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Introduction to Myopathies
Myopathies are a group of rare diseases that lead to muscle
weakness and problems with muscle tone and contraction. Most
myopathies are progressive although the rates of progression
vary considerably. Many myopathies are caused by inherited gene
defects.
The congenital myopathies are a group of conditions generally
present with symptoms at birth. However, these symptoms may
not be noticed until later in childhood, adolescence, or adult
life. The skeletal, or voluntary muscles are generally affected
with problems that range from stiffness (myotonia) and weakness
of varying degrees of severity to problems with breathing and
swallowing. Some myopathies may be congenital and have life-threatening
complications. These necessitate assistive medical devices and/or
physical therapy. Other myopathies are less severe and symptoms
can be managed through medication, lifestyle modifications,
exercise and diet. These disorders can be congenital or late-onset
and can be inherited in an X-linked, autosomal dominant, or
autosomal recessive pattern.
If we look at the muscle of an individual with a muscular myopathy
under a microscope, we would see small changes in the structure
of the muscle cells. We know that the myopathies are caused
by mutations in genes that code for ion channel proteins, filament
proteins, and proteins needed for muscle development. But we
have not found all the genes involved with the myopathies and
still have much to learn about this set of neuromuscular diseases.
In order to better understand centronuclear and myotubular myopathy,
it is best to have a general understanding of muscle and muscle
cells and of general genetic concepts. It may be helpful to
visit the Muscle Anatomy
Review section and the Genetics
Review section before continuing with this section of the
web site.
Background
Different researchers and physicians classify myotubular myopathy
and centronuclear myopathy differently. Some see the two disorders
as separate, while others see them as different extremes of
each other. The researchers at Children’s Hospital Boston
consider myotubular and centronuclear myopathies to be different
extremes of the same disorder. However, X-linked myotubular
includes a distinct subset of infants who have a severe myopathy
and rarely survive infancy.
Usually, centronuclear myopathy is a pathological diagnosis
(meaning the diagnosis is made after seeing pictures of the
muscle tissue from a muscle biopsy) that may be given retrospectively
to children who survive infancy and have a milder form of
myotubular myopathy. Individuals with centronuclear myopathy
have immature myofibers with central nuclei (which gives the
disorder its name), but they are more mature than the myofibers
in myotubular myopathy. Centronuclear myopathy causes general
lack of muscle strength and tone and each person with this
disorder may have a different clinical presentation.
Clinical Picture
During the development of the fetus in the womb, the muscles
undergo a complex series of changes. In MTM and CNM the muscles
cells stop their maturation. When symptoms are seen at birth,
they usually include hypotonia (floppiness), swallowing and
breathing difficulties, and facial weakness. Sometimes the severity
of the disease is lethal, while in other cases, there is slow
progressive muscle weakness which affects the face, arms, legs,
and breathing muscles.
There is a wide range of symptoms that not all individuals may
have. These may include drooping eyelids, drooling, footdrop,
and weakness of the limbs and trunk. Some children experience
constipation. Hearing, vision, and intelligence are usually
not affected.
In general, the earlier the symptoms present, the more severe
and progressive the disorder may be. In most cases of MTM, however,
the disease is slowly progressive and most affected individuals
become weaker in their twenties or thirties and may lose the
ability to walk.
Myotubular myopathy is subdivided into three different types:
X-linked, autosomal dominant and autosomal recessive.
X-Linked is the most severe form and usually is
evident at birth in affected males. Because this is a serious
condition, almost all boys with this condition die shortly
after birth or before the age of one. However, there is
better diagnosis and treatment now, which allows for these
children to survive longer and very slowly gain muscle strength.
Intelligence is normal in these individuals, assuming there
was not a lack of oxygen in the newborn period. Boys with
the X-linked form may have associated problems that include
hydrocephalus ("water on the brain"), liver dysfunction,
bleeding and hematologic problems, and genitourinary abnormalities,
including undescended testes. Although we do not understand
the cause for these problems yet, it is important for the
physician to be aware that these problems may be present.
Autosomal forms of myotubular myopathy are less severe
and the symptoms can be very variable. Autosomal means that
the genetic mutation lies not in the sex chromosomes, but
in the chromosomes that both men and women share. Therefore,
both boys and girls can inherit autosomal MTM, while the
X-linked form usually affects males only. Less is known
about autosomal MTM.
