| Facts About Charcot-Marie-Tooth & Related Diseases |
Updated 5/09 |
For the Spanish version of this publication, click here: En Español |
What is Charcot-Marie-Tooth Disease?
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| CMT causes degeneration of the peripheral nerves, leading to muscle weakness in the body’s extremities. |
Charcot-Marie-Tooth disease (CMT) is a neurological disorder, named after the three physicians who first described it in 1886 — Jean-Martin Charcot and Pierre Marie of France, and Howard Henry Tooth of the United Kingdom. Although most people have never heard of CMT, it affects some 115,000 Americans.
Unlike other neurological disorders, CMT usually isn’t life-threatening, and it almost never affects the brain. It causes damage to the peripheral nerves — tracts of nerve cell fibers that connect the brain and spinal cord to muscles and sensory organs.
Peripheral nerves control movement by relaying impulses from the spinal cord to muscles. They convey sensation by carrying feelings like pain and temperature from the hands and feet to the spinal cord. They also help control balance, by carrying information about the position of the body in space.
They transmit information about the feet and hands to the spinal cord and thenthe brain, so that the brain knows where to place the feet when walking and where the hands should be placed to reach for something.
Nerve damage, or neuropathy, causes muscle weakness and wasting, and some loss of sensation, mostly in the extremities of the body: the feet, the lower legs, the hands and the forearms.
Although CMT can look very similar to an acquired neuropathy — a type of nerve damage caused by diabetes, immunological abnormalities or exposure to certain chemicals or drugs — it isn’t caused by anything a person does, and it isn’t contagious. It’s hereditary, meaning that it can be passed down through a family from one generation to the next. (See “Does it Run in the Family?”)
Because of these features, CMT is sometimes called hereditary motor and sensory neuropathy (HMSN). Some doctors also use the old-fashioned name peroneal muscular atrophy, which refers to wasting of the peroneal muscle in the lower leg.
There are even more names for CMT because the disease exists in many different forms, each unique in its severity, age of onset, progression and exact symptoms. For example, Dejerine-Sottas disease (DS) is a severe form of CMT that manifests during infancy or early childhood.
Although there’s no cure for CMT, there are treatments that can be used to effectively manage its symptoms. Those treatments, described here along with a general overview of CMT, have allowed many people with the disease to lead active, productive lives.
What causes CMT?
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Peripheral nerves control movement by relaying impulses from the spinal cord (not shown) to the muscles (shown in the forearm). They also convey sensation and help with balance and awareness of the body’s position.
A single movement-controlling peripheral nerve is composed of many long nerve cell branches — or axons — that extend from the spinal cord and connect to muscle fibers. Each axon is surrounded by myelin made from the wrappings of Schwann cells. |
CMT is caused by defects in genes, which are segments of DNA contained in the chromosomes of the body’s cells. Genes are recipes for making the proteins that serve essential functions in our bodies. Each form of CMT is linked to a specific gene, and all of those genes make proteins found within the peripheral nerves.
Peripheral nerves provide an essential relay between your brain and the rest of your body. When you decide to move your leg, your brain sends an electrical signal to muscle-controlling nerve cells in your spinal cord, which then use the peripheral nerves to pass the signal on to your leg muscles.
And if you hurt your leg, you feel it because pain-sensitive nerve cells there have sent a signal through your peripheral nerves to your brain.
The peripheral nerves are made up of fibers, or axons, that extend from sensory nerve cells and muscle-controlling nerve cells, and carry electrical signals to and from the spinal cord.
In order for you to move and react with precision and speed, axons have to transmit their signals within a fraction of a second. This is a real challenge for axons that have to stretch over long distances, like the ones connected to muscles in your fingers and toes.
To give axons a performance boost, each one is surrounded by a coating called myelin. Similar to the way plastic coating is used to insulate electrical wiring, myelin insulates the electrical signals in axons. It also provides essential nourishment to the axons.
Some 20 genes have been implicated in CMT, each one linked to a specific type (and in many cases, more than one type) of the disease. (See “What are the different types of CMT?”) Some of those genes make proteins needed in axons, and others make proteins needed in myelin.
Defective myelin genes can cause a breakdown of myelin (called demyelination) while defective axon genes can cause an impairment of axon function (axonopathy).
