripping or falling
• Decreased sensation or a loss of feeling in your legs and feet

As Charcot-Marie-Tooth disease progresses, symptoms may spread from the feet and legs to the hands and arms. The severity of symptoms can vary greatly from person to person, even among family members.

Diagnosis of Charcot-Marie-Tooth disease

Diagnosis of CMT begins with a detailed medical history, family history, and neurological examination.

Family History

• A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records, including the results of molecular genetic testing and EMG and NCV studies.

Physical Exam

Treatment of Charcot-Marie-Tooth

Non Pharmacological

There is no cure for CMT, but physical and occupational therapies, braces and other orthopedic devices, and orthopedic surgery can help people cope with the disabling symptoms of the disease.  In addition, pain-relief drugs can be prescribed for individuals who have severe nerve pain.

• Maintaining mobility, flexibility, and muscle strength – Beginning a treatment program early may delay or reduce nerve degeneration and muscle weakness before it progresses to the point of disability.  Physical therapy includes muscle strength training, muscle and ligament stretching, and moderate aerobic exercise.  A specialized exercise program approved by the person’s physician can help build stamina, increase endurance, and maintain overall health.
• Braces – Many individuals with CMT require ankle braces and other orthopedic devices to maintain everyday mobility and prevent injury.  Braces can help prevent ankle sprains by providing support and stability during activities such as walking or climbing stairs.  High-top shoes or boots also can give the person support for weak ankles.  Thumb splints can help with hand weakness and loss of fine motor skills.  Assistive devices should be used before disability sets in because the devices may prevent muscle strain and reduce muscle weakening. Some people with CMT may decide to have orthopedic surgery to treat severe foot and joint deformities, improve the ability to walk, and lessen pain.
• Occupational therapy –  involves learning new ways to cope with the activities of daily living.  For example, individuals with weakness in their arms and hands may learn to use Velcro closures or clasps instead of buttons on their clothes, or new ways of feeding themselves using assistive technology.
• Genetic counseling – Because CMT follows the principles of Mendelian inheritance, genetic counseling for recurrence of CMT1 and CMT2 is relatively straightforward if the family history for an affected individual is defined. Because of intrafamilial variability in disease expression, definition of parental disease status requires either testing for a mutation defined in the propositus or, if the mutation is not identifiable, a thorough neurological exam with objective NCS.

Medications

Symptomatic treatment may have a substantial impact on the quality of life.

• NSAIDs – Nonsteroidal anti-inflammatory drugs may help to relieve lower back or leg pain.
• Antiepileptic drugs – Neuropathic pain can be treated with antiepileptic drugs (gabapentin, pregabalin, topiramate) or tricyclic antidepressants (amitriptyline).^{[rx, rx]}
• Beta-blockers – The tremor may respond to β-blockers or primidone.^[rx] Caffeine and nicotine can aggravate the fine intentional tremor, thus avoidance of these substances is recommended.
• Neurotoxic drugs – excessive alcohol should be avoided. A small dose of vincristine can produce a devastating effect in patients with CMT, thus early detection of HMSN can avoid life-threatening vincristine neurotoxicity.^[rx]
• Vitamin C – Potential therapeutic approaches aiming at normalizing dosage by small molecules in the CMT1A duplication models include vitamin C and onapristone, a progesterone antagonist.^{[rx, rx, rx]} An alternate molecular mechanism, point mutations in Pmp22 in the Trembler and Trembler J mouse models cause peripheral neuropathy; the disease was modified by the administration of curcumin likely by alleviating the unfolded protein response.^[rx]
• Systemic biology-based modeling – anti-sense oligonucleotides, adenoviral vector-based drug delivery, and RNA interference technology. In CMT1A, agents target PMP22 overexpression such as ascorbic acid, onapristone, geldanamycin, and rapamycin have been beneficial in animal models and cell lines with improved muscle mass and weakness. However, these agents were not useful in human clinical trials.[rx] PXT3003 (a combination of baclofen, naltrexone, and d-sorbitol) has shown a reduction in the toxic effects of PMP22 over-expression in mice and humans. A significant number of subjects who received PXT3003 showed non-deterioration or improvement in CMT Neuropathy score(CMTNS), Overall Neuropathy Limitations Scale (ONLS), 10-meter walk test, and conduction velocities as compared to placebo. PXT3003 was well tolerated and safe.[rx] Curcumin reduces endoplasmic reticulum stress and improves MPZ associated neuropathy in mice.[rx]

Lifestyle and home remedies

Some habits may prevent complications caused by Charcot-Marie-Tooth disease and help you manage its effects.

Started early and followed regularly, at-home activities can provide protection and relief:

• Stretch regularly – Stretching can help improve or maintain the range of motion of your joints and reduce the risk of injury. It’s also helpful in improving your flexibility, balance and coordination. If you have Charcot-Marie-Tooth disease, regular stretching can prevent or reduce joint deformities that may result from uneven pulling of muscle on your bones.
• Exercise daily – Regular exercise keeps your bones and muscles strong. Low-impact exercises, such as biking and swimming, are less stressful on fragile muscles and joints. By strengthening your muscles and bones, you can improve your balance and coordination, reducing your risk of falls.
• Improve your stability – Muscle weakness associated with Charcot-Marie-Tooth disease may cause you to be unsteady on your feet, resulting in falls and serious injury. Walking with a cane or a walker can increase your stability. Good lighting at night can help you avoid stumbling and falling.

Here are some important points of which to take note

• CMTs are common inherited neuromuscular disorders characterized by progressive weakness, wasting, and skeletal deformities.
• Electrophysiological tests are useful to confirm the diagnosis of neuropathy and exclude alternative conditions that present with foot drop and/or foot deformities such as distal myopathies, muscular dystrophies, and idiopathic pes cavus, among others.
• Electrophysiological tests are useful to screen other family members for asymptomatic neuropathy.
• Patients of demyelinating CMTs have slowed conduction velocities within the first few years of life. Clinical manifestations of weakness, wasting, and deformities arise from axonal loss over the years.
• There is striking phenotypic variability suggesting the potential role for modifier genes and epigenetic factors.
• A detailed pedigree chart covering three or four generations is essential to find the pattern of inheritance. This is necessary before carrying out genetic studies.
• All patients should have genetic counseling before genetic testing.
• In the case of demyelinating neuropathies, the patient should first undergo testing for PMP22 duplication since it is the commonest genetic abnormality. After excluding copy number variations in PMP22, they need targeted gene sequencing or whole-exome sequencing.
• In the case of axonal neuropathies, the patient is first tested for mutations in MFN2. Alternately, the patient can directly undergo target gene sequencing or whole-exome sequencing.
• Establishing the genetic diagnosis is crucial for genetic counseling, reproductive planning, and considering the patient for potential upcoming therapies.
• Patients need to undergo specific tests to detect subclinical involvement of other organs/ systems to recommend timely prophylactic measures.
• Patients should avoid using drugs that worsen neuropathy.
• Patient education and counseling, regular follow-up, emphasis on rehabilitation measures, and consideration for therapeutic trials by a multi-disciplinary team are very important.

What research is being done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

Ongoing research on CMT includes efforts to identify more of the mutant genes and proteins that cause the various disease subtypes, discover the mechanisms of nerve degeneration and muscle atrophy with the goal of developing interventions to stop or slow down these debilitating processes, and develop therapies to reverse nerve degeneration and muscle atrophy.

The NINDS supports the NIH’s Rare Diseases Clinical Research Network, which is made up of different research consortia aimed at improving the availability of rare diseases information, clinical studies, and clinical research information.  The Network’s Inherited Neuropathies Consortium conducts studies that include a natural history analysis of CMT, the search for new genes and those that modify an individual’s symptoms, therapy development, and training programs to educate future investigators for the inherited neuropathies.  For more information on the Rare Diseases Clinical Research Network and its consortia, see Rare Diseases Info.

Scientists are studying PMP22 gene regulation to design and validate assays that measure the presence, amount, or activity of a target object.  Other studies examine the effects of small molecules on the biological system in order to develop novel treatments.  High-throughput screens (a way to quickly assess the biological activity of large numbers of compounds) may identify candidate medications that reduce PMP22 levels. Additional research focuses on how the mitochondria, the cell’s power plant, may play a role in the axonal degeneration seen in CMT, as well as other diseases.

An NIH longitudinal collaborative study hopes to determine the natural history of CMT and how the presence of a certain gene mutation may result in disease types and symptoms.  Also, a two-part study is looking for new genes that cause the disease as well as genes that do not cause the disease but may modify a person’s symptoms.  Other NIH-funded scientists are using next-generation sequencing (which can quickly identify the structure of millions of small fragments of DNA at the same time) to identify novel CMT genes.

Gene therapy is another promising area of research.  Experiments involving cell cultures and animal models of the disease have shown that it is possible to deliver genes to Schwann cells and muscles.  Other studies show trophic factors or nerve growth factors, such as the hormone androgen that prevent nerve degeneration.

References

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Charcot-Marie-Tooth Syndrome/Charcot-Marie-Tooth disease (CMT) is slowly progressive neurodegenerative hereditary chronic motor and sensory neuropathy disease and one of a group of disorders that cause damage to the peripheral nerves, the nerves that transmit information and signals from the brain and spinal cord to and from the rest of the body, as well as sensory information such as touch back to the spinal cord and brain.  CMT can also directly affect the nerves that control the muscles.  Progressive muscle weakness typically becomes noticeable in adolescence or early adulthood, but the onset of disease can occur at any age.  Because longer nerves are affected first, symptoms usually begin in the feet and lower legs and then can affect the fingers, hands, and arms.  Most individuals with CMT have some amount of physical disability, although some people may never know they have the disease.

CMT, also known as hereditary motor and sensory neuropathy, slowly progressive inherited neurological disorders distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands is one of the most common neuropathy affecting an estimated. It is possible to have two or more types of CMT, which happens when the person has mutations in two or more genes, each of which causes a form of the disease.  CMT is a heterogeneous genetic disease, meaning mutations in different genes can produce similar clinical symptoms.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves. During the last decade over two dozen genes have been identified in which mutations cause CMT. The disease illustrates a multitude of genetic principles, including diverse mutational mechanisms from point mutations to copy number variation (CNV), allelic heterogeneity, age-dependent penetrance and variable expressivity.

Types of Charcot-Marie-Tooth Disease

There are many different types of CMT disease, which may share some symptoms but vary by pattern of inheritance, age of onset, and whether the axon or myelin sheath is involved.