Individuals with autosomal dominant MTM have the
highest risk of passing on MTM to offspring. This risk is
50% with each pregnancy because only one of the genes for
MTM needs to have an alteration for the individual to inherit
MTM. Generally this is the most mild form and children first
have problems in late childhood or as young adults. Autosomal
dominant MTM is progressive, meaning it gets worse over
time. Mainly, the proximal muscles, or those closest to
the trunk of the body are affected, such as the shoulders
and thighs. Also, this form is slightly more common than
the autosomal recessive form.
The autosomal recessive form of MTM can begin at
birth, but is often less severe than the X-linked form.
The clinical features or symptoms of each of the three types
overlap, so diagnosing which form an individual has may be
complicated, especially if there is only one affect individual
in a family. Also, there is no absolute test which can tell
what the pattern of inheritance is in an isolated case of
MTM. It is important to try to figure out the pattern of inheritance
so that families can use the information in family planning.
Other Ways MTM/CNM Affect the Body
Some children who have X-linked MTM are also diagnosed with
some other disorders. These other abnormalities occur too
frequently in children with MTM to be unrelated. They include:
- Hydrocephalus – This is an accumulation of fluid
surrounding the brain. The fluid normally would be absorbed
by the body but in some children with MTM, it is not absorbed.
Generally it is controlled with a "shunt" which
is surgically inserted into the ventricle in the brain,
with attached tubing that can extend to the area surrounding
the heart, lung, or abdominal cavity. A shunt may last for
many years, or need to be revised periodically.
- Liver Dysfunction
- Abnormal extraocular (eye) muscles
- Blood disorders, especially spherocytosis - This is an
inherited disorder of the red blood cells. It is the most
common (1 in 5,000 of Northern European ancestry) disorder
of the red blood cell membrane, which is the sheath that
contains the hemoglobin molecules that carry oxygen through
the blood stream.
- Gall stones
- Genitourinary abnormalities (especially undescended testes
in males)
Different people have different levels of symptoms of MTM/CNM.
Some people have only mild problems, while others have more
severe muscle deterioration and severe complications.
It is not yet possible to predict the course that MTM/CNM
will take in an individual. Awareness of the problems associated
with these disorders and the treatment that is available for
them can lead to a longer and higher quality life.
MTM and CNM are genetic diseases. This means that the symptoms
of MTM and CNM are present because there is a change in the
DNA of a person, at a particular location in a gene. We know
that a mutation in the MTM1 gene on the X chromosome results
in X-linked MTM. As for the autosomal forms of these diseases,
we do not yet know where the mutation lies in the DNA that causes
the symptoms. We know that these mutations occur on one of the
autosomes. These are the non-sex chromosomes (chromosomes 1
through 22) that both males and females have in common. This
means that both males and females are equally likely to inherit
a genetic alteration that leads to the autosomal forms of MTM/CNM.
Ways a Person gets MTM/CNM
X-linked Form:
- Most of the time, the mother carries an abnormal MTM1
gene that she passed on to her son. Statistically, there
is a two-thirds chance of a mother of an isolated (no other
cases of MTM in the family) male with X-linked MTM being
a carrier. This means that there is a 50% (or 1 in 2) chance
of each male child being affected with MTM. There would
also be a 50% chance that each daughter would be a carrier
of the altered MTM gene, but would not be affected. A carrier
daughter could pass on the altered gene to her children.
- Occasionally, a genetic alteration can occur in the sperm
or egg that formed the embryo by chance. This is called
a sporadic mutation. If this occurs, then no other family
members other than the affected person’s children are
not at increased risk to get MTM. Since boys only have one
X chromosome, one sporadic mutation in one of the MTM genes
would be enough to cause the child to get MTM. In contrast,
a female who has one sporadic mutation will be an unaffected
carrier. In the case of a sporadic mutation in a family
(when the mother is not a carrier), there is a 1-3% risk
that another child will be affected with MTM.
Autosomal Forms
1. Inheritance of the genetic alteration from the
parents.