In either case, the end result is the same: Defects in the axon or the myelin cause progressive damage to the axons.
The longest axons in the body are especially sensitive to damage, which explains why CMT mostly causes motor and sensory problems in the body’s extremities.
Nerves other than those that go to and from the extremities can be affected at the severe end of the CMT spectrum. If the nerves that go to and from the diaphragm or intercostal (between the ribs) muscles are affected, respiratory impairment can result.
What happens to someone with CMT, and how is it treated?
Partly because there are different types of CMT, the exact symptoms vary greatly from person to person. This section provides a general picture of CMT, and the next section describes different types of the disease.
Muscle weakness
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| A doctor examines a patient with foot drop. |
In general, people with CMT experience slowly progressive weakness and wasting in the distal muscles, which control the extremities. These muscles control foot and hand movements. More proximal muscles, those closer to the trunk, such as the leg and arm muscles, are rarely affected.
Usually, weakness begins in the feet and ankles, and manifests itself as foot drop — difficulty lifting the foot at the ankle, so that the toes point downward during walking. Foot drop causes frequent tripping, and with increasing weakness and attempts at compensation, the affected person develops an abnormal gait.
Many people with CMT make their first visits to a neurologist after they notice frequent trips and falls, ankle sprains, or ankle fractures, caused by foot drop.
When these problems occur, some people find they can overcome them just by wearing boots or high-top shoes to support the ankles.
Others might require leg braces, such as an ankle-foot orthosis (AFO), a removable cast that fits snuggly around the foot and ankle. Once made of clunky metal struts that required special shoes, AFOs are now made of lightweight plastic that’s custom-molded to fit the wearer’s legs, and can be worn underneath pants and tennis shoes.
For people with more proximal weakness, there’s the knee-ankle-foot orthosis (KAFO), which extends up the leg, just above the knee. They usually can be worn under trousers. Some orthoses allow movement of the ankle or knee, while others prevent movement to add more support.
Most people with CMT won’t need a wheelchair or motorized scooter, but an older person with advanced CMT or someone with a severe type might require one of these to get around, especially when traversing long distances. Like AFOs, wheelchairs aren’t what they used to be. There are wheelchairs that can be used on almost any terrain — from shopping mall to hiking trail — many of them powered by the flip of a switch.
MDA assists with purchase and repair of AFOs and wheelchairs.
Late in the course of CMT, many people experience weakness in the hands and forearms, and have difficulty with gripping and fine finger movements, such as turning doorknobs, and buttoning and zippering clothes. Often, these problems can be overcome with occupational therapy, which helps people accomplish the “job” of daily living through the use of assistive devices.
For example, an occupational therapist might recommend that you put special rubber grips on your home’s doors, or buy clothes that fasten with Velcro or snaps. Your MDA clinic can refer you to an occupational therapist.
Weakness of the respiratory muscles is rare in people with CMT, but when it occurs it can be life-threatening. If you regularly experience shortness of breath, you should have your breathing checked by a specialist, who might recommend occasional or nighttime use of a device that delivers air under pressure into the lungs.
Although it’s usually too slight to cause disability or discomfort, some people with CMT experience tremor (involuntary shaking). CMT with obvious tremor is sometimes called Roussy-Levy syndrome.
Contractures and bone deformities
Many people with CMT eventually develop contractures (stiffened joints) that result in deformities of the feet and hands.
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| Foot contractures resulting in high-arched feet often occur in CMT. |
The contractures occur because as some muscles around a joint weaken, others remain strong, contracting and pulling on the joint. Over time, the bones around the joint shift into abnormal positions.
For example, as muscles that lift the foot at the ankle become weak, muscles that lower and curl the foot downward contract and tighten, causing the most common type of foot deformity — a shortened foot with a high arch (pes cavus). As the contracture gets worse, the toes can become locked in a flexed position.
A small fraction of people with CMT develop “flat feet” (pes planus), presumably because of a different pattern of muscle weakness.
During walking, these deformities can cause unusual friction against the toes, heel and ball of the foot, leading to painful abrasions, blisters and calluses. If left untreated, the contractures and secondary abrasions tend to worsen over time, making it increasingly difficult to walk.
As CMT progresses, contractures in the hand can lock the fingers in a flexed position, and in rare cases severe proximal weakness can lead to scoliosis (side-to-side curvature of the spine) or kyphosis (front-to-back spine curvature).