In general the three autosomal dominant neuropathy types based on NCV (normal >40-45 meters/second) were the following [Stojkovic 2016]:

• Demyelinating (CMT1) defined as NCV <35 m/s. The clinical findings of distal muscle weakness and atrophy and sensory loss were usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually became symptomatic between ages five and 25 years. Fewer than 5% of individuals became wheelchair dependent. Life span was not shortened.
• Axonal (non-demyelinating) (CMT 2) defined as NCV >45m/s. The clinical findings were distal muscle weakness and atrophy. Although axonal peripheral neuropathy shows extensive clinical overlap with demyelinating peripheral neuropathy, in general individuals with axonal neuropathy tended to be less disabled and have less sensory loss than individuals with demyelinating neuropathy.
• Dominant intermediate CMT (DI-CMT) defined as NCV 35-45 m/s. The clinical findings are a relatively typical CMT phenotype. NCVs are so variable that within a family some affected individuals fall in the demyelinating neuropathy range, whereas others fall in the axonal neuropathy range.

CMT1 – is caused by abnormalities in the myelin sheath.  The autosomal dominant disorder has six main subtypes.

• CMT1A – results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP22).  The PMP22 protein is a critical component of the myelin sheath.  Overexpression of this gene causes the abnormal structure and function of the myelin sheath.  CMT1A is usually slowly progressive.  Individuals experience weakness and atrophy of the muscles of the lower legs beginning in childhood; later they experience hand weakness, sensory loss, and foot and leg problems.  A different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP22 genes.  In this case, abnormally low levels of the PMP22 gene result in episodic, recurrent demyelinating neuropathy.
• CMT1B – is caused by mutations in the gene that carries the instructions for manufacturing the myelin protein zero (MPZ, also called P0), which is another critical component of the myelin sheath.  Most of these mutations are point mutations, meaning a mistake occurs in only one letter of the DNA genetic code.  To date, scientists have identified more than 120 different point mutations in the P0 gene.  CMT1B produces symptoms similar to those found in CMT1A.
• Other less common causes of CMT1 result from mutations within the SIMPLE (also called LITAF), EGR2, PMP22, and NEFL genes, respectively.

CMT2

• Results from abnormalities in the axon of the peripheral nerve cell, rather than the myelin sheath, and is less common than CMT1.  This autosomal dominant disorder has more than a dozen subtypes (some of which have their own variants), with each subtype being associated with mutations in a specific gene.  Symptoms are similar to those seen in CMT1, but people with CMT2 often have less disability and sensory loss than individuals with CMT1.  The onset of CMT2 is usually in childhood or adolescence.  Some types of CMT2 may have vocal cord or phrenic nerve involvement, causing speech or breathing problems.

CMT3, or Dejerine-Sottas disease

• It is a particularly severe demyelinating neuropathy that begins in infancy.  Infants have severe muscle atrophy, weakness, delayed motor skills development, and sensory problems.  Symptoms may progress to severe disability, loss of sensation, and curvature of the spine.  This rare disorder can be caused by mutations in multiple genes, including PMP22, MPZ, and EGR2, and can be inherited either dominantly or recessively.

CMT4

• It comprises several different subtypes of demyelinating and axonal and motor neuropathies that are inherited autosomal recessively.   Each neuropathy subtype is caused by a mutation in a different gene (several genes have been identified in CMT4).  The mutations may affect a particular ethnic population and produce distinct physiologic or clinical characteristics.  People with CMT4 generally develop symptoms of leg weakness in childhood and by adolescence they may not be able to walk.  CMT4 is rare in the United States.

CMTX1 (also called CMT X, Type 1)

• It is the second most common form of CMT.  This X-linked disease is caused by mutations in a gene that provides instructions for making the protein connexin-32.  The connexin-32 protein is found in myelinating Schwann cells—cells that wrap around nerve axons and make up the myelin sheath.  Males who inherit the mutated gene show moderate to severe symptoms of the disease beginning in late childhood or adolescence.  Females who inherit a mutated gene often develop milder symptoms than males or do not show symptoms.

Disease phenotypes

• Charcot–Marie–Tooth Disease  – As CMT1 and CMT2 present with similar clinical features, distinction on the basis of the neurological exam is often impossible. The onset of clinical symptoms is in the first or second decade of life. Weakness starts distally in the feet and progresses proximally in an ascending pattern. Neuropathic bony deformities develop including pes cavus (high-arched feet) and hammer toes. With further progression the hands become weak. Muscle stretch reflexes disappear early in the ankles and later in the patella and upper limbs. Mild sensory loss to pain, temperature or vibration sensation in the legs is consistent with the phenotype. Patients also complain of numbness and tingling in their feet and hands, but paresthesias are not as common as in acquired neuropathies. Restless leg syndrome occurs in nearly 40% of patients with the axonal form.^[rx]
• Hereditary neuropathy with liability to pressure palsies (MIM 162500) – The clinical phenotype is characterized by recurrent nerve dysfunction at compression sites. Asymmetric palsies occur after relatively minor compression or trauma. Repeated attacks result in the inability of full reversal. Thus with ageing the patients with hereditary neuropathy with liability to pressure palsies (HNPP) can have significant clinical overlap with CMT1. Electrophysiological findings include mildly slowed NCV, increased distal motor latencies and conduction blocks.^[rx] The neuropathological hallmark is sausage-like thickening of myelin sheaths (tomacula).
• Dejerine–Sottas neuropathy (MIM 145900) – Dejerine–Sottas neuropathy (DSN) is a clinically distinct entity defined by delayed motor milestones. Signs of lower motor neuron-type lesion accompany the delayed motor milestones. Neurophysiological studies reveal severe slowing of NCV (<10 m/s). Neuropathology reveals pronounced demyelination, and a greater number of onion bulbs are present compared to CMT. Cerebrospinal fluid proteins may be elevated. Most patients have significant disability.
• Congentital hypomyelinating neuropathy (MIM 605253) – Congentital hypomyelinating neuropathy (CHN) is usually present at birth, although frequently the delayed motor development draws the first attention to the peripheral neuropathy. The distinction between DSN and CHN is often difficult by clinical examination as they both may present as a hypotonic infant. The differentiation of CHN and DSN is based on pathology: the presence of onion bulbs suggest DSN whereas their absence indicate CHN. CHN may present as arthrogryposis multiplex congenita.^[rx]
• Roussy–Levy syndrome (MIM 180800) – Roussy–Levy syndrome (RLS) was originally described as demyelinating CMT associated with sensory ataxia and tremor. As molecular data became available, it was shown that these patients have the same molecular abnormalities as observed in patients clinically classified as demyelinating CMT. RLS represents the spectrum of CMT.

Causes Charcot-Marie-Tooth Disease

A nerve cell communicates information to distant targets by sending electrical signals down a long, thin part of the cell called the axon.  The axon is surrounded by myelin, a covering that acts like the insulation on an electrical wire and aids the high-speed transmission of electrical signals.  Without an intact axon and myelin sheath, signals that run along the nerve and axon are either slow or have a weak signal, meaning that the peripheral nerve cells become unable to activate muscles or relay sensory information from the limbs back to the spinal cord and the brain.

CMT is caused by mutations in genes that support or produce proteins involved in the structure and function of either the peripheral nerve axon or the myelin sheath. More than 40 genes have been identified in CMT, with each gene linked to one or more types of the disease.  In addition, multiple genes can be linked to one type of CMT.  More than half of all cases of CMT are caused by a duplication of the PMP22 gene on chromosome 17.

Although different proteins are abnormal in different forms of CMT disease, all of the mutations mainly affect the normal function of the peripheral nerves.  Gene defects in myelin cause dysfunction of the coating, which distorts or blocks nerve signals, while other mutations limit axon function and cause axonal loss.

CMTs may occur due to any one of the following molecular and cellular mechanisms

• Myelin assembly – genes involved in myelin compaction (MPZ), gap junctions formation (GJB1), the interaction of Schwann cells with the extracellular matrix as well as in regulating cell spreading, cell migration and apoptosis (PMP22)
• Cytoskeletal structure – genes involved in actin polymerization (INF2), membrane-protein interactions to stabilize the myelin sheath (PRX), intermediate filaments (NEFL), cell signaling (FGD4), axonal transport (DYNC1H1)
• Endosomal sorting and cell signaling – genes regulating vesicular transport, membrane trafficking, transport of intracellular organelles and cell signaling (LITAF, MTMR2, SBF1, SBF2, SH3TC2, NDRG1, FIG4, RAB7A, TFG, DNM2, SIMPLE)
• Proteasome and protein aggregation – genes regulating microtubules (HSPB1, HSPB8), cell adhesion (LRSAM1), ubiquitin ligase (TRIM2)
• Mitochondria – genes regulating mitochondrial dynamics, structure, and the function of the respiratory chain (MFN2, GDAP1, MT-ATP6, PDK3)
• Others – genes regulating cell fusion-fission apparatus (DNM2), calcium homeostasis (TRPV4) glucose metabolism (HK1), transcription (EGR2, HINT1, PRPS1, AARS, GARS, MARS, KARS, YARS)

Because of the close functional interaction, demyelinating neuropathies eventually lead to functional axonopathies and clinically manifest secondary axonal degeneration.[rx][rx] Thus common secondary phenomena in CMTs include axonal loss, secondary Schwann cell proliferation, and acceleration of pathology due to immune-mediated mechanisms.[rx]

Symptoms of Charcot-Marie-Tooth Disease

CMT affects both sensory and motor nerves (nerves that trigger an impulse for a muscle to contract) in the arms, hands, legs, and feet.  The affected nerves slowly degenerate and lose the ability to communicate with their distant targets.  Motor nerve degeneration results in muscle weakness and a decrease in muscle bulk (atrophy) in the arms, legs, hands, or feet.

Typical early features include weakness or paralysis of the foot and lower leg muscles, which can cause difficulty lifting the foot (foot drop) and a high-stepped gait with frequent tripping or falling.  Individuals also may notice balance problems.  Foot deformities, such as high arches and curled toes (hammertoes), are also common in CMT.  The lower legs may take on an “inverted champagne bottle” shape due to the loss of muscle bulk.  As the disease progresses, weakness and atrophy may occur in the hands, causing difficulty with fine motor skills.  Degeneration of sensory nerve axons may result in a reduced ability to feel heat, cold, and touch.  The senses of vibration and position (proprioception) are often decreased in individuals with CMT.  The disease also can cause curvature of the spine (scoliosis) and hip displacement.  Many people with CMT develop contractures—chronic shortening of muscles or tendons around joints, which prevents the joints from moving freely.  Muscle cramping is common.  Nerve pain can range from mild to severe, and some individuals may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Some people with CMT experience tremors and vision and hearing can also be affected. In rare cases, breathing difficulties may occur if the nerves that control the muscles of the diaphragm are affected.