- Autosomal recessive form: In this instance, a
mother and a father pass on an altered MTM/CNM gene to
their son or daughter. The parents are healthy, but the
child who inherits two altered copies of the MTM/CNM gene
is affected. There would be a 25% chance with each pregnancy
that the child would be affected with MTM/CNM, and a 50%
chance that the child would be an unaffected carrier of
MTM. A son or daughter who inherits only one altered gene
carry the defect but do not show the disease. An affected
patient will pass one of the two altered dysferlin genes
on to every child. However, that child will not develop
the myopathy unless the child also inherits a genetic
mutation in the dysferlin gene from a second parent. This
is an unlikely event.
- Autosomal dominant form: An affected parent who
has an altered gene can pass on this altered gene to a
child. In this instance, only one altered gene needs to
be present to cause disease. There is a 50% chance with
each pregnancy that the child would be affected with MTM/CNM.
2. Development of a new mutation that is not inherited
from a parent.
In addition to inheriting an altered MTM/CNM gene from
a parent, an individual can develop a new mutation in
a gene. This typically occurs in the sperm or egg that
formed the embryo from which the individual developed.
This new gene defect is called a sporadic mutation. If
this sporadic mutation occurred in an autosomal recessive
form of the gene, then the child wouldn’t be affected
with MTM/CNM unless the child also inherited a genetic
mutation in an MTM/CNM gene from a parent. In the autosomal
dominant form of MTM/CNM, one sporadic mutation in one
of the genes would be enough to cause the child to get
MTM/CNM. If this occurs, then the only family members
at risk for the disease other than the affected person
are that person’s children.
It may be that a person is the first in the family to
have MTM. This can happen if there is a new sporadic mutation
that is dominant, or to a child who has a sporadic mutation
on one of the genes that causes MTM/CNM. It also can happen
if there is an autosomal recessive form of MTM/CNM in
the family. In this case, when a person is the first in
the family to have MTM/CNM, this usually reflects the
fact that this is the only family member to inherit two
copies of the defect in the MTM/CNM gene (one from each
parent). Unaffected siblings may be carriers of only one
defective gene, in which case they will not have symptoms.
Other family members may be carriers, having no disease
symptoms. Carriers have the genetic alteration on a chromosome
and can have a child with the disease, but only if the
child’s other parent is also a carrier. It is not
unusual for carriers of a rare autosomal recessive disease
not to know they are carriers until some one in the family
develops the rare genetic disease.
Testing for and Diagnosing MTM/CNM
There, unfortunately, is no easy way to test for MTM/CNM. The
best way to test an individual is to do a muscle biopsy, where
a small amount of muscle is surgically removed from the individual,
usually from the thigh or upper arm. Scientists look at the
muscle under a microscope, and what is termed a “pathological
diagnosis” can be made. In X-linked MTM, all muscles of
the body are affected and 50-90% of the fibers that the scientists
look at will be abnormal. Once the diagnosis is made, genetic
testing may be performed to see if this in the X-linked form
(in males). If no mutations are found, this may indicate that
the patient has one of the autosomal forms, or that the mutation
on the X chromosome was missed or not found.
Some doctors perform muscle biopsies on mothers of isolated
males with X-linked MTM. The biopsy can detect some abnormal
muscle cells in 50-70% of carrier females, signifying that they
are carriers. However, a normal test does not rule out being
a carrier for MTM.
In some families, researchers are able to find a mutation in
the MTM gene of the affected individual. In this case, the mother
can then usually be tested for the presence of this mutation.
This is the best way to find out if a woman is a carrier and
can allow doctors and genetic counselors to provide information
to the family on recurrence risk.
Regarding prenatal diagnosis, usually this can be offered if
the specific mutation is identified. Affected babies usually
exhibit decreased fetal movement and there is an excess of amniotic
fluid around the baby.
In families where there is more than one affected male, the
X-linked MTM gene can be found in individuals using an indirect
genetic test. We have found that the X-linked MTM gene lies
on the bottom of the X chromosome. This has makes it possible
to track the disease in a family in cases where more than one
boy is affected. This tracking is called linkage analysis. If
geneticists can track the disease, prenatal diagnosis may be
possible. This type of testing requires that several members
of the family have blood tests in order to participate in the
linkage analysis of their DNA. We do not know where the genes
lie for the autosomal forms of MTM. This means that no linkage
analysis or DNA testing is available for the autosomal forms
of this disorder.
