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Single Gene
Disorders and Disability (SGDD) |
Until the 1980s, little was known about the specific cause of any kind of
muscular dystrophy. However, during that decade, the gene for DMD was
identified. Genes contain codes, or recipes, if you will, for proteins.
Proteins are very important biological components (parts) in all forms of
life. In 1986, MDA-supported researchers identified the gene that, when
flawed (a problem known as a mutation), causes DMD. They found that the
gene’s failure to make a working version of the muscle protein dystrophin is
the cause of the disease. Flawed dystrophin was also found in Becker
muscular dystrophy (BMD), so that we now view DMD and BMD as variants of the
same disease (DBMD). Patients with DBMD have decreased or abnormal
dystrophin in their muscles. Further research has shown that dystrophin is
found inside the muscle cell, where it helps support the cell membrane and
minimizes injury related to the stress of muscle movement. Dystrophin could
have other functions that have not yet been defined.
The particular gene that causes DBMD
is found on the X chromosome. A functional copy of the gene is needed for
normal muscle function. Males carry one X chromosome and one Y chromosome.
Females carry two X chromosomes. Because the gene involved in DMD is on the
X chromosome, it is called X-linked. Because males have only one X
chromosome, a male carrying a copy with a DBMD mutation will have the
condition. Because females have two copies of the X chromosome, a female can
have one copy with a DBMD mutation and one functional copy. The functional
copy is usually enough to compensate, and a female with a DBMD mutation
usually has few or no symptoms. However, because she can pass the mutation
on to her children, she is called a “carrier”. Each son born to a woman with
a dystrophin mutation on one of her two X chromosomes has a 50% chance of
inheriting the flawed gene and having DBMD. Each of her daughters has a 50%
chance of inheriting the mutation and being a carrier. For more information
on genes and mutations, see “About Genes and Mutations”.
Most boys with DBMD inherited the
mutation from their mother. However, in about one-third of the patients with
DBMD, the mother is not a carrier. Rather, there was a new mutation that
formed in the egg that produced that child. In these cases, it is unlikely
that future children will also have DBMD. However, in some cases, more than
one egg was affected, in which case the chance of having another child with
DBMD is increased.
Genetic counselors are professionals
that help families understand how genes run in families and what the chances
are that future children will also have DBMD. They can help arrange for
genetic testing and can help families understand the test results. For more
information on genetic counseling, or to find a genetic counselor in your
area, see the National Society of Genetic Counselors at
www.nsgc.org.
DBMD Mutation in Females
Females rarely get DBMD. Because
females have two copies of the X chromosome, the second functional copy is
usually enough to compensate for the flawed one. In females, one of the X
chromosomes in each cell is turned “off” in a process called X inactivation.
The X chromosome that gets turned “off” is random, so on average a female
with a DBMD mutation will have the functional (or, nonmutated) X “on” in
about half of her cells and the flawed X “on” in the other half. If, by
random chance, most of her muscle cells end up with the flawed X “on” (and
the functional one “off”), then she will have the signs and symptoms of DBMD.
However, this is rare. These females are sometimes referred to as
manifesting carriers, and their form of the disease can be mild or it can be
as severe as is seen in males.
Carrier females in later adult life
(whether or not they are manifesting) sometimes develop heart problems that
are characterized by shortness of breath or an inability to do moderate
exercise. The chance that a carrier female will develop heart problems is
not known. These heart problems, if untreated, can be serious and life
threatening.
DIAGNOSIS
Boys with DMD are usually diagnosed
when they are around 3 to 6 years of age. In diagnosing DBMD (or any form of
muscular dystrophy), a doctor begins by taking a patient and family history
and performing a physical examination. Much can be learned from these,
including the pattern of muscle weakness. The history and physical can
suggest the diagnosis, even before any diagnostic tests are done. It is,
however, important to do the diagnostic tests because other diseases have
some of the same symptoms as DBMD. Following are brief descriptions of some
of the more commonly performed tests or procedures recommended when DMD is
suspected.
Creatine Kinase (CK) Test
Creatine kinase (CK) is a blood test. CK is normally found at high levels in
the muscle and low levels in the blood. When there is injury to muscle or
when there is a breakdown of the muscle membrane as in DBMD, the CK leaks
out of the muscle and into the blood. In DBMD, the CK level is usually 20 to
200 times higher than normal. Very few other diseases cause such a high
level of CK in the blood. The blood level of CK is increased from the time
of birth in people with DBMD.
Many of the signs and symptoms of DMD
are exceedingly difficult to detect in the early stages because many other
conditions can produce similar signs and symptoms. Moreover, parents often
are told by their doctor (or even several doctors) that their child will
outgrow the clumsiness or other performance problems. Because of this
difficulty in diagnosing, doctors are now being taught to do a CK test on
young boys with these signs and symptoms, even if they do not find anything
when they examine the child.
Genetic Testing
When a child is found to have an extremely high CK level, the next step
usually is genetic testing on the blood to look for a mutation in the
dystrophin gene. There are two types of genetic testing for DBMD. The first
looks for large pieces of the dystrophin gene that are either missing
(deleted) or duplicated. If a deletion or duplication is found in the
dystrophin gene, then the diagnosis is confirmed and additional testing is
generally not needed. Approximately 65% to 70% of patients with DBMD have a
deletion or duplication that can be identified with this type of test.
The remaining 30% to 35% of DBMD
patients have a tiny mutation that is much more difficult to find. In recent
years, several approaches have been developed to identify these very small
changes (point mutations). Currently, this type of testing is not routinely
used to make a diagnosis, but is useful for genetic counseling.
The gene that carries the mutation for
DBMD is the largest human gene that has been identified, which can make the
task of identifying the flaw in the gene difficult. Hundreds of different
mutations in the dystrophin gene have been found to result in DBMD. For more
details on genes and mutations, see “About Genes and
Mutations”.
Muscle Biopsy
Not all mutations in DBMD patients can be identified, so a negative genetic
test does not necessarily mean that the patient does not have DBMD.
Therefore, if the genetic testing is negative, then a muscle biopsy is
usually recommended to make a diagnosis.
When seen under a microscope, muscle
from patients with DBMD looks different from muscle of individuals who do
not have DBMD. By examining a small sample of the patient’s muscle, doctors
can tell a great deal about what is actually happening inside the muscle.
Modern techniques can use the biopsy to distinguish MD from inflammation and
other disorders. Other tests on the biopsy sample can provide information
about which muscle proteins are present in the muscle cells, and whether
they are present in the expected amounts and in the right places. During a
muscle biopsy, a small piece of muscle (about the size of a pencil eraser)
is removed and cut into very thin slices. These slices are stained with a
series of special dyes to show the different types of muscle and are studied
by a pathologist (a doctor who evaluates diagnostic tests). The slices can
also be stained to see whether or not functional dystrophin is present in
sufficient levels for normal muscle function.
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Date: September 1, 2006
Content source: National Center on Birth Defects and Developmental
Disabilities
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