The severity of symptoms can vary greatly among individuals and even among family members with the disease and gene mutation.  Progression of symptoms is gradual.

Signs and symptoms of Charcot-Marie-Tooth disease may include

• Weakness in your legs, ankles and feet
• Loss of muscle bulk in your legs and feet
• High foot arches
• Curled toes (hammertoes)
• Decreased ability to run
• Difficulty lifting your foot at the ankle (footdrop)
• Awkward or higher than normal step (gait)
• Frequent tripping or falling
• Decreased sensation or a loss of feeling in your legs and feet

As Charcot-Marie-Tooth disease progresses, symptoms may spread from the feet and legs to the hands and arms. The severity of symptoms can vary greatly from person to person, even among family members.

Diagnosis of Charcot-Marie-Tooth disease

Diagnosis of CMT begins with a detailed medical history, family history, and neurological examination.

Family History

• A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records, including the results of molecular genetic testing and EMG and NCV studies.

Physical Exam

Treatment of Charcot-Marie-Tooth

Non Pharmacological

There is no cure for CMT, but physical and occupational therapies, braces and other orthopedic devices, and orthopedic surgery can help people cope with the disabling symptoms of the disease.  In addition, pain-relief drugs can be prescribed for individuals who have severe nerve pain.

• Maintaining mobility, flexibility, and muscle strength – Beginning a treatment program early may delay or reduce nerve degeneration and muscle weakness before it progresses to the point of disability.  Physical therapy includes muscle strength training, muscle and ligament stretching, and moderate aerobic exercise.  A specialized exercise program approved by the person’s physician can help build stamina, increase endurance, and maintain overall health.
• Braces – Many individuals with CMT require ankle braces and other orthopedic devices to maintain everyday mobility and prevent injury.  Braces can help prevent ankle sprains by providing support and stability during activities such as walking or climbing stairs.  High-top shoes or boots also can give the person support for weak ankles.  Thumb splints can help with hand weakness and loss of fine motor skills.  Assistive devices should be used before disability sets in because the devices may prevent muscle strain and reduce muscle weakening. Some people with CMT may decide to have orthopedic surgery to treat severe foot and joint deformities, improve the ability to walk, and lessen pain.
• Occupational therapy –  involves learning new ways to cope with the activities of daily living.  For example, individuals with weakness in their arms and hands may learn to use Velcro closures or clasps instead of buttons on their clothes, or new ways of feeding themselves using assistive technology.
• Genetic counseling – Because CMT follows the principles of Mendelian inheritance, genetic counseling for recurrence of CMT1 and CMT2 is relatively straightforward if the family history for an affected individual is defined. Because of intrafamilial variability in disease expression, definition of parental disease status requires either testing for a mutation defined in the propositus or, if the mutation is not identifiable, a thorough neurological exam with objective NCS.

Medications

Symptomatic treatment may have a substantial impact on the quality of life.

• NSAIDs – Nonsteroidal anti-inflammatory drugs may help to relieve lower back or leg pain.
• Antiepileptic drugs – Neuropathic pain can be treated with antiepileptic drugs (gabapentin, pregabalin, topiramate) or tricyclic antidepressants (amitriptyline).^{[rx, rx]}
• Beta-blockers – The tremor may respond to β-blockers or primidone.^[rx] Caffeine and nicotine can aggravate the fine intentional tremor, thus avoidance of these substances is recommended.
• Neurotoxic drugs – excessive alcohol should be avoided. A small dose of vincristine can produce a devastating effect in patients with CMT, thus early detection of HMSN can avoid life-threatening vincristine neurotoxicity.^[rx]
• Vitamin C – Potential therapeutic approaches aiming at normalizing dosage by small molecules in the CMT1A duplication models include vitamin C and onapristone, a progesterone antagonist.^{[rx, rx, rx]} An alternate molecular mechanism, point mutations in Pmp22 in the Trembler and Trembler J mouse models cause peripheral neuropathy; the disease was modified by the administration of curcumin likely by alleviating the unfolded protein response.^[rx]
• Systemic biology-based modeling – anti-sense oligonucleotides, adenoviral vector-based drug delivery, and RNA interference technology. In CMT1A, agents target PMP22 overexpression such as ascorbic acid, onapristone, geldanamycin, and rapamycin have been beneficial in animal models and cell lines with improved muscle mass and weakness. However, these agents were not useful in human clinical trials.[rx] PXT3003 (a combination of baclofen, naltrexone, and d-sorbitol) has shown a reduction in the toxic effects of PMP22 over-expression in mice and humans. A significant number of subjects who received PXT3003 showed non-deterioration or improvement in CMT Neuropathy score(CMTNS), Overall Neuropathy Limitations Scale (ONLS), 10-meter walk test, and conduction velocities as compared to placebo. PXT3003 was well tolerated and safe.[rx] Curcumin reduces endoplasmic reticulum stress and improves MPZ associated neuropathy in mice.[rx]

Lifestyle and home remedies

Some habits may prevent complications caused by Charcot-Marie-Tooth disease and help you manage its effects.

Started early and followed regularly, at-home activities can provide protection and relief:

• Stretch regularly – Stretching can help improve or maintain the range of motion of your joints and reduce the risk of injury. It’s also helpful in improving your flexibility, balance and coordination. If you have Charcot-Marie-Tooth disease, regular stretching can prevent or reduce joint deformities that may result from uneven pulling of muscle on your bones.
• Exercise daily – Regular exercise keeps your bones and muscles strong. Low-impact exercises, such as biking and swimming, are less stressful on fragile muscles and joints. By strengthening your muscles and bones, you can improve your balance and coordination, reducing your risk of falls.
• Improve your stability – Muscle weakness associated with Charcot-Marie-Tooth disease may cause you to be unsteady on your feet, resulting in falls and serious injury. Walking with a cane or a walker can increase your stability. Good lighting at night can help you avoid stumbling and falling.

Here are some important points of which to take note

• CMTs are common inherited neuromuscular disorders characterized by progressive weakness, wasting, and skeletal deformities.
• Electrophysiological tests are useful to confirm the diagnosis of neuropathy and exclude alternative conditions that present with foot drop and/or foot deformities such as distal myopathies, muscular dystrophies, and idiopathic pes cavus, among others.
• Electrophysiological tests are useful to screen other family members for asymptomatic neuropathy.
• Patients of demyelinating CMTs have slowed conduction velocities within the first few years of life. Clinical manifestations of weakness, wasting, and deformities arise from axonal loss over the years.
• There is striking phenotypic variability suggesting the potential role for modifier genes and epigenetic factors.
• A detailed pedigree chart covering three or four generations is essential to find the pattern of inheritance. This is necessary before carrying out genetic studies.
• All patients should have genetic counseling before genetic testing.
• In the case of demyelinating neuropathies, the patient should first undergo testing for PMP22 duplication since it is the commonest genetic abnormality. After excluding copy number variations in PMP22, they need targeted gene sequencing or whole-exome sequencing.
• In the case of axonal neuropathies, the patient is first tested for mutations in MFN2. Alternately, the patient can directly undergo target gene sequencing or whole-exome sequencing.
• Establishing the genetic diagnosis is crucial for genetic counseling, reproductive planning, and considering the patient for potential upcoming therapies.
• Patients need to undergo specific tests to detect subclinical involvement of other organs/ systems to recommend timely prophylactic measures.
• Patients should avoid using drugs that worsen neuropathy.
• Patient education and counseling, regular follow-up, emphasis on rehabilitation measures, and consideration for therapeutic trials by a multi-disciplinary team are very important.

What research is being done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

Ongoing research on CMT includes efforts to identify more of the mutant genes and proteins that cause the various disease subtypes, discover the mechanisms of nerve degeneration and muscle atrophy with the goal of developing interventions to stop or slow down these debilitating processes, and develop therapies to reverse nerve degeneration and muscle atrophy.

The NINDS supports the NIH’s Rare Diseases Clinical Research Network, which is made up of different research consortia aimed at improving the availability of rare diseases information, clinical studies, and clinical research information.  The Network’s Inherited Neuropathies Consortium conducts studies that include a natural history analysis of CMT, the search for new genes and those that modify an individual’s symptoms, therapy development, and training programs to educate future investigators for the inherited neuropathies.  For more information on the Rare Diseases Clinical Research Network and its consortia, see Rare Diseases Info.

Scientists are studying PMP22 gene regulation to design and validate assays that measure the presence, amount, or activity of a target object.  Other studies examine the effects of small molecules on the biological system in order to develop novel treatments.  High-throughput screens (a way to quickly assess the biological activity of large numbers of compounds) may identify candidate medications that reduce PMP22 levels. Additional research focuses on how the mitochondria, the cell’s power plant, may play a role in the axonal degeneration seen in CMT, as well as other diseases.

An NIH longitudinal collaborative study hopes to determine the natural history of CMT and how the presence of a certain gene mutation may result in disease types and symptoms.  Also, a two-part study is looking for new genes that cause the disease as well as genes that do not cause the disease but may modify a person’s symptoms.  Other NIH-funded scientists are using next-generation sequencing (which can quickly identify the structure of millions of small fragments of DNA at the same time) to identify novel CMT genes.

Gene therapy is another promising area of research.  Experiments involving cell cultures and animal models of the disease have shown that it is possible to deliver genes to Schwann cells and muscles.  Other studies show trophic factors or nerve growth factors, such as the hormone androgen that prevent nerve degeneration.

References

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Charcot-Marie-Tooth Hereditary Neuropathy/Charcot-Marie-Tooth disease (CMT) is slowly progressive neurodegenerative hereditary chronic motor and sensory neuropathy disease and one of a group of disorders that cause damage to the peripheral nerves, the nerves that transmit information and signals from the brain and spinal cord to and from the rest of the body, as well as sensory information such as touch back to the spinal cord and brain.  CMT can also directly affect the nerves that control the muscles.  Progressive muscle weakness typically becomes noticeable in adolescence or early adulthood, but the onset of disease can occur at any age.  Because longer nerves are affected first, symptoms usually begin in the feet and lower legs and then can affect the fingers, hands, and arms.  Most individuals with CMT have some amount of physical disability, although some people may never know they have the disease.

CMT, also known as hereditary motor and sensory neuropathy, slowly progressive inherited neurological disorders distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands is one of the most common neuropathy affecting an estimated. It is possible to have two or more types of CMT, which happens when the person has mutations in two or more genes, each of which causes a form of the disease.  CMT is a heterogeneous genetic disease, meaning mutations in different genes can produce similar clinical symptoms.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves. During the last decade over two dozen genes have been identified in which mutations cause CMT. The disease illustrates a multitude of genetic principles, including diverse mutational mechanisms from point mutations to copy number variation (CNV), allelic heterogeneity, age-dependent penetrance and variable expressivity.

