Charcot-Marie-Tooth disease (CMT) is one of the most common inherited
neurological disorders, affecting approximately 1 in 2,500 people in the
United States. The disease is named for the three physicians who first
identified it in 1886 - Jean-Marie-Charcot and Pierre Marie in Paris,
France, and Howard Henry Tooth in Cambridge, England. CMT, also known as
hereditary motor and sensory neuropathy (HMSN) or peroneal muscular
atrophy, comprises a group of disorders that affect peripheral nerves. The
peripheral nerves lie outside the brain and spinal cord and supply the
muscles and sensory organs in the limbs. Disorders that affect the
peripheral nerves are called peripheral neuropathies.
The neuropathy of CMT affects both motor and sensory nerves. A typical
feature includes weakness of the foot and lower leg muscles, which may
result in foot drop and a high-stepped gait with frequent tripping or
falls. Foot deformities, such as high arches and hammertoes (a condition
in which the middle joint of a toe bends upwards) are also characteristic
due to weakness of the small muscles in the feet. In addition, the lower
legs may take on an “inverted champagne bottle” appearance due to the loss
of muscle bulk. Later in the disease, weakness and muscle atrophy may
occur in the hands, resulting in difficulty with fine motor skills.
Although sensory nerves are also involved, patients rarely notice
significant numbness or pain.
Onset of symptoms is most often in adolescence or early adulthood,
however presentation may be delayed until mid-adulthood. The severity of
symptoms is quite variable in different patients and some people may never
realize they have the disorder. Progression of symptoms is very gradual.
CMT is not fatal and people with most forms of CMT have a normal life
expectancy.
There are many forms of CMT disease. The principal types include CMT1,
CMT2, CMT3, CMT4, and CMTX. CMT1 is the most frequent and results
from abnormalities in the myelin sheath. There are three main types of
CMT1. CMT1A is an autosomal dominant disease resulting from a
duplication of the gene on chromosome 17 that carries the instructions for
producing the peripheral myelin protein-22 (PMP-22). The PMP-22 protein is
a critical component of the myelin sheath. An overabundance of this gene
causes the structure and function of the myelin sheath to be abnormal.
Patients experience weakness and atrophy of the muscles of the lower legs
beginning in adolescence; later they experience hand weakness and sensory
loss. Interestingly, a different neuropathy distinct from CMT1A called
hereditary neuropathy with predisposition to pressure palsy (HNPP)
is caused by a deletion of one of the PMP-22 genes. In this case
abnormally low levels of the PMP-22 gene result in episodic, recurrent
demyelinating neuropathy. CMT1B is an autosomal dominant disease
caused by mutations in the gene that carries the instructions for
manufacturing the myelin protein zero (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 30 different point
mutations in the P0 gene. As a result of abnormalities in P0, CMT1B
produces symptoms similar to those found in CMT1A. The gene defect that
causes CMT1C, which also has symptoms similar to those found in CMT1A, has
not yet been identified.
CMT2 is less common than CMT1 and results from abnormalities in
the axon of the peripheral nerve cell rather than the myelin sheath.
Recently a mutation was identified in the gene that codes for the kinesin
family member 1B-beta protein in families with CMT2A. Kinesins are
proteins that act as motors to help power the transport of materials along
the train tracks (microtubules) of the cell. Another recent finding is a
mutation in the neurofilament-light gene, identified in a Russian family
with CMT2E. Neurofilaments are structural proteins that help maintain the
normal shape of a cell. Genes that cause other forms of CMT2 have not yet
been identified.
CMT3 or Dejerine-Sottas disease is a severe demyelinating
neuropathy that begins in infancy. Infants have severe muscle atrophy,
weakness, and sensory problems. This rare disorder can be caused by a
specific point mutation in the P0 gene or a point mutation in the PMP-22
gene.