A small fraction of people with severe CMT also experience hip displacement at an early age.
One of the most effective ways to keep muscles from tightening up and forming contractures is to begin a regular program of physical therapy, which usually consists of low-impact exercises and stretching.
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| Hand contractures can occur late in the course of CMT. |
Your MDA clinic can help get you started on an individualized physical therapy program.
Foot contractures can also be delayed by using AFOs, which force the feet into a normal position and decrease stress on the ankles. Similarly, splints can be used to prevent unintended flexing of the toes and fingers.
If these methods fail and severe contractures occur, surgery can be used to loosen up tight muscles and tendons, or to correct bone deformities. Surgery is often necessary for advanced scoliosis.
Sensory loss and associated symptoms
Because CMT causes damage to sensory axons, most people with CMT have a decreased sensitivity to heat, touch and pain in the feet and lower legs.
Although people with CMT often complain that their feet get cold (caused as much by a loss of insulating muscle as by damage to sensory axons), most of these sensory losses are undetectable except by a neurological exam — but it’s important to recognize that they occur.
Combined with the regular abrasions caused by foot deformities, the lack of pain sensitivity makes people with CMT at risk for developing ulcerations — wounds that have gone unnoticed and become severely infected. If you have CMT, and especially if you have any foot deformities, you should check your feet regularly for injuries.
Paradoxically, some people with CMT experience more pain — a combination of painful muscle cramps and neuropathic pain. This pain isn’t caused by an external trigger, but by defective signals in sensory axons. Both types of pain usually can be alleviated with medication.
In many people with CMT, sensory loss is associated with dry skin and hair loss in the affected area.
In rare cases, sensory loss can include gradual hearing impairment and sometimes deafness. Watching out for these potential problems will enable you to seek appropriate treatment if necessary.
Drug warning
The use of certain prescription drugs or excess alcohol can lead to acquired neuropathy, and thus might exacerbate CMT. Case studies have shown that the chemotherapy drug vincristine can cause rapid deterioration in people with CMT.
When taking a prescription drug for the first time, it’s a good idea to consult your doctor about its possible effects on CMT. Or, enter the specific name of the drug into an Internet search engine, along with the words “prescribing information,” to receive a full explanation of what the drug does and what its side effects may be.
You’re unlikely to see anything specific about CMT. However, if the medication’s side effect description mentions words like neuropathy, paresthesias, neuropathic pain or peripheral nerve damage, you may want to consult your physician about its use in CMT and possible alternatives.
Lists of contraindicated (forbidden) drugs for people with CMT are often composed mostly of medications used to treat serious conditions, such as cancer. In these cases, there may be no alternative to taking the drug, with the awareness that CMT symptoms may worsen.
What are the different types of CMT?
The many different types of CMT are distinguished by age of onset, inheritance pattern, severity, and whether they’re linked to defects in axon or myelin.
While those distinctions are useful, it’s important to realize that, because of the vast number of genetic defects that can lead to CMT, some people fall on the borders between different types and many have specific “subtypes” not detailed here.
(For more information about the genetics and inheritance of CMT, see “Does it Run in the Family?”)
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| For axons and Schwann cells, communication is the key to a healthy relationship. Axons send chemical messages (red) that attract Schwann cells and encourage myelin formation, and Schwann cells appear to send messages (green) that nourish and protect axons. The various genetic defects that cause CMT often disrupt these interactions. |
CMT1 and CMT2
Onset: usually childhood or adolescence
Inheritance: type 1, autosomal dominant; type 2, autosomal dominant or recessive
Features: These are the two most common forms of CMT. (In fact, a subtype called CMT1A, caused by a defect in the PMP22 gene on chromosome 17, accounts for around 60 percent of all CMT cases.)
CMT1 is caused by demyelination, and CMT2 is caused by axonopathy, but both produce the classic symptoms described above.
CMT2 is sometimes associated with a treatable condition called restless legs syndrome, an irresistible urge to move the legs while sitting or lying down.
CMTX
Onset: childhood or adolescence
Inheritance: X-linked
Features: CMTX has symptoms similar to those of CMT1 and CMT2. Because of its linkage to the X chromosome, it often affects males more severely than females.