Types of Charcot-Marie-Tooth Disease

There are many different types of CMT disease, which may share some symptoms but vary by pattern of inheritance, age of onset, and whether the axon or myelin sheath is involved.

In general the three autosomal dominant neuropathy types based on NCV (normal >40-45 meters/second) were the following [Stojkovic 2016]:

• Demyelinating (CMT1) defined as NCV <35 m/s. The clinical findings of distal muscle weakness and atrophy and sensory loss were usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually became symptomatic between ages five and 25 years. Fewer than 5% of individuals became wheelchair dependent. Life span was not shortened.
• Axonal (non-demyelinating) (CMT 2) defined as NCV >45m/s. The clinical findings were distal muscle weakness and atrophy. Although axonal peripheral neuropathy shows extensive clinical overlap with demyelinating peripheral neuropathy, in general individuals with axonal neuropathy tended to be less disabled and have less sensory loss than individuals with demyelinating neuropathy.
• Dominant intermediate CMT (DI-CMT) defined as NCV 35-45 m/s. The clinical findings are a relatively typical CMT phenotype. NCVs are so variable that within a family some affected individuals fall in the demyelinating neuropathy range, whereas others fall in the axonal neuropathy range.

CMT1 – is caused by abnormalities in the myelin sheath.  The autosomal dominant disorder has six main subtypes.

• CMT1A – results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP22).  The PMP22 protein is a critical component of the myelin sheath.  Overexpression of this gene causes the abnormal structure and function of the myelin sheath.  CMT1A is usually slowly progressive.  Individuals experience weakness and atrophy of the muscles of the lower legs beginning in childhood; later they experience hand weakness, sensory loss, and foot and leg problems.  A different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP22 genes.  In this case, abnormally low levels of the PMP22 gene result in episodic, recurrent demyelinating neuropathy.
• CMT1B – is caused by mutations in the gene that carries the instructions for manufacturing the myelin protein zero (MPZ, also called P0), which is another critical component of the myelin sheath.  Most of these mutations are point mutations, meaning a mistake occurs in only one letter of the DNA genetic code.  To date, scientists have identified more than 120 different point mutations in the P0 gene.  CMT1B produces symptoms similar to those found in CMT1A.
• Other less common causes of CMT1 result from mutations within the SIMPLE (also called LITAF), EGR2, PMP22, and NEFL genes, respectively.

CMT2

• Results from abnormalities in the axon of the peripheral nerve cell, rather than the myelin sheath, and is less common than CMT1.  This autosomal dominant disorder has more than a dozen subtypes (some of which have their own variants), with each subtype being associated with mutations in a specific gene.  Symptoms are similar to those seen in CMT1, but people with CMT2 often have less disability and sensory loss than individuals with CMT1.  The onset of CMT2 is usually in childhood or adolescence.  Some types of CMT2 may have vocal cord or phrenic nerve involvement, causing speech or breathing problems.

CMT3, or Dejerine-Sottas disease

• It is a particularly severe demyelinating neuropathy that begins in infancy.  Infants have severe muscle atrophy, weakness, delayed motor skills development, and sensory problems.  Symptoms may progress to severe disability, loss of sensation, and curvature of the spine.  This rare disorder can be caused by mutations in multiple genes, including PMP22, MPZ, and EGR2, and can be inherited either dominantly or recessively.

CMT4

• It comprises several different subtypes of demyelinating and axonal and motor neuropathies that are inherited autosomal recessively.   Each neuropathy subtype is caused by a mutation in a different gene (several genes have been identified in CMT4).  The mutations may affect a particular ethnic population and produce distinct physiologic or clinical characteristics.  People with CMT4 generally develop symptoms of leg weakness in childhood and by adolescence they may not be able to walk.  CMT4 is rare in the United States.

CMTX1 (also called CMT X, Type 1)

• It is the second most common form of CMT.  This X-linked disease is caused by mutations in a gene that provides instructions for making the protein connexin-32.  The connexin-32 protein is found in myelinating Schwann cells—cells that wrap around nerve axons and make up the myelin sheath.  Males who inherit the mutated gene show moderate to severe symptoms of the disease beginning in late childhood or adolescence.  Females who inherit a mutated gene often develop milder symptoms than males or do not show symptoms.

Disease phenotypes

• Charcot–Marie–Tooth Disease  – As CMT1 and CMT2 present with similar clinical features, distinction on the basis of the neurological exam is often impossible. The onset of clinical symptoms is in the first or second decade of life. Weakness starts distally in the feet and progresses proximally in an ascending pattern. Neuropathic bony deformities develop including pes cavus (high-arched feet) and hammer toes. With further progression the hands become weak. Muscle stretch reflexes disappear early in the ankles and later in the patella and upper limbs. Mild sensory loss to pain, temperature or vibration sensation in the legs is consistent with the phenotype. Patients also complain of numbness and tingling in their feet and hands, but paresthesias are not as common as in acquired neuropathies. Restless leg syndrome occurs in nearly 40% of patients with the axonal form.^[rx]
• Hereditary neuropathy with liability to pressure palsies (MIM 162500) – The clinical phenotype is characterized by recurrent nerve dysfunction at compression sites. Asymmetric palsies occur after relatively minor compression or trauma. Repeated attacks result in the inability of full reversal. Thus with ageing the patients with hereditary neuropathy with liability to pressure palsies (HNPP) can have significant clinical overlap with CMT1. Electrophysiological findings include mildly slowed NCV, increased distal motor latencies and conduction blocks.^[rx] The neuropathological hallmark is sausage-like thickening of myelin sheaths (tomacula).
• Dejerine–Sottas neuropathy (MIM 145900) – Dejerine–Sottas neuropathy (DSN) is a clinically distinct entity defined by delayed motor milestones. Signs of lower motor neuron-type lesion accompany the delayed motor milestones. Neurophysiological studies reveal severe slowing of NCV (<10 m/s). Neuropathology reveals pronounced demyelination, and a greater number of onion bulbs are present compared to CMT. Cerebrospinal fluid proteins may be elevated. Most patients have significant disability.
• Congentital hypomyelinating neuropathy (MIM 605253) – Congentital hypomyelinating neuropathy (CHN) is usually present at birth, although frequently the delayed motor development draws the first attention to the peripheral neuropathy. The distinction between DSN and CHN is often difficult by clinical examination as they both may present as a hypotonic infant. The differentiation of CHN and DSN is based on pathology: the presence of onion bulbs suggest DSN whereas their absence indicate CHN. CHN may present as arthrogryposis multiplex congenita.^[rx]
• Roussy–Levy syndrome (MIM 180800) – Roussy–Levy syndrome (RLS) was originally described as demyelinating CMT associated with sensory ataxia and tremor. As molecular data became available, it was shown that these patients have the same molecular abnormalities as observed in patients clinically classified as demyelinating CMT. RLS represents the spectrum of CMT.

Causes Charcot-Marie-Tooth Disease

A nerve cell communicates information to distant targets by sending electrical signals down a long, thin part of the cell called the axon.  The axon is surrounded by myelin, a covering that acts like the insulation on an electrical wire and aids the high-speed transmission of electrical signals.  Without an intact axon and myelin sheath, signals that run along the nerve and axon are either slow or have a weak signal, meaning that the peripheral nerve cells become unable to activate muscles or relay sensory information from the limbs back to the spinal cord and the brain.

CMT is caused by mutations in genes that support or produce proteins involved in the structure and function of either the peripheral nerve axon or the myelin sheath. More than 40 genes have been identified in CMT, with each gene linked to one or more types of the disease.  In addition, multiple genes can be linked to one type of CMT.  More than half of all cases of CMT are caused by a duplication of the PMP22 gene on chromosome 17.

Although different proteins are abnormal in different forms of CMT disease, all of the mutations mainly affect the normal function of the peripheral nerves.  Gene defects in myelin cause dysfunction of the coating, which distorts or blocks nerve signals, while other mutations limit axon function and cause axonal loss.

CMTs may occur due to any one of the following molecular and cellular mechanisms

• Myelin assembly – genes involved in myelin compaction (MPZ), gap junctions formation (GJB1), the interaction of Schwann cells with the extracellular matrix as well as in regulating cell spreading, cell migration and apoptosis (PMP22)
• Cytoskeletal structure – genes involved in actin polymerization (INF2), membrane-protein interactions to stabilize the myelin sheath (PRX), intermediate filaments (NEFL), cell signaling (FGD4), axonal transport (DYNC1H1)
• Endosomal sorting and cell signaling – genes regulating vesicular transport, membrane trafficking, transport of intracellular organelles and cell signaling (LITAF, MTMR2, SBF1, SBF2, SH3TC2, NDRG1, FIG4, RAB7A, TFG, DNM2, SIMPLE)
• Proteasome and protein aggregation – genes regulating microtubules (HSPB1, HSPB8), cell adhesion (LRSAM1), ubiquitin ligase (TRIM2)
• Mitochondria – genes regulating mitochondrial dynamics, structure, and the function of the respiratory chain (MFN2, GDAP1, MT-ATP6, PDK3)
• Others – genes regulating cell fusion-fission apparatus (DNM2), calcium homeostasis (TRPV4) glucose metabolism (HK1), transcription (EGR2, HINT1, PRPS1, AARS, GARS, MARS, KARS, YARS)

Because of the close functional interaction, demyelinating neuropathies eventually lead to functional axonopathies and clinically manifest secondary axonal degeneration.[rx][rx] Thus common secondary phenomena in CMTs include axonal loss, secondary Schwann cell proliferation, and acceleration of pathology due to immune-mediated mechanisms.[rx]

Symptoms of Charcot-Marie-Tooth Disease

CMT affects both sensory and motor nerves (nerves that trigger an impulse for a muscle to contract) in the arms, hands, legs, and feet.  The affected nerves slowly degenerate and lose the ability to communicate with their distant targets.  Motor nerve degeneration results in muscle weakness and a decrease in muscle bulk (atrophy) in the arms, legs, hands, or feet.

Typical early features include weakness or paralysis of the foot and lower leg muscles, which can cause difficulty lifting the foot (foot drop) and a high-stepped gait with frequent tripping or falling.  Individuals also may notice balance problems.  Foot deformities, such as high arches and curled toes (hammertoes), are also common in CMT.  The lower legs may take on an “inverted champagne bottle” shape due to the loss of muscle bulk.  As the disease progresses, weakness and atrophy may occur in the hands, causing difficulty with fine motor skills.  Degeneration of sensory nerve axons may result in a reduced ability to feel heat, cold, and touch.  The senses of vibration and position (proprioception) are often decreased in individuals with CMT.  The disease also can cause curvature of the spine (scoliosis) and hip displacement.  Many people with CMT develop contractures—chronic shortening of muscles or tendons around joints, which prevents the joints from moving freely.  Muscle cramping is common.  Nerve pain can range from mild to severe, and some individuals may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Some people with CMT experience tremors and vision and hearing can also be affected. In rare cases, breathing difficulties may occur if the nerves that control the muscles of the diaphragm are affected.

