Charcot Marie Tooth disease is an inheritable neuromuscular disease, and it is the world’s most commonly inherited neuromuscular disease. Commonly referred to as CMT, the chances of inheriting the disease and how the disease is inherited are both determined by the specific genetic mutation. Currently, there are about 100 different gene mutations identified to cause CMT. Each gene mutation accounts for a specific subtype. CMT can affect everybody differently, and even within the same family.
CMT is so named for the three physicians who first described it, Jean-Martin Charcot (1825-1893), Pierre Marie (1853-1940), and Howard Henry Tooth (1856-1925), CMT is, at its core definition, a genetic polyneuropathy of the Peripheral Nervous System (PNS). The nerves that comprise the PNS lie outside of the brain and
spinal cord, and they supply the muscles and sensory organs in the limbs. For conversation purposes, CMT is typically referred to as a genetic neuromuscular disease. CMT is understood to affect 1 in 2500 people, or about 0.04% of the population.
Other names that CMT is sometimes to referred are: Hereditary Motor and Sensory Neuropathy (HMSN), Peroneal Muscular Atrophy (PMA), Charcot Marie Tooth Hereditary Neuropathy, and Charcot Marie Tooth Syndrome. Each of these refer to the same disease that is known as CMT.
What are the Symptoms of Charcot Marie Tooth Disease?
According to the Charcot-Marie-Tooth Association, the first signs of Charcot Marie Tooth disease may include toe-walking, frequent tripping, ankle sprains, clumsiness, and “burning” or pins-and-needles sensations in the feet or hands. Structural foot deformities such as high arches (pes cavus) and hammertoes are common, but some people have flat feet (pes planus). Foot drop, poor balance, and problems walking, as muscle wasting in the lower legs and feet progresses, can also be early signs of CMT.
Difficulty with tasks involving manual dexterity, such as writing, and manipulating zippers and buttons, often accompanies muscle wasting in the hands. Abnormal sensation, loss of ability to feel light touch, inability to differentiate between hot/cold, and the loss of proprioception are also common. Many people experience neuropathic pain, muscle pain, and joint pain. Poor tolerance to cool, cold, and/or hot temperatures is typical. Many people with CMT have chronically cold hands and feet.
Additional symptoms may include flexed fingers, contractures, tremor, knee and/or hip problems, cramps, thenar muscle atrophy causing weakness of the muscles between the thumb and forefinger, loss of hand strength, chronic fatigue, sleep apnea, breathing difficulties, vocal difficulties, swallowing difficulties, absent or reduced reflexes, poor circulation, scoliosis, hyperkyphosis, and hearing loss.
What Causes Charcot Marie Tooth Disease?
A nerve cell communicates information to targets by sending electrical signals down a long, thin part of the cell called the axon. The axon is insulated (wrapped) by a sheath. The substance this sheath is made of is called myelin. This myelin sheath functions to protect the axon from damage and to also increase the speed and efficiency at which these electrical signals travel. Charcot Marie Tooth disease disrupts the normal healthy function of the axon or the myelin, and sometimes both. Without a healthy and efficiently performing axon and its myelin sheath, peripheral nerve cells are unable to correctly activate target muscles or to efficiently relay sensory information from the limbs back to the brain.
CMT is caused by mutations in genes that produce proteins involved in the structure and function of either the peripheral nerve axon or its myelin sheath. Although different proteins are abnormal in different subtypes of CMT, all of the mutations affect the normal function of the peripheral nerves. Consequently, these nerves slowly degenerate and lose the ability to communicate with their targets. The degeneration of motor nerves results in muscle weakness and atrophy in the extremities (arms, legs, hands, feet). The degeneration of sensory nerves results in a reduced ability to feel touch, hot and cold, and can result in dysregulation of pain signals.
The gene mutations in CMT are inheritable. How these mutations are inherited depends on the mutation itself. Each person normally possesses two copies of every gene-- one inherited from each parent. Some subtypes of CMT are inherited in an autosomal dominant pattern, meaning that only one copy of the gene mutation is needed to cause that particular subtype of CMT. Other subtypes of CMT are inherited in an autosomal recessive pattern, meaning that both copies of the gene must have the same mutation in order to have that particular subtype of CMT. Still, other subtypes of CMT are inherited in an X-Linked pattern, meaning that the responsible gene is located on the X Chromosome-- one of the two gender-chromosomes.