CMT4 comprises several different subtypes of autosomal recessive
demyelinating motor and sensory neuropathies. Each neuropathy subtype is
caused by a different genetic mutation, may affect a particular ethnic
population, and produces distinct physiologic or clinical characteristics.
Patients with CMT4 generally develop symptoms of leg weakness in childhood
and by adolescence they may not be able to walk. The gene abnormalities
responsible for CMT4 have yet to be identified.
CMTX is an X-linked dominant disease and is caused by a point
mutation in the connexin-32 gene on the X chromosome. The connexin-32
protein is expressed in Schwann cells-cells that wrap around nerve axons,
making up a single segment of the myelin sheath. This protein may be
involved in Schwann cell communication with the axon. Males who inherit
one mutated gene from their mothers show moderate to severe symptoms of
the disease beginning in late childhood or adolescence (the Y chromosome
that males inherit from their fathers does not have the connexin-32 gene).
Females who inherit one mutated gene from one parent and one normal gene
from the other parent may develop mild symptoms in adolescence or later or
may not develop symptoms of the disease at all.
A nerve cell communicates information to distant targets by sending
electrical signals down a long, thin part of the cell called the axon. In
order to increase the speed at which these electrical signals travel, the
axon is insulated by myelin, which is produced by another type of cell
called the Schwann cell. Myelin twists around the axon like a jelly-roll
cake and prevents dissipation of the electrical signals. Without an intact
axon and myelin sheath, peripheral nerve cells are unable to activate
target muscles or 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 the
myelin sheath. Although different proteins are abnormal in different forms
of CMT disease, 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 distant targets. The degeneration of
motor nerves results in muscle weakness and atrophy in the extremities
(arms, legs, hands, or feet), and the degeneration of sensory nerves
results in a reduced ability to feel heat, cold, and pain.
The gene mutations in CMT disease are usually inherited. Each of us
normally possesses two copies of every gene, one inherited from each
parent. Some forms of CMT are inherited in an autosomal dominant fashion,
which means that only one copy of the abnormal gene is needed to cause the
disease. Other forms of CMT are inherited in an autosomal recessive
fashion, which means that both copies of the abnormal gene must be present
to cause the disease. Still other forms of CMT are inherited in an
X-linked fashion, which means that the abnormal gene is located on the X
chromosome. The X and Y chromosomes determine an individual’s sex.
Individuals with two X chromosomes are female and individuals with one X
and one Y chromosome are male. In rare cases the gene mutation causing CMT
disease is a new mutation which occurs spontaneously in the patient’s
genetic material and has not been passed down through the family.
Diagnosis of CMT begins with a standard patient history, family
history, and neurological examination. Patients will be asked about the
nature and duration of their symptoms and whether other family members
have the disease. During the neurological examination a physician will
look for evidence of muscle weakness in the arms, legs, hands, and feet,
decreased muscle bulk, reduced tendon reflexes, and sensory loss. Doctors
look for evidence of foot deformities, such as high arches, hammertoes,
inverted heel, or flat feet. Other orthopedic problems, such as mild
scoliosis or hip dysplasia, may also be present. A specific sign that may
be found in patients with CMT1 is nerve enlargement that may be felt or
even seen through the skin. These enlarged nerves, called hypertrophic
nerves, are caused by abnormally thickened myelin sheaths.
If CMT is suspected, the physician may order electrodiagnostic tests
for the patient. This testing consists of two parts: nerve conduction
studies and electromyography (EMG). During nerve conduction studies,
electrodes are placed on the skin over a peripheral motor or sensory
nerve. These electrodes produce a small electric shock that may cause mild
discomfort. This electrical impulse stimulates sensory and motor nerves
and provides quantifiable information that the doctor can use to arrive at
a diagnosis. EMG involves inserting a needle electrode through the skin to
measure the bioelectrical activity of muscles. Specific abnormalities in
the readings signify axon degeneration. EMG may be useful in further
characterizing the distribution and severity of peripheral nerve
involvement.