The severity of symptoms can vary greatly among individuals and even among family members with the disease and gene mutation.  Progression of symptoms is gradual.

Signs and symptoms of Charcot-Marie-Tooth disease may include

• Weakness in your legs, ankles and feet
• Loss of muscle bulk in your legs and feet
• High foot arches
• Curled toes (hammertoes)
• Decreased ability to run
• Difficulty lifting your foot at the ankle (footdrop)
• Awkward or higher than normal step (gait)
• Frequent tripping or falling
• Decreased sensation or a loss of feeling in your legs and feet

As Charcot-Marie-Tooth disease progresses, symptoms may spread from the feet and legs to the hands and arms. The severity of symptoms can vary greatly from person to person, even among family members.

Diagnosis of Charcot-Marie-Tooth disease

Diagnosis of CMT begins with a detailed medical history, family history, and neurological examination.

Family History

• A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records, including the results of molecular genetic testing and EMG and NCV studies.

Physical Exam

Treatment of Charcot-Marie-Tooth

Non Pharmacological

There is no cure for CMT, but physical and occupational therapies, braces and other orthopedic devices, and orthopedic surgery can help people cope with the disabling symptoms of the disease.  In addition, pain-relief drugs can be prescribed for individuals who have severe nerve pain.

• Maintaining mobility, flexibility, and muscle strength – Beginning a treatment program early may delay or reduce nerve degeneration and muscle weakness before it progresses to the point of disability.  Physical therapy includes muscle strength training, muscle and ligament stretching, and moderate aerobic exercise.  A specialized exercise program approved by the person’s physician can help build stamina, increase endurance, and maintain overall health.
• Braces – Many individuals with CMT require ankle braces and other orthopedic devices to maintain everyday mobility and prevent injury.  Braces can help prevent ankle sprains by providing support and stability during activities such as walking or climbing stairs.  High-top shoes or boots also can give the person support for weak ankles.  Thumb splints can help with hand weakness and loss of fine motor skills.  Assistive devices should be used before disability sets in because the devices may prevent muscle strain and reduce muscle weakening. Some people with CMT may decide to have orthopedic surgery to treat severe foot and joint deformities, improve the ability to walk, and lessen pain.
• Occupational therapy –  involves learning new ways to cope with the activities of daily living.  For example, individuals with weakness in their arms and hands may learn to use Velcro closures or clasps instead of buttons on their clothes, or new ways of feeding themselves using assistive technology.
• Genetic counseling – Because CMT follows the principles of Mendelian inheritance, genetic counseling for recurrence of CMT1 and CMT2 is relatively straightforward if the family history for an affected individual is defined. Because of intrafamilial variability in disease expression, definition of parental disease status requires either testing for a mutation defined in the propositus or, if the mutation is not identifiable, a thorough neurological exam with objective NCS.

Medications

Symptomatic treatment may have a substantial impact on the quality of life.

• NSAIDs – Nonsteroidal anti-inflammatory drugs may help to relieve lower back or leg pain.
• Antiepileptic drugs – Neuropathic pain can be treated with antiepileptic drugs (gabapentin, pregabalin, topiramate) or tricyclic antidepressants (amitriptyline).^{[rx, rx]}
• Beta-blockers – The tremor may respond to β-blockers or primidone.^[rx] Caffeine and nicotine can aggravate the fine intentional tremor, thus avoidance of these substances is recommended.
• Neurotoxic drugs – excessive alcohol should be avoided. A small dose of vincristine can produce a devastating effect in patients with CMT, thus early detection of HMSN can avoid life-threatening vincristine neurotoxicity.^[rx]
• Vitamin C – Potential therapeutic approaches aiming at normalizing dosage by small molecules in the CMT1A duplication models include vitamin C and onapristone, a progesterone antagonist.^{[rx, rx, rx]} An alternate molecular mechanism, point mutations in Pmp22 in the Trembler and Trembler J mouse models cause peripheral neuropathy; the disease was modified by the administration of curcumin likely by alleviating the unfolded protein response.^[rx]
• Systemic biology-based modeling – anti-sense oligonucleotides, adenoviral vector-based drug delivery, and RNA interference technology. In CMT1A, agents target PMP22 overexpression such as ascorbic acid, onapristone, geldanamycin, and rapamycin have been beneficial in animal models and cell lines with improved muscle mass and weakness. However, these agents were not useful in human clinical trials.[rx] PXT3003 (a combination of baclofen, naltrexone, and d-sorbitol) has shown a reduction in the toxic effects of PMP22 over-expression in mice and humans. A significant number of subjects who received PXT3003 showed non-deterioration or improvement in CMT Neuropathy score(CMTNS), Overall Neuropathy Limitations Scale (ONLS), 10-meter walk test, and conduction velocities as compared to placebo. PXT3003 was well tolerated and safe.[rx] Curcumin reduces endoplasmic reticulum stress and improves MPZ associated neuropathy in mice.[rx]

Lifestyle and home remedies

Some habits may prevent complications caused by Charcot-Marie-Tooth disease and help you manage its effects.

Started early and followed regularly, at-home activities can provide protection and relief:

• Stretch regularly – Stretching can help improve or maintain the range of motion of your joints and reduce the risk of injury. It’s also helpful in improving your flexibility, balance and coordination. If you have Charcot-Marie-Tooth disease, regular stretching can prevent or reduce joint deformities that may result from uneven pulling of muscle on your bones.
• Exercise daily – Regular exercise keeps your bones and muscles strong. Low-impact exercises, such as biking and swimming, are less stressful on fragile muscles and joints. By strengthening your muscles and bones, you can improve your balance and coordination, reducing your risk of falls.
• Improve your stability – Muscle weakness associated with Charcot-Marie-Tooth disease may cause you to be unsteady on your feet, resulting in falls and serious injury. Walking with a cane or a walker can increase your stability. Good lighting at night can help you avoid stumbling and falling.

Here are some important points of which to take note

• CMTs are common inherited neuromuscular disorders characterized by progressive weakness, wasting, and skeletal deformities.
• Electrophysiological tests are useful to confirm the diagnosis of neuropathy and exclude alternative conditions that present with foot drop and/or foot deformities such as distal myopathies, muscular dystrophies, and idiopathic pes cavus, among others.
• Electrophysiological tests are useful to screen other family members for asymptomatic neuropathy.
• Patients of demyelinating CMTs have slowed conduction velocities within the first few years of life. Clinical manifestations of weakness, wasting, and deformities arise from axonal loss over the years.
• There is striking phenotypic variability suggesting the potential role for modifier genes and epigenetic factors.
• A detailed pedigree chart covering three or four generations is essential to find the pattern of inheritance. This is necessary before carrying out genetic studies.
• All patients should have genetic counseling before genetic testing.
• In the case of demyelinating neuropathies, the patient should first undergo testing for PMP22 duplication since it is the commonest genetic abnormality. After excluding copy number variations in PMP22, they need targeted gene sequencing or whole-exome sequencing.
• In the case of axonal neuropathies, the patient is first tested for mutations in MFN2. Alternately, the patient can directly undergo target gene sequencing or whole-exome sequencing.
• Establishing the genetic diagnosis is crucial for genetic counseling, reproductive planning, and considering the patient for potential upcoming therapies.
• Patients need to undergo specific tests to detect subclinical involvement of other organs/ systems to recommend timely prophylactic measures.
• Patients should avoid using drugs that worsen neuropathy.
• Patient education and counseling, regular follow-up, emphasis on rehabilitation measures, and consideration for therapeutic trials by a multi-disciplinary team are very important.

What research is being done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

Ongoing research on CMT includes efforts to identify more of the mutant genes and proteins that cause the various disease subtypes, discover the mechanisms of nerve degeneration and muscle atrophy with the goal of developing interventions to stop or slow down these debilitating processes, and develop therapies to reverse nerve degeneration and muscle atrophy.

The NINDS supports the NIH’s Rare Diseases Clinical Research Network, which is made up of different research consortia aimed at improving the availability of rare diseases information, clinical studies, and clinical research information.  The Network’s Inherited Neuropathies Consortium conducts studies that include a natural history analysis of CMT, the search for new genes and those that modify an individual’s symptoms, therapy development, and training programs to educate future investigators for the inherited neuropathies.  For more information on the Rare Diseases Clinical Research Network and its consortia, see Rare Diseases Info.

Scientists are studying PMP22 gene regulation to design and validate assays that measure the presence, amount, or activity of a target object.  Other studies examine the effects of small molecules on the biological system in order to develop novel treatments.  High-throughput screens (a way to quickly assess the biological activity of large numbers of compounds) may identify candidate medications that reduce PMP22 levels. Additional research focuses on how the mitochondria, the cell’s power plant, may play a role in the axonal degeneration seen in CMT, as well as other diseases.

An NIH longitudinal collaborative study hopes to determine the natural history of CMT and how the presence of a certain gene mutation may result in disease types and symptoms.  Also, a two-part study is looking for new genes that cause the disease as well as genes that do not cause the disease but may modify a person’s symptoms.  Other NIH-funded scientists are using next-generation sequencing (which can quickly identify the structure of millions of small fragments of DNA at the same time) to identify novel CMT genes.

Gene therapy is another promising area of research.  Experiments involving cell cultures and animal models of the disease have shown that it is possible to deliver genes to Schwann cells and muscles.  Other studies show trophic factors or nerve growth factors, such as the hormone androgen that prevent nerve degeneration.

References

People Also Reading

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Charcot-Marie-Tooth disease (CMT) is slowly progressive neurodegenerative hereditary chronic motor and sensory neuropathy disease and one of a group of disorders that cause damage to the peripheral nerves, the nerves that transmit information and signals from the brain and spinal cord to and from the rest of the body, as well as sensory information such as touch back to the spinal cord and brain.  CMT can also directly affect the nerves that control the muscles.  Progressive muscle weakness typically becomes noticeable in adolescence or early adulthood, but the onset of disease can occur at any age.  Because longer nerves are affected first, symptoms usually begin in the feet and lower legs and then can affect the fingers, hands, and arms.  Most individuals with CMT have some amount of physical disability, although some people may never know they have the disease.