Although Charcot Marie Tooth disease is inheritable, a person does not have to have inherited the disease-causing gene mutation. It is possible for the disease-causing gene mutation to occur on its own without a prior family history. When this happens, it is referred to as a de novo case. When a de novo case occurs, the chances of passing the gene mutation on is the same as if they had inherited the gene mutation.
What are the Types of Charcot Marie Tooth Disease?
Currently, there are 6 basic type categories/classifications for Charcot Marie Tooth disease. They are 1, 2, 4, X-Linked, Dominant Intermediate, and Recessive Intermediate. Each type is a group of subtypes. The types are grouped according to clinical nerve characteristics (demyelinating, axon-related, or a clinical characteristic overlap of both) and inheritance pattern (autosomal dominant, autosomal recessive, or X-Linked). Each subtype is understood to be caused by a unique gene mutation. Things in the CMT world move and change rapidly. New gene associations are being discovered almost daily. Therefore, subtype names and type classifications are subject to change at any moment. However, there is still a general method to categorizing and classifying the types of CMT.
The Type 1s, or CMT 1, are each understood to be a demyelinating subtype that are each autosomal dominant in inheritance, with one exception: CMT1F. CMT1F is understood to be either autosomal dominant or autosomal recessive in inheritance. CMT1F is sometimes expressed as 1F/2E (or 2E/1F, depending on author), because CMT1F and CMT2E are understood to be caused by a mutation of the same gene (different mutations, same gene). CMT1 also includes the autosomal dominant subtype HNPP (Hereditary Neuropathy with Liability to Pressure Palsies).
The Type 2s, or CMT 2, are each understood to be an axon-related subtype that are each autosomal dominant. However, there a few exceptions to the autosomal dominant rule in the Type 2 category. The Type 2 subtypes CMT2B1, CMT2B2, CMT2R, CMT2S, CMT2X, and CMT2DD are each understood to be autosomal recessive in inheritance. The Type 2 subtypes CMT2P and CMT2T are each understood to be either autosomal dominant or autosomal recessive in inheritance.
The Type 4s, or CMT4, are each autosomal recessive in inheritance, and the subtype can be demyelinating or it can be axon-related. The subtype CMT4J is understood to be both axon-related and demyelinating at the same time.
The X-Linked Types, or CMTX, are each caused by a mutation in a gene that is found on the X Chromosome. These, thus far, are each understood to be a demyelinating subtype. They can be either dominant or recessive, and are termed X-Linked Dominant or X-Linked Recessive.
The Dominant Intermediate Types, or CMTDI, are each understood to exhibit clinical nerve characteristics that overlap that which is seen in the demyelinating subtypes and that which is seen in the axon-related subtypes; and each are understood to be autosomal dominant in inheritance.
The Recessive Intermediate Types, or CMTRI, are each understood to exhibit clinical nerve characteristics that overlap that which is seen in the demyelinating subtypes and that which is seen in the axon-related subtypes; and each are understood to be autosomal recessive in inheritance.
How is Charcot Marie Tooth Disease Diagnosed?
According to the National Institutes of Health, when Charcot Marie Tooth disease is suspected, diagnosis begins with a standard medical history, a family history, and a neurological examination. The patient will typically be asked about the nature and duration of their symptoms, and, because CMT is hereditary, whether other family members have CMT. Knowing if there is an established family history of CMT will help guide the physician's diagnostic decisions.
The physician typically performs a neurological exam, looking for evidence of muscle weakness in the patient's arms, hands, legs, and feet; decreased muscle bulk, reduced tendon reflexes, and sensory loss. The physician will typically look for evidence of foot deformities, such as high arches, hammertoes, an inverted heel, or flat feet. Other orthopedic problems, such as scoliosis, hyperkyphosis, or hip dysplasia may also be present. If CMT is suspected after the physical exam is performed, the physician may order electrodiagnostic tests.
According to the Charcot-Marie-Tooth Association, electrodiagnostic testing used to diagnose CMT usually includes a nerve conduction study (NCS), which measures the strength and speed of electrical signals moving down the peripheral nerves. Delayed responses are a sign of demyelination (CMT1), and small responses in signal strength are a sign of axonopathy (CMT2). An electromyogram (EMG) is also used to measure the electrical signals’ strength in the muscles of the arms and/or legs. NCVs and EMGs may cause discomfort for some. For these people, it may be possible to modify the study, perhaps testing fewer nerves than the physician requested. In limited circumstances, sedation can be used for the NCS, but sedation reduces the accuracy and usefulness of an EMG. Generally, electrodiagnostic tests are performed by a lab technician, a neurologist, or by a physician who specializes in physical medicine and rehabilitation-- a physiatrist.
