Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders. Autosomal recessive inheritance diseases.

1. 1 | P a g e
Kursk State Medical University
The department of Biology, Medical Genetics
and Ecology
Head of the department: Prof. A.P.Ivanov
Teacher in charge : Prof. V.A. Polonikov
Topic : Charcot-Marie-Tooth disease
Name : Vihari Vichakshana Rajaguru
Group : No 32
Year : 4th year 2nd semester
(2016)

2. 2 | P a g e
What is Charcot-Marie-Tooth disease?
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-Martin 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.

3. 3 | P a g e
History
The disease is named after those who classically described it: Jean-
Martin Charcot (1825–1893), his pupil Pierre Marie(1853–1940) ("Sur une
forme particulière d'atrophie musculaire progressive, souvent familiale
débutant par les pieds et les jambes et atteignant plus tard les mains". Revue
médicale. Paris. 6: 97–138. 1886.), and Howard Henry Tooth (1856–1925)
("The peroneal type of progressive muscular atrophy", dissertation,
London, 1886.)
Jean Martin Charcot
What are the symptoms of Charcot-Marie-
Tooth disease?
The neuropathy of CMT affects both motor and sensory nerves. (Motor
nerves cause muscles to contract and control voluntary muscle activity
such as speaking, walking, breathing, and swallowing.) 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

4. 4 | P a g e
difficulty with carrying out fine motor skills (the coordination of small
movements usually in the fingers, hands, wrists, feet, and tongue).
Onset of symptoms is most often in adolescence or early adulthood, but
some individuals develop symptoms in mid-adulthood. The severity of
symptoms varies greatly among individuals and even among family
members with the disease. Progression of symptoms is gradual. Pain
can range from mild to severe, and some people may need to rely on
foot or leg braces or other orthopedic devices to maintain mobility.
Although in rare cases, individuals may have respiratory muscle
weakness, CMT is not considered a fatal disease and people with most
forms of CMT have a normal life expectancy.
What 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. 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 the loss of electrical signals.

5. 5 | P a g e
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 in some cases 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 individual's genetic material and has
not been passed down through the family.
Is there a gene implicated in Charcot-Marie-
Tooth?
The newly discovered GARS gene (see Gene Discovery Opens Door to
FurtherResearch In InheritedNeurologicalDisorders [News Release]) is
implicated in CMT type 2D, a form of CMT that primarily affects the

6. 6 | P a g e
hands and the forearms. CMT type 2D is inherited in an autosomal
dominant fashion.
Even though the GARS gene is implicated in only two specific types of
CMT, this discovery will guide researchers in studying other forms of
these diseases, as well as other neurological disorders.
Because carpal tunnel syndrome affects the hands and the forearms,
scientists may now investigate whether the GARS gene plays some role
in this disorder. And two defective forms of the gene implicated in Lou
Gehrig's disease are known to interact with a GARS family member.
Ultimately, the GARS gene and its family may provide a rich new
resource for scientists investigating inherited and non-inherited
neurological diseases.
What are the types of Charcot-Marie-Tooth
disease?
There are many forms of CMT disease, including CMT1, CMT2, CMT3,
CMT4, and CMTX. CMT1,caused by abnormalities in the myelin sheath,
has three main types. CMT1A is an autosomal dominant disease that
results 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.
Overexpression of this gene causes the structure and function of the
myelin sheath to be abnormal.

7. 7 | P a g e
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 120 different point mutations in the P0 gene. As a result of
abnormalities in P0, CMT1B produces symptoms similar to those found
in CMT1A. The less common CMT1C, CMT1D, and CMT1E, which also
have symptoms similar to those found in CMT1A, are caused by
mutations in the LITAF, EGR2, and NEFL genes, respectively.
CMT2 results from abnormalities in the axon of the peripheral nerve cell
rather than the myelin sheath. It is less common than CMT1. CMT2A,
the most common axonal form of CMT, is caused by mutations in
Mitofusin 2, a protein associated with mitochondrial fusion.
CMT2A has also been linked to mutations in the gene that codes for the
kinesin family member 1B-beta protein, but this has not been replicated
in other cases. Kinesins are proteins that act as motors to help power
the transport of materials along the cell. Other less common forms of
CMT2 have been recently identified and are associated with various