CMT4
Onset: infancy, childhood or adolescence
Inheritance: autosomal recessive
Features: CMT4, a demyelinating form of CMT, causes weakness, usually mostly distal, but sometimes involving proximal muscles. Sensory dysfunction can also occur. When CMT4 begins in infancy, it’s characterized by low muscle tone. Young children with CMT4 generally have delayed motor (movement-related) development.
Dejerine-Sottas Disease
Onset: early childhood (generally before 3 years)
Inheritance: autosomal dominant or recessive
Features: DS is sometimes classified as a subgroup of CMT4 and is also sometimes called HMSN3. It’s a severe neuropathy, with generalized weakness sometimes progressing to severe disability, loss of sensation, curvature of the spine and sometimes mild hearing loss.
Several of the genes that, when flawed, cause Dejerine-Sottas disease, are the same genes that, when flawed in a different way, lead to various forms of CMT.
Congenital Hypomyelinating Neuropathy (CHN)
Onset: congenital (at or near birth)
Inheritance: autosomal recessive, spontaneous
Features: Unlike other types of CMT, CHN is associated with reduced myelin formation (hypomyelination) from birth rather than a breakdown of existing myelin. Both genetically and clinically, it’s similar to DS, but usually has an earlier onset and a nonprogressive or slowly progressive course.
Many children with CHN grow up and experience gradual improvements in strength.
How is CMT diagnosed?
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| Adults and children with CMT find many ways to remain independent. |
A combination of lower leg weakness and foot deformities is a red flag for CMT, but isn’t sufficient for diagnosis. When a patient has those symptoms, a well-trained neurologist will usually start with a physical exam to look for further signs of distal weakness and sensory loss.
As a test for leg weakness, the neurologist might ask the patient to walk on his heels, or to move part of his leg against an opposing force.
To look for sensory loss, the neurologist will usually test the patient’s deep tendon reflexes (like the knee-jerk reflex), which are reduced or absent in most people with CMT.
During this initial evaluation, the neurologist also will ask about the patient’s family history. A family history of CMT-like symptoms, combined with signs of nerve damage from the individual’s physical exam, strongly point to CMT or another hereditary neuropathy.
Lack of a family history doesn’t rule out CMT, but might prompt the neurologist to ask about diabetes, over-exposure to certain drugs and other potential causes of neuropathy.
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| Doctors have many tests for diagnosing CMT. |
Next, if the diagnosis is still consistent with CMT, the neurologist may arrange for genetic testing. These tests, done by drawing a blood sample, are designed to detect the most common genetic defects known to cause CMT. Many, but certainly not all, of the genetic mutations underlying CMT can be detected with a DNA blood test.
A positive genetic test result can provide a definite diagnosis and useful information for family planning. But once again, a negative result doesn’t rule out CMT.
The neurologist may also perform a nerve conduction velocity (NCV) test, which measures the strength and speed of electrical signals transmitted through nerves.
It’s done by placing surface electrodes, similar to those used for electrocardiograms, on the skin at various points over a nerve. One electrode delivers a mild shock that stimulates an electrical response in the nerve, and the others record this response as it travels through the nerve.
Delayed responses are a sign of demyelination and small responses are a sign of axonopathy. Thus, NCV is often used to distinguish between CMT1 and CMT2.
Other procedures sometimes used to diagnose CMT include electromyography (EMG), which measures the electrical signals in muscles, and less commonly, nerve biopsy, which involves the removal and examination of a small piece of nerve.
Axons, Myelin and CMT
| There are more than 30 genes that, when flawed, can cause CMT or Dejerine-Sottas disease. Many carry instructions for structural components of the axon (nerve fiber) or of the myelin sheath that surrounds it. |
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| Myelin structural components |
Axon structural components |
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Peripheral myelin protein 22 (PMP22) — CMT1(A), DS*, CMT4
Controls Schwann cell division. |
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Neurofilament-light (NF-L) — CMT2 (single large Russian family)
Acts as backbone and conveyor belt within axon. |
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Myelin protein zero (MPZ, or P0) — CMT1(B), CMT2, DS*, CMT4
Holds layers of myelin together. |
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*DS = Dejerine-Sottas |
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Connexin 32 (Cx32, a.k.a. GJB1) — CMTX
Forms pores between layers of myelin. |
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Facts About Charcot-Marie-Tooth & Related Diseases
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