CMT, also known as hereditary motor and sensory neuropathy, slowly progressive inherited neurological disorders distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands is one of the most common neuropathy affecting an estimated. It is possible to have two or more types of CMT, which happens when the person has mutations in two or more genes, each of which causes a form of the disease.  CMT is a heterogeneous genetic disease, meaning mutations in different genes can produce similar clinical symptoms.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves. During the last decade over two dozen genes have been identified in which mutations cause CMT. The disease illustrates a multitude of genetic principles, including diverse mutational mechanisms from point mutations to copy number variation (CNV), allelic heterogeneity, age-dependent penetrance and variable expressivity.

Types of Charcot-Marie-Tooth Disease

There are many different types of CMT disease, which may share some symptoms but vary by pattern of inheritance, age of onset, and whether the axon or myelin sheath is involved.

In general the three autosomal dominant neuropathy types based on NCV (normal >40-45 meters/second) were the following [Stojkovic 2016]:

• Demyelinating (CMT1) defined as NCV <35 m/s. The clinical findings of distal muscle weakness and atrophy and sensory loss were usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually became symptomatic between ages five and 25 years. Fewer than 5% of individuals became wheelchair dependent. Life span was not shortened.
• Axonal (non-demyelinating) (CMT 2) defined as NCV >45m/s. The clinical findings were distal muscle weakness and atrophy. Although axonal peripheral neuropathy shows extensive clinical overlap with demyelinating peripheral neuropathy, in general individuals with axonal neuropathy tended to be less disabled and have less sensory loss than individuals with demyelinating neuropathy.
• Dominant intermediate CMT (DI-CMT) defined as NCV 35-45 m/s. The clinical findings are a relatively typical CMT phenotype. NCVs are so variable that within a family some affected individuals fall in the demyelinating neuropathy range, whereas others fall in the axonal neuropathy range.

CMT1 – is caused by abnormalities in the myelin sheath.  The autosomal dominant disorder has six main subtypes.

• CMT1A – results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP22).  The PMP22 protein is a critical component of the myelin sheath.  Overexpression of this gene causes the abnormal structure and function of the myelin sheath.  CMT1A is usually slowly progressive.  Individuals experience weakness and atrophy of the muscles of the lower legs beginning in childhood; later they experience hand weakness, sensory loss, and foot and leg problems.  A different neuropathy distinct from CMT1A called hereditary neuropathy with predisposition to pressure palsy (HNPP) is caused by a deletion of one of the PMP22 genes.  In this case, abnormally low levels of the PMP22 gene result in episodic, recurrent demyelinating neuropathy.
• CMT1B – is caused by mutations in the gene that carries the instructions for manufacturing the myelin protein zero (MPZ, also called P0), which is another critical component of the myelin sheath.  Most of these mutations are point mutations, meaning a mistake occurs in only one letter of the DNA genetic code.  To date, scientists have identified more than 120 different point mutations in the P0 gene.  CMT1B produces symptoms similar to those found in CMT1A.
• Other less common causes of CMT1 result from mutations within the SIMPLE (also called LITAF), EGR2, PMP22, and NEFL genes, respectively.

CMT2

• Results from abnormalities in the axon of the peripheral nerve cell, rather than the myelin sheath, and is less common than CMT1.  This autosomal dominant disorder has more than a dozen subtypes (some of which have their own variants), with each subtype being associated with mutations in a specific gene.  Symptoms are similar to those seen in CMT1, but people with CMT2 often have less disability and sensory loss than individuals with CMT1.  The onset of CMT2 is usually in childhood or adolescence.  Some types of CMT2 may have vocal cord or phrenic nerve involvement, causing speech or breathing problems.

CMT3, or Dejerine-Sottas disease

• It is a particularly severe demyelinating neuropathy that begins in infancy.  Infants have severe muscle atrophy, weakness, delayed motor skills development, and sensory problems.  Symptoms may progress to severe disability, loss of sensation, and curvature of the spine.  This rare disorder can be caused by mutations in multiple genes, including PMP22, MPZ, and EGR2, and can be inherited either dominantly or recessively.

CMT4

• It comprises several different subtypes of demyelinating and axonal and motor neuropathies that are inherited autosomal recessively.   Each neuropathy subtype is caused by a mutation in a different gene (several genes have been identified in CMT4).  The mutations may affect a particular ethnic population and produce distinct physiologic or clinical characteristics.  People with CMT4 generally develop symptoms of leg weakness in childhood and by adolescence they may not be able to walk.  CMT4 is rare in the United States.

CMTX1 (also called CMT X, Type 1)

• It is the second most common form of CMT.  This X-linked disease is caused by mutations in a gene that provides instructions for making the protein connexin-32.  The connexin-32 protein is found in myelinating Schwann cells—cells that wrap around nerve axons and make up the myelin sheath.  Males who inherit the mutated gene show moderate to severe symptoms of the disease beginning in late childhood or adolescence.  Females who inherit a mutated gene often develop milder symptoms than males or do not show symptoms.

Disease phenotypes

• Charcot–Marie–Tooth Disease  – As CMT1 and CMT2 present with similar clinical features, distinction on the basis of the neurological exam is often impossible. The onset of clinical symptoms is in the first or second decade of life. Weakness starts distally in the feet and progresses proximally in an ascending pattern. Neuropathic bony deformities develop including pes cavus (high-arched feet) and hammer toes. With further progression the hands become weak. Muscle stretch reflexes disappear early in the ankles and later in the patella and upper limbs. Mild sensory loss to pain, temperature or vibration sensation in the legs is consistent with the phenotype. Patients also complain of numbness and tingling in their feet and hands, but paresthesias are not as common as in acquired neuropathies. Restless leg syndrome occurs in nearly 40% of patients with the axonal form.^[rx]
• Hereditary neuropathy with liability to pressure palsies (MIM 162500) – The clinical phenotype is characterized by recurrent nerve dysfunction at compression sites. Asymmetric palsies occur after relatively minor compression or trauma. Repeated attacks result in the inability of full reversal. Thus with ageing the patients with hereditary neuropathy with liability to pressure palsies (HNPP) can have significant clinical overlap with CMT1. Electrophysiological findings include mildly slowed NCV, increased distal motor latencies and conduction blocks.^[rx] The neuropathological hallmark is sausage-like thickening of myelin sheaths (tomacula).
• Dejerine–Sottas neuropathy (MIM 145900) – Dejerine–Sottas neuropathy (DSN) is a clinically distinct entity defined by delayed motor milestones. Signs of lower motor neuron-type lesion accompany the delayed motor milestones. Neurophysiological studies reveal severe slowing of NCV (<10 m/s). Neuropathology reveals pronounced demyelination, and a greater number of onion bulbs are present compared to CMT. Cerebrospinal fluid proteins may be elevated. Most patients have significant disability.
• Congentital hypomyelinating neuropathy (MIM 605253) – Congentital hypomyelinating neuropathy (CHN) is usually present at birth, although frequently the delayed motor development draws the first attention to the peripheral neuropathy. The distinction between DSN and CHN is often difficult by clinical examination as they both may present as a hypotonic infant. The differentiation of CHN and DSN is based on pathology: the presence of onion bulbs suggest DSN whereas their absence indicate CHN. CHN may present as arthrogryposis multiplex congenita.^[rx]
• Roussy–Levy syndrome (MIM 180800) – Roussy–Levy syndrome (RLS) was originally described as demyelinating CMT associated with sensory ataxia and tremor. As molecular data became available, it was shown that these patients have the same molecular abnormalities as observed in patients clinically classified as demyelinating CMT. RLS represents the spectrum of CMT.

Causes Charcot-Marie-Tooth Disease

A nerve cell communicates information to distant targets by sending electrical signals down a long, thin part of the cell called the axon.  The axon is surrounded by myelin, a covering that acts like the insulation on an electrical wire and aids the high-speed transmission of electrical signals.  Without an intact axon and myelin sheath, signals that run along the nerve and axon are either slow or have a weak signal, meaning that the peripheral nerve cells become unable to activate muscles or relay sensory information from the limbs back to the spinal cord and the brain.

CMT is caused by mutations in genes that support or produce proteins involved in the structure and function of either the peripheral nerve axon or the myelin sheath. More than 40 genes have been identified in CMT, with each gene linked to one or more types of the disease.  In addition, multiple genes can be linked to one type of CMT.  More than half of all cases of CMT are caused by a duplication of the PMP22 gene on chromosome 17.

Although different proteins are abnormal in different forms of CMT disease, all of the mutations mainly affect the normal function of the peripheral nerves.  Gene defects in myelin cause dysfunction of the coating, which distorts or blocks nerve signals, while other mutations limit axon function and cause axonal loss.

CMTs may occur due to any one of the following molecular and cellular mechanisms

• Myelin assembly – genes involved in myelin compaction (MPZ), gap junctions formation (GJB1), the interaction of Schwann cells with the extracellular matrix as well as in regulating cell spreading, cell migration and apoptosis (PMP22)
• Cytoskeletal structure – genes involved in actin polymerization (INF2), membrane-protein interactions to stabilize the myelin sheath (PRX), intermediate filaments (NEFL), cell signaling (FGD4), axonal transport (DYNC1H1)
• Endosomal sorting and cell signaling – genes regulating vesicular transport, membrane trafficking, transport of intracellular organelles and cell signaling (LITAF, MTMR2, SBF1, SBF2, SH3TC2, NDRG1, FIG4, RAB7A, TFG, DNM2, SIMPLE)
• Proteasome and protein aggregation – genes regulating microtubules (HSPB1, HSPB8), cell adhesion (LRSAM1), ubiquitin ligase (TRIM2)
• Mitochondria – genes regulating mitochondrial dynamics, structure, and the function of the respiratory chain (MFN2, GDAP1, MT-ATP6, PDK3)
• Others – genes regulating cell fusion-fission apparatus (DNM2), calcium homeostasis (TRPV4) glucose metabolism (HK1), transcription (EGR2, HINT1, PRPS1, AARS, GARS, MARS, KARS, YARS)

Because of the close functional interaction, demyelinating neuropathies eventually lead to functional axonopathies and clinically manifest secondary axonal degeneration.[rx][rx] Thus common secondary phenomena in CMTs include axonal loss, secondary Schwann cell proliferation, and acceleration of pathology due to immune-mediated mechanisms.[rx]

Symptoms of Charcot-Marie-Tooth Disease

CMT affects both sensory and motor nerves (nerves that trigger an impulse for a muscle to contract) in the arms, hands, legs, and feet.  The affected nerves slowly degenerate and lose the ability to communicate with their distant targets.  Motor nerve degeneration results in muscle weakness and a decrease in muscle bulk (atrophy) in the arms, legs, hands, or feet.