If the electrodiagnostic test results are consistent with findings that are known to be consistent with CMT, a physician will typically be able to diagnose the patient with either a demyelinating type or with an axon-related type-- CMT1 or CMT2, respectfully. Electrodiagnostic testing can help a physician to determine if the patient is presenting with a demyelinating type or an axon-related type, but electrodiagnostic testing cannot pinpoint the exact subtype. To determine the exact subtype, and to confirm the diagnosis, a genetic test is needed.
There are over 100 different gene mutations currently understood to cause CMT. Because there isn't a lab that tests in a single panel for all known mutations that are understood to cause CMT, physicians can use electrodiagnostic findings to help guide the genetic test choice.
The genetic tests used for confirming the Charcot Marie Tooth Disease diagnosis and for pinpointing the exact subtype are performed by blood draw or by saliva sample, depending on the lab being used and the test ordered. Tests are available for many of the genetic causes of CMT, but not for all. A "positive" genetic test can provide a definitive diagnosis, will typically provide the information needed to help the physician determine the exact subtype, and can provide useful information for family planning. However, a "negative" result does not rule out CMT. The reasons a genetic test for CMT can be "negative" when symptoms and electrodiagnostic test results indicate CMT are many. The most common reason a test could be "negative" is that the specific test ordered did not include testing for the specific gene mutation that the patient has.
How is Charcot Marie Tooth Disease Treated?
Currently, there is no known treatment or cure for Charcot Marie Tooth disease. Patient care focuses on supportive care and symptom management in a multidisciplinary approach. Physical therapy, occupational therapy, AFOs, other orthopedic devices as needed, and even orthopedic surgery can help patients cope with the potentially disabling symptoms of CMT. Chronic pain can be present with CMT. Careful pain management administered by a physician can significantly improve the overall quality-of-life for the CMT patient.
Physical and occupational therapy, the preferred symptom management tool for CMT, involves muscle strength training, muscle and ligament stretching, stamina training, and moderate aerobic exercise. Most physiotherapists recommend a specialized treatment program to fit individual abilities and needs, and designed with the approval of the patient's physician. Physiotherapists also suggest entering into a PT/OT program early because muscle strengthening may delay or reduce muscle atrophy. As such, strength training is most useful if it begins, under the guidance of the physiotherapist and physician, before nerve degeneration and muscle weakness progress to the point of disability.
Proper stretching may prevent or reduce joint deformities that result from uneven muscle pull on bones and joints. Exercises to help build stamina or increase endurance will help prevent the fatigue that results from performing everyday routine activities. Moderate aerobic activity can help to maintain cardiovascular fitness and overall health. Most physiotherapists recommend low-impact or no-impact exercises, such as biking or swimming, rather than activities that can put stress on fragile muscles and joints, as can occur with walking or jogging.
Many CMT patients require ankle braces and other orthopedic devices to maintain everyday mobility and to prevent injury. Ankle braces can help prevent ankle sprains by providing support and stability during activities such as walking or climbing stairs. High-top shoes or boots can also help to provide a degree of 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 help to prevent muscle strain, thereby reducing muscle weakening.
What Research is Being Conducted for Charcot Marie Tooth Disease?
Research into all things related to Charcot Marie Tooth disease is occurring in all corners of the globe. From natural history studies, to identifying new gene mutations, to developing effective drug therapies for treating CMT, researchers are leaving nothing unturned as they work to unravel the mysteries of CMT. Follow the links below to learn what the prominent organizations are currently working on.
Where Can I Learn more about Charcot Marie Tooth Disease?
Would you like to learn more about Charcot Marie Tooth disease, or are you in need of patient support resources, or something in between the two? Especially if you are new to a diagnosis of CMT, whether it's yourself or a loved one who is newly diagnosed, all of this can be very overwhelming, and it can be difficult to find resources. A good starting place is our Resources page, where you'll find helpful information and links to additional resources.
CMT Quick Facts
Most Common Inherited Neuropathy
More Than 100 Different Genetic Causes
Affects 1 in 2,500 People
More Than 3 Million CMTers World Wide
Affects All Ethnicities and Age Groups
Affects the Nerves that Control the Muscles, but the Muscles are not Directly Diseased
Progressive Over One's Lifetime
Is Not an Autoimmune Disease
Is Not Acquired and Is Not Contagious
Currently No Cure nor Direct Treatment