Myo: refers to muscle
Pathy: refers to disease
Centro: refers to the center of
Nuclear: pertaining to the nucleus of a cell
Myotubular: appearance of muscle fibers that look like myotubes,
which are the muscle cells found only during fetal development
between 12 and 20 weeks of gestation
Myotubular Myopathy Inheritance: X-linked, Autosomal Recessive, and Autosomal
Dominant Genetic Alteration: Gene MTM1 on Xq28 Incidence: Unknown Onset: congenital to childhood Muscles Affected: Eye, facial, and neck muscles. The
heart muscle and the muscles of breathing may be affected.
Generalized muscle weakness.
Centronuclear Myopathy Inheritance: X-linked, Autosomal Recessive, and Autosomal
Dominant Genetic Alteration: unknown Incidence: Unknown Onset: Infancy to childhood Muscles Affected: Eye, facial, and neck muscles. The
heart muscle and the muscles of breathing may be affected.
Centronuclear Myopathy
X-Linked Diagram
X-Linked Inheritance
Autosomal Dominant Diagram
Autosomal Dominant Inheritance
Autosomal Recessive Diagram
Autosomal Recessive Inheritance
Introduction to Myopathies
The term "myopathy," in general, refers to disease of the
muscle. 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 that generally
present with symptoms at birth. However, some myopathies are characterized
by symptoms that 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 severity to problems with breathing and swallowing. Some of
the congenital myopathies may have life-threatening complications
that require careful medical monitoring and assistance. Other myopathies
are less severe and symptoms can be managed through medication, changes
in ones lifestyle, exercise and diet. Myopathies can be inherited
in an X-linked, autosomal dominant, or autosomal recessive pattern.
Human skeletal muscles are made up of special cells (myofibers) that
are surrounded by a membrane (called the sarcolemma) and are arranged
in bundles. Several proteins surround each muscle fiber along the
membrane and are contained within the cell and are essential for our
muscle cells to function normally. These proteins work together, and
when one of them is absent or malfunctioning, often the result is
muscular disease. If we study the muscle of an individual with a myopathy
under a microscope, we would see small changes in the structure of
the muscle cells. We know that the genetic 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 yet 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, like all parts of
the body, the muscles undergo a complex series of changes. In MTM
and CNM, the muscles cells stop their maturation and do not develop
as they normally would. These immature cells can cause symptoms that
are seen at birth, such as hypotonia (floppiness), swallowing and
breathing difficulties, and facial weakness. The facial weakness can
lead to a characteristic facial appearance that has been given the
name "myopathic facies" to describe the appearance of individuals
with myopathy.
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. Also, not all individuals may have
the same symptoms or the same level of severity of symptoms. Some
bodily changes that indicate a myopathy 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
noticeably weaker in their twenties or thirties and may lose the ability
to walk.
Types of Inheritance
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. (Females generally do not have the
X-linked form of myopathy because they have a "back-up"
X-chromosome that compensates for the genetically altered X-chromosome.)
Because this is a serious condition, almost all boys with this
condition die shortly after birth or before the age of one. However,
medicine has improved and there is better diagnostic ability and
treatment now, which allows for longer survival and the potential
for a slow gain in 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 (chromosomes numbered 1 through
22). 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
(those closest to the trunk of the body) are affected, such as
the shoulder and thigh muscles. 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. A baby needs
to inherit two copies of the altered gene to inherit this form
of myopathy, which carries a risk of 25% with each pregnancy if
each parent carries one altered gene.
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 affected 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 often diagnosed with
some other disorders. 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)
It is not yet possible to predict the symptoms that a given individual
will develop or 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.
What Causes MTM/CNM?
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, that can be inherited.
This genetic change alters a protein that is needed by skeletal muscle
to function normally.
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
(the non-sex chromosomes numbered 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. Rarely, a sporadic change in DNA that is not inherited
from a parent may cause MTM/CNM.
Ways a Person Gets MTM/CNM
(Please refer to the genetics review
section for a detailed description of inheritance patterns.)
X-linked Form:
Most of the time, the mother carries an abnormal MTM1 gene
that she passed on to her son. There is approximately an 80%
to 90% chance that the mother of an isolated (no other cases
of MTM in the family) male confirmed to have X-linked MTM is
a carrier. This means that there is a 50% (or 1 in 2) chance
that each male offspring of a carrier mother can be 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 at increased risk
to get MTM. Since boys only have one X chromosome, one sporadic
mutation in the MTM gene on the X chromosome would be enough
to cause a male 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 each child
would be an unaffected carrier of MTM/CNM. Carriers have the
genetic alteration on one 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.
If a person is affected with MTM/CNM, he or she will pass
one of the two altered genes on to every child. However, that
child will not develop the myopathy unless the child also
inherits a genetic mutation in the same MTM/CNM 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. Also, the severity
of the disease in the parent cannot be used to predict the
severity of disease in the child.
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 and is a very rare event.
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 in the case of autosomal recessive disease, if the child has
already inherited one gene mutation, and then sporadically acquires
a second. This would be an extremely rare event. 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.
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 (quadricep) or upper arm (deltoid). 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 muscle fibers that the scientists look
at will be abnormal. Once the diagnosis is made, genetic testing may
be performed to see if this is 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 X-linked
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.
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. This can lead to muscle weakness. Genetic test
results usually take 2-6 weeks to be reported.
Regarding prenatal diagnosis, usually this can be offered if the
specific mutation is identified in the family. In some cases, affected
babies may exhibit decreased fetal movement and generally 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
called linkage analysis. Researchers have found that the X-linked
MTM gene lies on the bottom of the X chromosome. This has made it
possible to track the disease in a family in cases where more than
one boy is affected. 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.
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 affect your family life and family planning, relationships,
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 training and expertise
in the field. Genetic counselors also provide information on prenatal
testing for muscular dystrophies and myopathies to see if an unborn
baby has inherited a known genetic mutation.
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.
Breathing problems that may make affected children susceptible to
forms of respiratory illness can be treated with antibiotics and other
helpful medications. Special feeding tubes may be used to help with
the feeding difficulties. In more severe cases, long-term survival
may require more involved medical and supportive procedures.
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, such as swimming, is recommended by some doctors
for individuals with neuromuscular disorders. A special type of
exercise therapy called physiotherapy is sometimes suggested for
individuals with MTM and CNM. The goal with physiotherapy 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). Devices may be implemented to help
individuals remain mobile. 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.
At some point during the course of MTM/CNM, a wheelchair may be
of great help to a person with CNM/MTM. 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 grateful
for the wheelchair and are actually more mobile, energetic and independent
than when they have to ambulate on weak legs.
Support
After one is confirmed to have myotubular myopathy or centronuclear
myopathy, one may have many questions and concerns and feel overwhelmed.
It is important to know that there are sources of support for the
patient or the family members of the patient. Contact a qualified
physician, a genetic
counselor, or your local Muscular Dystrophy Association clinic
to seek sources of emotional and informational support. 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 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.