Typical early features include weakness or paralysis of the foot and lower leg muscles, which can cause difficulty lifting the foot (foot drop) and a high-stepped gait with frequent tripping or falling.  Individuals also may notice balance problems.  Foot deformities, such as high arches and curled toes (hammertoes), are also common in CMT.  The lower legs may take on an “inverted champagne bottle” shape due to the loss of muscle bulk.  As the disease progresses, weakness and atrophy may occur in the hands, causing difficulty with fine motor skills.  Degeneration of sensory nerve axons may result in a reduced ability to feel heat, cold, and touch.  The senses of vibration and position (proprioception) are often decreased in individuals with CMT.  The disease also can cause curvature of the spine (scoliosis) and hip displacement.  Many people with CMT develop contractures—chronic shortening of muscles or tendons around joints, which prevents the joints from moving freely.  Muscle cramping is common.  Nerve pain can range from mild to severe, and some individuals may need to rely on foot or leg braces or other orthopedic devices to maintain mobility. Some people with CMT experience tremors and vision and hearing can also be affected. In rare cases, breathing difficulties may occur if the nerves that control the muscles of the diaphragm are affected.

The severity of symptoms can vary greatly among individuals and even among family members with the disease and gene mutation.  Progression of symptoms is gradual.

Signs and symptoms of Charcot-Marie-Tooth disease may include

• Weakness in your legs, ankles and feet
• Loss of muscle bulk in your legs and feet
• High foot arches
• Curled toes (hammertoes)
• Decreased ability to run
• Difficulty lifting your foot at the ankle (footdrop)
• Awkward or higher than normal step (gait)
• Frequent tripping or falling
• Decreased sensation or a loss of feeling in your legs and feet

As Charcot-Marie-Tooth disease progresses, symptoms may spread from the feet and legs to the hands and arms. The severity of symptoms can vary greatly from person to person, even among family members.

Diagnosis of Charcot-Marie-Tooth disease

Diagnosis of CMT begins with a detailed medical history, family history, and neurological examination.

Family History

• A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records, including the results of molecular genetic testing and EMG and NCV studies.

Physical Exam

Treatment of Charcot-Marie-Tooth

Non Pharmacological

There is no cure for CMT, but physical and occupational therapies, braces and other orthopedic devices, and orthopedic surgery can help people cope with the disabling symptoms of the disease.  In addition, pain-relief drugs can be prescribed for individuals who have severe nerve pain.

• Maintaining mobility, flexibility, and muscle strength – Beginning a treatment program early may delay or reduce nerve degeneration and muscle weakness before it progresses to the point of disability.  Physical therapy includes muscle strength training, muscle and ligament stretching, and moderate aerobic exercise.  A specialized exercise program approved by the person’s physician can help build stamina, increase endurance, and maintain overall health.
• Braces – Many individuals with CMT require ankle braces and other orthopedic devices to maintain everyday mobility and prevent injury.  Braces can help prevent ankle sprains by providing support and stability during activities such as walking or climbing stairs.  High-top shoes or boots also can give the person support for weak ankles.  Thumb splints can help with hand weakness and loss of fine motor skills.  Assistive devices should be used before disability sets in because the devices may prevent muscle strain and reduce muscle weakening. Some people with CMT may decide to have orthopedic surgery to treat severe foot and joint deformities, improve the ability to walk, and lessen pain.
• Occupational therapy –  involves learning new ways to cope with the activities of daily living.  For example, individuals with weakness in their arms and hands may learn to use Velcro closures or clasps instead of buttons on their clothes, or new ways of feeding themselves using assistive technology.
• Genetic counseling – Because CMT follows the principles of Mendelian inheritance, genetic counseling for recurrence of CMT1 and CMT2 is relatively straightforward if the family history for an affected individual is defined. Because of intrafamilial variability in disease expression, definition of parental disease status requires either testing for a mutation defined in the propositus or, if the mutation is not identifiable, a thorough neurological exam with objective NCS.

Medications

Symptomatic treatment may have a substantial impact on the quality of life.

• NSAIDs – Nonsteroidal anti-inflammatory drugs may help to relieve lower back or leg pain.
• Antiepileptic drugs – Neuropathic pain can be treated with antiepileptic drugs (gabapentin, pregabalin, topiramate) or tricyclic antidepressants (amitriptyline).^{[rx, rx]}
• Beta-blockers – The tremor may respond to β-blockers or primidone.^[rx] Caffeine and nicotine can aggravate the fine intentional tremor, thus avoidance of these substances is recommended.
• Neurotoxic drugs – excessive alcohol should be avoided. A small dose of vincristine can produce a devastating effect in patients with CMT, thus early detection of HMSN can avoid life-threatening vincristine neurotoxicity.^[rx]
• Vitamin C – Potential therapeutic approaches aiming at normalizing dosage by small molecules in the CMT1A duplication models include vitamin C and onapristone, a progesterone antagonist.^{[rx, rx, rx]} An alternate molecular mechanism, point mutations in Pmp22 in the Trembler and Trembler J mouse models cause peripheral neuropathy; the disease was modified by the administration of curcumin likely by alleviating the unfolded protein response.^[rx]
• Systemic biology-based modeling – anti-sense oligonucleotides, adenoviral vector-based drug delivery, and RNA interference technology. In CMT1A, agents target PMP22 overexpression such as ascorbic acid, onapristone, geldanamycin, and rapamycin have been beneficial in animal models and cell lines with improved muscle mass and weakness. However, these agents were not useful in human clinical trials.[rx] PXT3003 (a combination of baclofen, naltrexone, and d-sorbitol) has shown a reduction in the toxic effects of PMP22 over-expression in mice and humans. A significant number of subjects who received PXT3003 showed non-deterioration or improvement in CMT Neuropathy score(CMTNS), Overall Neuropathy Limitations Scale (ONLS), 10-meter walk test, and conduction velocities as compared to placebo. PXT3003 was well tolerated and safe.[rx] Curcumin reduces endoplasmic reticulum stress and improves MPZ associated neuropathy in mice.[rx]

Lifestyle and home remedies

Some habits may prevent complications caused by Charcot-Marie-Tooth disease and help you manage its effects.

Started early and followed regularly, at-home activities can provide protection and relief:

• Stretch regularly – Stretching can help improve or maintain the range of motion of your joints and reduce the risk of injury. It’s also helpful in improving your flexibility, balance and coordination. If you have Charcot-Marie-Tooth disease, regular stretching can prevent or reduce joint deformities that may result from uneven pulling of muscle on your bones.
• Exercise daily – Regular exercise keeps your bones and muscles strong. Low-impact exercises, such as biking and swimming, are less stressful on fragile muscles and joints. By strengthening your muscles and bones, you can improve your balance and coordination, reducing your risk of falls.
• Improve your stability – Muscle weakness associated with Charcot-Marie-Tooth disease may cause you to be unsteady on your feet, resulting in falls and serious injury. Walking with a cane or a walker can increase your stability. Good lighting at night can help you avoid stumbling and falling.

Here are some important points of which to take note

• CMTs are common inherited neuromuscular disorders characterized by progressive weakness, wasting, and skeletal deformities.
• Electrophysiological tests are useful to confirm the diagnosis of neuropathy and exclude alternative conditions that present with foot drop and/or foot deformities such as distal myopathies, muscular dystrophies, and idiopathic pes cavus, among others.
• Electrophysiological tests are useful to screen other family members for asymptomatic neuropathy.
• Patients of demyelinating CMTs have slowed conduction velocities within the first few years of life. Clinical manifestations of weakness, wasting, and deformities arise from axonal loss over the years.
• There is striking phenotypic variability suggesting the potential role for modifier genes and epigenetic factors.
• A detailed pedigree chart covering three or four generations is essential to find the pattern of inheritance. This is necessary before carrying out genetic studies.
• All patients should have genetic counseling before genetic testing.
• In the case of demyelinating neuropathies, the patient should first undergo testing for PMP22 duplication since it is the commonest genetic abnormality. After excluding copy number variations in PMP22, they need targeted gene sequencing or whole-exome sequencing.
• In the case of axonal neuropathies, the patient is first tested for mutations in MFN2. Alternately, the patient can directly undergo target gene sequencing or whole-exome sequencing.
• Establishing the genetic diagnosis is crucial for genetic counseling, reproductive planning, and considering the patient for potential upcoming therapies.
• Patients need to undergo specific tests to detect subclinical involvement of other organs/ systems to recommend timely prophylactic measures.
• Patients should avoid using drugs that worsen neuropathy.
• Patient education and counseling, regular follow-up, emphasis on rehabilitation measures, and consideration for therapeutic trials by a multi-disciplinary team are very important.

What research is being done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

Ongoing research on CMT includes efforts to identify more of the mutant genes and proteins that cause the various disease subtypes, discover the mechanisms of nerve degeneration and muscle atrophy with the goal of developing interventions to stop or slow down these debilitating processes, and develop therapies to reverse nerve degeneration and muscle atrophy.

The NINDS supports the NIH’s Rare Diseases Clinical Research Network, which is made up of different research consortia aimed at improving the availability of rare diseases information, clinical studies, and clinical research information.  The Network’s Inherited Neuropathies Consortium conducts studies that include a natural history analysis of CMT, the search for new genes and those that modify an individual’s symptoms, therapy development, and training programs to educate future investigators for the inherited neuropathies.  For more information on the Rare Diseases Clinical Research Network and its consortia, see Rare Diseases Info.

Scientists are studying PMP22 gene regulation to design and validate assays that measure the presence, amount, or activity of a target object.  Other studies examine the effects of small molecules on the biological system in order to develop novel treatments.  High-throughput screens (a way to quickly assess the biological activity of large numbers of compounds) may identify candidate medications that reduce PMP22 levels. Additional research focuses on how the mitochondria, the cell’s power plant, may play a role in the axonal degeneration seen in CMT, as well as other diseases.

An NIH longitudinal collaborative study hopes to determine the natural history of CMT and how the presence of a certain gene mutation may result in disease types and symptoms.  Also, a two-part study is looking for new genes that cause the disease as well as genes that do not cause the disease but may modify a person’s symptoms.  Other NIH-funded scientists are using next-generation sequencing (which can quickly identify the structure of millions of small fragments of DNA at the same time) to identify novel CMT genes.

Gene therapy is another promising area of research.  Experiments involving cell cultures and animal models of the disease have shown that it is possible to deliver genes to Schwann cells and muscles.  Other studies show trophic factors or nerve growth factors, such as the hormone androgen that prevent nerve degeneration.