8. 8 | P a g e
genes: CMT2B (associated with RAB7), CMT2D (GARS). CMT2E
(NEFL), CMT2H (HSP27), and CMT2l (HSP22).
CMT3 or Dejerine-Sottas disease is a severe demyelinating
neuropathy that begins in infancy. Infants have severe muscle atrophy,
weakness, and sensoryproblems.This rare disordercan be caused by a
specific point mutation in the P0 gene or a point mutation in the PMP-22
gene.
CMT Type
Chromosome;
Inheritance
Pattern
Age of
Onset
Clinical Features
Average
NCVs§
CMT 1A (PMP-
22¶ dupl.)
17p11; AD*
First
decade
Distal weakness 15-20 m/s
CMT 1B (P0 -
MPZ)**
1q22; AD
First
decade
Distal weakness <20 m/s
CMT 1C (non A,
non B)
16p13;AD
Second
decade
Distal weakness 26-42 m/s
CMT 1D (early
growth response
[EGR]–2
10q21; AD
First
decade
Distal weakness 15-20 m/s
CMT 1E 17p11; AD
First
decade
Distal weakness,
deafness
15-20 m/s
CMT 1F 8p21; AD
First
decade
Distal weakness 15-20 m/s
CMT X
(Connexin-32)
Xq13; XD‡ Second
decade
Distal weakness 25-40 m/s
CMT 2A 1p36; AD 10 y Distal weakness >38 m/s
CMT 2B 3q; AD
Second
decade
Distal weakness,
sensory loss, skin
ulcers
Axon loss;
Normal
Table 1. Charcot-Marie-Tooth Disorders: Genetic and ClinicalFeature Comparison

9. 9 | P a g e
CMT 2C 12q23-q24, AD
First
decade
Vocal cord,
diaphragm, and
distal weakness
>50 m/s
CMT 2D 7p14; AD 16-30 y
Distal weakness,
upper limb
predominantly
Axon loss;
N††
CMT 2E 8p21; AD 10-30 y
Distal weakness,
lower limb
predominantly
Axon loss;
N
CMT 2F 7q11-q21; AD 15-25 y Distal weakness
Axon loss;
N
CMT 2G 12q12-q13; ?AD 9-76 y Distal weakness
Axon loss;
N
CMT 2H ?; AR† 15-25 y
Distal weakness,
Pyramidal
features
Axon loss;
N
CMT 2I 1q22; AD 47-60 y Distal weakness
Axon loss;
N
CMT 2J 1q22; AD 40-50 y
Distal weakness,
hearing loss
Axon loss;
N
CMT 2K 8q13-q21; AR <4 y Distal weakness
Axon loss;
N
CMT 2L 12q24; AD 15-25 y Distal weakness
Axon loss;
N
CMT R-Ax
(Ouvrier)
AR
First
decade
Distal weakness
Axon loss;
N
CMT R-Ax
(Moroccan)
1q21; AR
Second
decade
Distal weakness
Axon loss;
N

10. 10 | P a g e
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.
Individuals with CMT4 generally develop symptoms of leg weakness in
childhood and by adolescence they may not be able to walk. Several
genes have been identified as causing CMT4, including GDAP1
(CMT4A), MTMR13 (CMT4B1), MTMR2 (CMT4B2), SH3TC2 (CMT4C),
NDG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), FDG4 (CMT4H), and
FIG4 (CMT4J).
CMTX 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
Cowchock
syndrome
Xq24-q26
First
decade
Distal weakness,
deafness, mental
retardation
Axon loss;
N
HNPP|| (PMP-22)
Or tomaculous
neuropathy
17p11; AD All ages
Episodic
weakness and
numbness
Conduction
Blocks

11. 11 | P a g e
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.
How is Charcot-Marie-Tooth disease
diagnosed?
Diagnosis of CMT begins with a standard medical history, family history,
and neurological examination. Individuals will be asked about the nature
and duration of their symptoms and whether other family members have
the disease.
During the neurologicalexamination a physician will look for evidence of
muscle weakness in the individual's 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 people 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.
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.

