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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. The X-inked MTM (XLMTM), and
its milder variant, centronuclear myopathy (CTNM), are a clinically
and genetically heterogeneous group of disorders characterized
by congenital skeletal muscle weakness which varies from rapidly
fatal in the infantile period (XLMTM) to relatively nonprogressive
and compatible with normal life span (CTNM). X-linked myotubular
myopathy includes a distinct subset of infants who have a severe
myopathy and rarely survive infancy. The unifying features are
skeletal muscle weakness and myopathic findings on muscle biopsy
including the presence of undifferentiated appearing small myofibers
with characteristic central nuclei or a central clear zone corresponding
to the internuclear space (“myotubes”). XLMTM is caused
by mutations of myotubularin, a novel dual specificity protein
phosphatase whose role in muscle differentiation is unknown.
Usually, centronuclear myopathy is a pathological diagnosis
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 but they are more mature than the myofibers in myotubular
myopathy. Centronuclear myopathy causes general lack of muscle
strength and hypotonia and is very heterogeneous.
Clinical Picture
In MTM and CNM, during the development of the fetus, muscle
cell maturation is arrested. When symptoms are seen at birth,
they usually include hypotonia, 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 ptosis, drooling, swallowing difficulties,
footdrop, and weakness of the limbs and trunk. Some children
experience bowel immotility. 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
- autosomal recessive
X-Linked is the most severe form and usually
is evident at birth in affected males and is generally
lethal before the age of one. Males with the X-linked
form may have associated problems that include hydrocephalus,
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. The autosomal
forms affect both sexes equally, unlike X-linked MTM.
Less is known about autosomal MTM.
Individuals with autosomal dominant MTM have
the highest risk of passing on MTM to offspring (50%
risk with each pregnancy). Generally this is the most
mild form and children first present with problems in
late childhood or as young adults. Autosomal dominant
MTM is progressive. Mainly, the proximal muscles are
affected. Also, this form is slightly more common than
the autosomal recessive form.
The autosomal recessive form of MTM sometimes
begins at birth, but the degree of symptom severity
is generally less than the X-linked form.
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
•Liver Dysfunction
•Abnormal extraocular muscles
•Blood disorders, especially spherocytosis
•Gall stones
•Genitourinary abnormalities (especially undescended
testes in males)
Different people have different levels of symptoms of MTM/CNM.
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. Diagnosing
which form an individual has may be complicated, especially
if there is only one affect individual in a family. It is
important to try to figure out the pattern of inheritance
so that families can use the information in family planning.
What Causes MTM/CNM?
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.
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. There is an 80-90%
chance of a mother of an isolated male with confirmed
X-linked MTM of being a carrier. If the mother is a carrier,
there is a 50% chance that each of her male offspring
will 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.
- There can be a sporadic mutation.
Autosomal Forms
- Inheritance of the genetic alteration from the parents
in an autosomal recessive or autosomal dominant form.
- Development of a new mutation (sporadic) that is not
inherited from a parent.
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 recessive inheritance,
if a child who has a sporadic mutation on one of the genes
also inherited a gene mutation from a parent. Again, it
is important to try to determine how the affected individuals
acquired the genetic alteration so that accurate recurrence
risks can be given to the family.
Testing for and Diagnosing MTM/CNM
The best way to test an individual is to do a muscle biopsy,
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 polyhydramnios.
Linkage analysis is available for families where there is more
than one affected male.
Genetic Testing
This can only be done for X-linked MTM and CNM. An important
point to remember when it comes to genetic testing is that it
is always best to test an affected individual first.
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.
Genetic testing either for research purposes or for diagnostic
testing, is an important and personal decision that involves
many factors. Physicians should encourage their patients to
speak with a qualified physician or genetic counselor to discuss
useful information about the implications of the testing and
to receive emotional support by someone with expertise in
the field. It is important for physicians and genetic counselors
to provide information on prenatal testing and recurrence
risks when necessary.
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.
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.
A 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.
Research
As more people participate in 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
Support
After your patient is diagnosed with CNM/MTM, he or she is likely
to feel overwhelmed. It may be helpful to let your patient know
that support is available. Contact a genetic counselor or your
local Muscular Dystrophy Association Clinic for more information.
Additionally, visit the Links section
on this Web site to learn more about other support and information.
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