Genetic Testing
This can only be done for X-linked MTM and CNM. From the blood,
DNA can be isolated and scientists can read the DNA code in
the area of the MTM gene on the X chromosome to see if any alterations
are present. When the DNA is has an alteration in it, such as
a portion that is deleted, a portion that is added, or the wrong
bases in the code are present, the protein that this gene codes
for may be missing or may not function properly, which leads
to muscle weakness. Genetic test results usually take 2-6 weeks
to be reported.
Currently, genetic testing for X-linked MTM is available at
a few laboratories that are CLIA-approved. (For a list of laboratories,
you can visit GENETESTS).
Testing for the autosomal forms of MTM and for CNM are available
on a research basis only. Keep consulting your Muscular Dystrophy
Association clinic physician or a genetic counselor to find
out when new testing is available. Also, visit Our
Research section of this web site to learn more about what
the Neuromuscular Disease Project scientists are studying.
Before one considers genetic testing either for research
purposes or for diagnostic testing, it is important to realize
several things. The decision to be genetically tested is a
very important and personal decision. It may effect your relationships,
family life, family planning, career and insurance decisions,
and psychological and emotional well-being. It is a decision
to be carefully made and it can have a very positive or a
less positive outcome. Genetic counselors are available to
individuals who are considering genetic testing. Genetic counseling
provides useful information about the implications of the
testing and emotional support by someone with expertise in
the field. Genetic counselors also provide information on
prenatal testing for muscular dystrophies to see if an unborn
baby has inherited a genetic mutation. This testing can be
done if there is an affected relative in the family or if
the mother is known to be a carrier of a genetic alteration
in an identified gene.
Treatment for MTM/CNM
Currently there is no medication or cure available for any form
of MTM/CNM. In milder cases, the disorder is managed symptomatically.
Because of the breathing problems that children have, they are
susceptible to the flu, pneumonia and respiratory disease. These
difficulties are treated with antibiotics and other helpful
medications. Nasogastric tubes may be used to help with the
feeding difficulties. In more severe cases, long-term survival
is less likely without a tracheotomy and mechanical ventilation.
In milder forms of MTM, some of the children have the ability
to walk. When muscles become more weakened, these children or
young adults can benefit from assistive walking devices, like
braces and walkers. In more severe cases, patients are usually
wheelchair bound and these individuals need significant assistance
for everyday living.
Exercise therapy is recommended by some doctors for individuals
with neuromuscular disorders. However, we do not know for
sure whether exercise is good or bad for certain types of
muscle diseases. The general consensus is that low-intensity
exercise may help overcome some of the muscle shrinkage (atrophy)
that comes from disuse of the muscle. However, it is probable
that high-intensity, strenuous exercise may actually further
damage the muscle by overstressing it.
Exercise therapy called Physiotherapy is sometimes recommended
for individuals with MTM and CNM. The goal is to keep the
muscles as active as possible to prevent the formation of
contractures (muscle tendon tightness that leads to restriction
in the range of joint movement). It is important that exercise
therapy be monitored carefully by a clinician who is familiar
with CNM and MTM, who can monitor any muscle damage that may
be occurring. It is beneficial to children and adults with
CNM and MTM to remain as active as possible so as to prevent
becoming overweight and straining their weakened muscles.
Some experts recommend swimming and water exercises to keep
muscles toned without causing undue stress on them.
Another goal of physiotherapy is to focus on assistive devices
that may help children be more mobile. Some of these aids
include splints, calipers, standing frames, and wheelchairs
when necessary. Many individuals initially see the wheelchair
as a sign of disability and want to postpone using it. However,
most users and their families find they are actually more
mobile, energetic and independent than when they have to try
walking on weak legs.
Support
After one is confirmed to have myotubular myopathy or centronuclear
myopathy, there are sources of support for the patient or the
family members of the patient. Being diagnosed with a neuromuscular
disorder can be overwhelming. Please visit our links
section to see a list of support groups and educational web
sites that could benefit a person with MTM/CNM or a family member
of a person with MTM/CNM.
Research
As more people participate in research for our neuromuscular
disease research, our knowledge of the mechanisms that cause
MTM/CNM will improve. As our understanding of these disorders
increases, we will be better able to treat , diagnose and manage
these conditions. Please use the links below to find out more
about the research being done and to stay informed about new
advances.
•Muscular
Dystrophy Association
•Our Research
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