If all other tests seem to suggest that a patient has CMT, a
neurologist may perform a nerve biopsy to confirm the diagnosis. A nerve
biopsy involves removing a small piece of peripheral nerve through an
incision in the skin. This is most often done by removing a piece of the
nerve that runs down the calf of the leg. The nerve is then examined under
a microscope. Patients with CMT1 typically show signs of abnormal
myelination. Specifically, “onion bulb” formations may be seen which
represent axons surrounded by layers of demyelinating and remyelinating
Schwann cells. Patients with CMT2 usually show signs of axon
degeneration.
Genetic testing is available for some types of CMT and may soon be
available for other types; such testing can be used to confirm a
diagnosis. In addition, genetic counseling is available to parents who
fear that they may pass mutant genes to their children.
There is no cure for CMT, but physical therapy, occupational therapy,
braces and other orthopedic devices, and even orthopedic surgery can help
patients cope with the disabling symptoms of the disease.
Physical and occupational therapy, the preferred treatment for CMT,
involves muscle strength training, muscle and ligament stretching, stamina
training, and moderate aerobic exercise. Most therapists recommend a
specialized treatment program designed with the approval of the patient’s
physician to fit individual abilities and needs. Therapists also suggest
entering into a treatment program early; muscle strengthening may delay or
reduce muscle atrophy, so strength training is most useful if it begins
before nerve degeneration and muscle weakness progress to the point of
disability.
Stretching may prevent or reduce joint deformities that result from
uneven muscle pull on bones. Exercises to help build stamina or increase
endurance will help prevent the fatigue that results from performing
everyday activities that require strength and mobility. Moderate aerobic
activity can help to maintain cardiovascular fitness and overall health.
Most therapists recommend low-impact or no-impact exercises, such as
biking or swimming, rather than activities such as walking or jogging,
which may put stress on fragile muscles and joints.
Many CMT patients require ankle braces and other orthopedic devices to
maintain everyday mobility and 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 give
the patient 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 CMT patients may decide to have
orthopedic surgery to reverse foot and joint deformities.
The NINDS supports research on CMT and other peripheral neuropathies in
an effort to learn how to better treat, prevent, and even cure these
disorders. Ongoing research includes efforts to identify more of the
mutant genes and proteins that cause the various disease subtypes, efforts
to discover the mechanisms of nerve degeneration and muscle atrophy with
the hope of developing interventions to stop or slow down these
debilitating processes, and efforts to find therapies to reverse nerve
degeneration and muscle atrophy.
One promising area of research involves gene therapy experiments.
Research with cell cultures and animal models has shown that it is
possible to deliver genes to Schwann cells and muscle. Another area of
research involves the use of trophic factors or nerve growth factors, such
as the hormone androgen, to prevent nerve degeneration.
Keeping on Top of Your Condition
Keeping in tune with your disease or condition not only makes treatment less intimidating but also increases its chance of success, and has been shown to lower a patients risk of complications. As well, as an informed patient, you are better able to discuss your condition and treatment options with your physician.
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BRAIN
P.O.
Box 5801
Bethesda, MD 20824
800-352-9424
http://www.ninds.nih.gov/
Charcot-Marie-Tooth Association (CMTA)
2700 Chestnut
Parkway
Chester, PA 19013
610-499-9264
800-606-CMTA (2682)
http://www.charcot-marie-tooth.org/
Muscular Dystrophy Association
3300 East Sunrise
Drive
Tucson, AZ 85718-3208
520-529-2000
800-572-1717
http://www.mdausa.org/
Neuropathy Association
60 East 42nd Street, Suite 942
New
York, NY 10165-0999
212-692-0662
800-247-6968
http://www.neuropathy.org/
National Ataxia Foundation
60 East 42nd Street
Suite
942
New York, NY 10165-0999
212-692-0662
800-247-6968
http://www.neuropathy.org/
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