12. 12 | P a g e
Genetic testing is available for some types of CMT and results are
usually enough to confirm a diagnosis. In addition, genetic counseling is
available to assist individuals in understanding their condition and plan
for the future.
If all the diagnostic work-up in inconclusive or genetic testing comes
back negative, a neurologist may perform a nerve biopsy to confirm the
diagnosis. A nerve biopsyinvolves 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.
Individuals 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. Individuals with CMT1 usually show signs of axon
degeneration. Recently, skin biopsy has been used to study
unmyelinated and myelinated nerve fibers in a minimally invasive way,
but their clinical use in CMT has not yet been established.
Diagnostic Considerations
In addition to the conditions listed in the differential diagnosis,other
problems to be consideredinclude the following:
 Acquired nongenetic causes of peripheral neuropathies
 Vitamin B12 deficiency
 Thyroid disease
 Diabetes mellitus
 Vasculitis
 Amyloid associated with chronic inflammation
 Occult malignancy
 Heavy-metal intoxication
 Chronic inflammatory demyelinating polyneuropathy
 Motor neuropathy with multiple conductionblock
 Other genetic neuropathies
 Familial brachial plexus neuropathy (ie, hereditary neuralgic
amyotrophy)
 Autosomalrecessive genetic disorders,such as Refsum disease or
metachromatic leukodystrophy

13. 13 | P a g e
 X-linked recessive genetic disorders,such as adrenomyeloneuropathy
or Pelizaeus-Merzbacher disease
 Amyloid neuropathies
 Hereditary ataxias with neuropathy (eg, Friedreichataxia)
Blindness,seizures, dementia, and mental retardation are not part of
Charcot-Marie-Tooth syndrome.
Differential Diagnoses
 Alcoholism
 Leprosy
 Neurosyphilis
 Pediatric HIV Infection
How is Charcot-Marie-Tooth disease treated?
There is no cure for CMT, but physical therapy, occupational therapy,
braces and other orthopedic devices, and even orthopedic surgery can
help individuals cope with the disabling symptoms of the disease. In
addition, pain-killing drugs can be prescribed for individuals who have
severe pain.
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 person'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.

14. 14 | P a g e
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
provide 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 individuals with CMT may decide to have orthopedic surgery to
reverse foot and joint deformities.
Prognosis
The severity of symptoms vary widely even for the same type of CMT.
There have been cases of monozygotic twins with varying levels of
disease severity, showing that identical genotypes are associated with
differentlevels of severity some patients are able to live a normal life and
are almost or entirely asymptomatic. A 2007 review stated that "Life
expectancy is not known to be altered in the majority of cases.
What research is being done?
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 discoverthe 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. Vitamin C
has been studied in CMT1A and the results of a multicentric trial are due
soon. Curcumin, a component of curry, is currently being studied as a
treatment strategy in an animal model of CMT1B.

15. 15 | P a g e
Research helps us better understand diseases and can lead to
advances in diagnosis and treatment. This sectionprovides resources to
help you learn about medical research and ways to get involved.
Clinical Research Resources
 ClinicalTrials.gov lists trials that are studying or have studied Charcot-
Marie-Tooth disease. Click on the link to go to ClinicalTrials.gov to read
descriptions of these studies.
 The Research Portfolio Online Reporting Tool (RePORT) provides
access to reports, data, and analyses of research activities at the
National Institutes of Health (NIH), including information on NIH
expenditures and the results of NIH-supported research. Although these
projects may not conduct studies on humans, you may want to contact
the investigators to learn more. To search for studies, enter the disease
name in the "Text Search" box. Then click "Submit Query".
Patient Registry
 The Inherited Neuropathies Consortium is a team of doctors, nurses,
research coordinators, and research labs throughout the U.S., working
together to improve the lives of people with Charcot Marie Tooth disease
through research. The Inherited Neuropathies Consortium has a registry
for patients who wish to be contacted about clinical research
opportunities.

16. 16 | P a g e
References
1. Charcot-Marie-Tooth Disease. MedlinePlus.
2016; http://www.nlm.nih.gov/medlineplus/ency/article/000
727.htm.
2. Charcot-Marie-Tooth Fact Sheet. National Institute of
Neurological Disorders and Stroke (NINDS).
2016; http://www.ninds.nih.gov/disorders/charcot_marie_to
oth/detail_charcot_marie_tooth.htm#102833092.
3. eMedicine Journal [emedicine.medscape.com]
There are two articles by Divakara Kedlaya, MBBS, Associate
Professor, Department of Physical Medicine and
Rehabilitation, Loma Linda University Medical Center, about
Charcot-Marie-Tooth Disease at the eMedicine Journal
website. One last updated in September 2012 and another
last updated on May 2012
4. http://emedicine.medscape.com/article/1173484-overview
5. https://en.wikipedia.org/wiki/Charcot%E2%80%93Marie%E
2%80%93Tooth_disease
6. Physical Medicine and Rehabilitation for Charcot-Marie-Tooth
Disease. Medscape. Retrieved March 20, 2012.