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Myasthenia gravis is a chronic autoimmune, neuromuscular disease that causes weakness in the skeletal muscles that worsens after periods of activity and improves after periods of rest. These muscles are responsible for functions involving breathing and moving parts of the body, including the arms and legs.

The name myasthenia gravis, which is Latin and Greek in origin, means “grave, or serious, muscle weakness.” There is no known cure, but with current therapies, most cases of myasthenia gravis are not as “grave” as the name implies. Available treatments can control symptoms and often allow people to have a relatively high quality of life. Most individuals with the condition have a normal life expectancy.

What are the symptoms of myasthenia gravis?

The hallmark of myasthenia gravis is muscle weakness that worsens after periods of activity and improves after periods of rest. Certain muscles such as those that control eye and eyelid movement, facial expression, chewing, talking, and swallowing are often (but not always) involved in the disorder.

The onset of the disorder may be sudden, and symptoms often are not immediately recognized as myasthenia gravis. The degree of muscle weakness involved in myasthenia gravis varies greatly among individuals.

People with myasthenia gravis may experience the following symptoms:

• weakness of the eye muscles (called ocular myasthenia)
• drooping of one or both eyelids (ptosis)
• blurred or double vision (diplopia)
• a change in facial expression
• difficulty swallowing
• shortness of breath
• impaired speech (dysarthria)
• weakness in the arms, hands, fingers, legs, and neck.

Sometimes the severe weakness of myasthenia gravis may cause respiratory failure, which requires immediate emergency medical care.

What is a myasthenic crisis?

A myasthenic crisis is a medical emergency that occurs when the muscles that control breathing weaken to the point where individuals require a ventilator to help them breathe. It may be triggered by infection, stress, surgery, or an adverse reaction to the medication. Approximately 15 to 20 percent of people with myasthenia gravis experience at least one myasthenic crisis. However, up to one-half of people may have no obvious cause for their myasthenic crisis. Certain medications have been shown to cause myasthenia gravis. However, sometimes these medications may still be used if it is more important to treat an underlying condition.

What causes myasthenia gravis?

Antibodies

Myasthenia gravis is an autoimmune disease, which means the immune system—which normally protects the body from foreign organisms—mistakenly attacks itself.

Myasthenia gravis is caused by an error in the transmission of nerve impulses to muscles. It occurs when normal communication between the nerve and muscle is interrupted at the neuromuscular junction—the place where nerve cells connect with the muscles they control.

Neurotransmitters are chemicals that neurons, or brain cells, use to communicate information. Normally when electrical signals or impulses travel down a motor nerve, the nerve endings release a neurotransmitter called acetylcholine that binds to sites called acetylcholine receptors on the muscle. The binding of acetylcholine to its receptor activates the muscle and causes a muscle contraction.

In myasthenia gravis, antibodies (immune proteins produced by the body’s immune system) block, alter, or destroy the receptors for acetylcholine at the neuromuscular junction, which prevents the muscle from contracting. This is most often caused by antibodies to the acetylcholine receptor itself, but antibodies to other proteins, such as MuSK (Muscle-Specific Kinase) protein, also can impair transmission at the neuromuscular junction.

The thymus gland

The thymus gland controls immune function and may be associated with myasthenia gravis. It grows gradually until puberty, and then gets smaller and is replaced by fat. Throughout childhood, the thymus plays an important role in the development of the immune system because it is responsible for producing T-lymphocytes or T cells, a specific type of white blood cell that protects the body from viruses and infections.

In many adults with myasthenia gravis, the thymus gland remains large. People with the disease typically have clusters of immune cells in their thymus gland and may develop thymomas (tumors of the thymus gland). Thymomas are most often harmless, but they can become cancerous. Scientists believe the thymus gland may give incorrect instructions to developing immune cells, ultimately causing the immune system to attack its own cells and tissues and produce acetylcholine receptor antibodies—setting the stage for the attack on neuromuscular transmission.

Who gets myasthenia gravis?

Myasthenia gravis affects both men and women and occurs across all racial and ethnic groups. It most commonly impacts young adult women (under 40) and older men (over 60), but it can occur at any age, including childhood. Myasthenia gravis is not inherited nor is it contagious. Occasionally, the disease may occur in more than one member of the same family..

Although myasthenia gravis is rarely seen in infants, the fetus may acquire antibodies from a mother affected with myasthenia gravis—a condition called neonatal myasthenia. Neonatal myasthenia gravis is generally temporary, and the child’s symptoms usually disappear within two to three months after birth. Rarely, children of a healthy mother may develop congenital myasthenia. This is not an autoimmune disorder but is caused by defective genes that produce abnormal proteins in the neuromuscular junction and can cause similar symptoms to myasthenia gravis.

How is myasthenia gravis diagnosed?

A doctor may perform or order several tests to confirm the diagnosis of myasthenia gravis:

• A physical and neurological examination. A physician will first review an individual’s medical history and conduct a physical examination. In a neurological examination, the physician will check muscle strength and tone, coordination, sense of touch, and look for impairment of eye movements.
• An edrophonium test.  This test uses injections of edrophonium chloride to briefly relieve weakness in people with myasthenia gravis. The drug blocks the breakdown of acetylcholine and temporarily increases the levels of acetylcholine at the neuromuscular junction. It is usually used to test ocular muscle weakness.
• A blood test.  Most individuals with myasthenia gravis have abnormally elevated levels of acetylcholine receptor antibodies. A second antibody—called the anti-MuSK antibody—has been found in about half of individuals with myasthenia gravis who do not have acetylcholine receptor antibodies. A blood test can also detect this antibody. However, in some individuals with myasthenia gravis, neither of these antibodies is present. These individuals are said to have seronegative (negative antibody) myasthenia.
• Electrodiagnostics.  Diagnostic tests include repetitive nerve stimulation, which repeatedly stimulates a person’s nerves with small pulses of electricity to tire specific muscles. Muscle fibers in myasthenia gravis, as well as other neuromuscular disorders, do not respond as well to repeated electrical stimulation compared to muscles from normal individuals. Single fiber electromyography (EMG), considered the most sensitive test for myasthenia gravis, detects impaired nerve-to-muscle transmission. EMG can be very helpful in diagnosing mild cases of myasthenia gravis when other tests fail to demonstrate abnormalities.
• Diagnostic imaging.  Diagnostic imaging of the chest using computed tomography (CT) or magnetic resonance imaging (MRI) may identify the presence of a thymoma.
• Pulmonary function testing.  Measuring breathing strength can help predict if respiration may fail and lead to a myasthenic crisis.

Because weakness is a common symptom of many other disorders, the diagnosis of myasthenia gravis is often missed or delayed (sometimes up to two years) in people who experience mild weakness or in those individuals whose weakness is restricted to only a few muscles.

How is myasthenia gravis treated?

Today, myasthenia gravis can generally be controlled. There are several therapies available to help reduce and improve muscle weakness.

• Thymectomy.  This operation to remove the thymus gland (which often is abnormal in individuals with myasthenia gravis) can reduce symptoms and may cure some people, possibly by rebalancing the immune system. An NINDS-funded study found that thymectomy is helpful both for people with thymoma and those with no evidence of the tumors. The clinical trial followed 126 people with myasthenia gravis and no visible thymoma and found that the surgery reduced muscle weakness and the need for immunosuppressive drugs.
• Monoclonal antibody.  This treatment targets the process by which acetylcholine antibodies injure the neuromuscular junction. In 2017, the U.S. Food and Drug Administration approved the use of eculizumab for the treatment of generalized myasthenia gravis in adults who test positive for the anti-acetylcholine receptor (AchR) antibody.
• Anticholinesterase medications.  Medications to treat the disorder include anticholinesterase agents such as Mestinon or pyridostigmine, which slow the breakdown of acetylcholine at the neuromuscular junction and thereby improve neuromuscular transmission and increase muscle strength.
• Immunosuppressive drugs.  These drugs improve muscle strength by suppressing the production of abnormal antibodies. They include prednisone, azathioprine, mycophenolate mofetil, and tacrolimus. The drugs can cause significant side effects and must be carefully monitored by a physician.
• Plasmapheresis and intravenous immunoglobulin.  These therapies may be options in severe cases of myasthenia gravis. Individuals can have antibodies in their plasma (a liquid component in blood) that attack the neuromuscular junction. These treatments remove the destructive antibodies, although their effectiveness usually only lasts for a few weeks to months.
  • Plasmapheresis is a procedure using a machine to remove harmful antibodies in plasma and replace them with good plasma or a plasma substitute.
  • Intravenous immunoglobulin is a highly concentrated injection of antibodies pooled from many healthy donors that temporarily changes the way the immune system operates.  It works by binding to the antibodies that cause myasthenia gravis and removing them from circulation.

What is the prognosis?

With treatment, most individuals with myasthenia can significantly improve their muscle weakness and lead normal or nearly normal lives.

Some cases of myasthenia gravis may go into remission—either temporarily or permanently— and muscle weakness may disappear completely so that medications can be discontinued. Stable, long-lasting complete remissions are the goal of thymectomy and may occur in about 50 percent of individuals who undergo this procedure.

What research is being done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.  The NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world.

Although there is no cure for myasthenia gravis, management of the disorder has improved over the past 30 years. There is a greater understanding about the causes, structure and function of the neuromuscular junction, the fundamental aspects of the thymus gland and of autoimmunity. Technological advances have led to more timely and accurate diagnosis of myasthenia gravis and new and enhanced therapies have improved treatment options. Researchers are working to develop better medications, identify new ways to diagnose and treat individuals, and improve treatment options.

Medication

Some people with myasthenia gravis do not respond favorably to available treatment options, which usually include long-term suppression of the immune system. New drugs are being tested, either alone or in combination with existing drug therapies, to see if they are more effective in targeting the causes of the disease.

Diagnostics and biomarkers

In addition to developing new medications, researchers are trying to find better ways to diagnose and treat this disorder. For example, NINDS-funded researchers are exploring the assembly and function of connections between nerves and muscle fibers to understand the fundamental processes in neuromuscular development. This research could reveal new therapies for neuromuscular diseases like myasthenia gravis.

Researchers are also exploring better ways to treat myasthenia gravis by developing new tools to diagnose people with undetectable antibodies and identify potential biomarkers (signs that can help diagnose or measure the progression of a disease) to predict an individual’s response to immunosuppressive drugs.

New treatment options

Findings from a recent NINDS-supported study yielded conclusive evidence about the benefits of surgery for individuals without thymoma, a subject that had been debated for decades. Researchers hope that this trial will become a model for rigorously testing other treatment options, and that other studies will continue to examine different therapies to see if they are superior to standard care options.

Assistive technologies, such as magnetic devices, may also help people with myasthenia gravis to control some symptoms of the disorder.

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