DMD - A Guide for Parents
Section 1_2
Becker
Muscular Dystrophy
There are many forms of muscular dystrophy. However, the one most closely
resembling the Duchenne form is called Becker muscular dystrophy. This
very close resemblance comes about because the genetic abnormality causing
Becker muscular dystrophy is also found in the dystrophin gene on the
X chromosome. (More information on the genetic aspects of Duchenne muscular
dystrophy is contained in the following section titled, Genetic Counselling).
In many patients with Becker dystrophy, a deletion of part of the gene
can be found. However, patients with these two forms of muscular dystrophy
differ. This difference is due to the way that the types of deletions
in the two forms affect the production of dystrophin. The type of deletion
present in patients with Duchenne muscular dystrophy is such that almost
no dystrophin is produced. On the other hand, patients with Becker dystrophy
have a deletion in the genetic material that still allows a small amount
of dystrophin to be produced. This allows the muscles to function better
than those of a Duchenne patient. Patients with Becker muscular dystrophy
have almost all of the problems associated with Duchenne muscular dystrophy
except that the disease is usually later in its onset and the disease
progresses more slowly. Indeed the diagnosis may not be made until late
in the first decade or in the second or third decades. It is much more
difficult to predict the long term future of a boy with Becker dystrophy
because some will require a wheelchair in the late teenage years while
others will be walking, albeit with difficulty, into their forties or
fifties.
Genetic
Counselling
A diagnosis of Duchenne muscular dystrophy can
be so distressing that it is easy to subconsciously decide to put genetic
issues aside for consideration some time later. Parents are fully occupied
in coming to terms with the diagnosis and meeting the demands of everyday
life. However the genetic aspects are important in making decisions
about having more children. Because of the way in which Duchenne muscular
dystrophy is inherited, all family members must have a clear understanding
of the issues involved.
This section endeavours to explain the genetics of Duchenne muscular
dystrophy. If after reading it and speaking with your medical adviser
you are still confused, please seek to clarify what you do not understand.
Doctors know that they may need to go over complicated information several
times. The consequences of not grasping the facts are too serious not
to attempt complete understanding. In addition to a verbal explanation
of your genetic situation, it is the policy of many counsellors to confirm
the contents of a counselling consultation in writing.
The
Genetic Background to Duchenne Muscular Dystrophy
Duchenne muscular dystrophy is described as a sex-linked (or X-linked)
recessive inherited disease. What does this mean? To understand this
some elementary knowledge of biology is required.
Genes
and Chromosomes
Every tissue in the body is made up of cells. Muscle tissue is made
up of thousands of muscle cells (or muscle fibres). Each cell has genetic
material that determines how that cell (and hence our body) functions.
The basic units of genetic material which are responsible for heredity
or inheritance are called genes. Individual genes cannot be seen even
with the most powerful microscope. Genes are organised into larger structures
called chromosomes which can be seen with the use of a microscope. All
cells in the body (except egg and sperm cells) have 46 chromosomes,
each chromosome being built from thousands of genes. The genes are lined
up in a certain order like beads on a string.
The forty-six chromosomes in each cell are arranged in pairs. In each
pair one chromosome comes from the mother and the other comes from the
father. Forty-four of these chromosomes occur as twenty-two similar
pairs. The two remaining chromosomes have the extremely important role
of determining our sex. X and Y are arbitrary names given to these sex
determining chromosomes. Females have two X chromosomes while in males
the two chromosomes are an X chromosome and a Y chromosome. Hence the
chromosome makeup of a female is designated as XX and that of a male
as XY.
How
sex is determined
The egg and sperm cells responsible for creating new life are unlike
all other cells. Each sperm and egg cell contains only twenty-three
chromosomes. When the egg and sperm join together at fertilisation,
the first cell of the future child is created. This new cell has a total
of forty-six chromosomes (twenty- three pairs).
The egg cell (from the mother) always contains an X chromosome, but
the sperm cell (from the father) may contain either an X or a Y. If
the father's sperm containing an X chromosome fertilises the egg the
resulting embryo will have an XX combination which will produce a girl.
If the sperm has a Y chromosome, after fertilisation there will be an
XY combination.
This combination will produce a boy. A boy can only
get his one X chromosome from his mother, never his father.
Why
do boys develop Duchenne muscular dystrophy?
The X chromosome is quite large and contains many genes which perform
important functions that have nothing to do with sex determination.
One of the genes on the X chromosome causes cells to manufacture the
protein called dystrophin which is needed to maintain healthy muscles.
This gene is now called the dystrophin gene. Duchenne muscular dystrophy
is caused by abnormalities of the dystrophin gene.
The dystrophin gene is part of the X chromosome. It is not contained
on Y chromosomes. A boy has only one X chromosome in every cell of the
body including his muscle cells. If there is an abnormality of the dystrophin
gene, either because part of the gene is missing or because it functions
abnormally, dystrophin will not be produced in adequate quantities and
he will develop Duchenne muscular dystrophy. If part of the gene is
missing this is called a deletion.(FIG) If the same problem occurs in
a female the result is not nearly as serious because there is a second
X chromosome with a normal dystrophin gene to control the production
of dystrophin.
Carriers
A female who has the defective dystrophin gene is called a carrier.
If a carrier mother passed her X chromosome with the defective dystrophin
gene onto a daughter, the daughter would not develop Duchenne muscular
dystrophy because she would have received an X chromosome with a normal
dystrophin gene from her father. In this case the normal gene overcomes
the potentially harmful effects of the abnormal gene. This daughter
would herself also be a carrier (see below for risks of daughters being
carriers).
A son may develop Duchenne muscular dystrophy if he inherits an X chromosome
with a defective dystrophin gene from his carrier mother. This process
whereby a carrier mother may have an affected son but has daughters
who are not affected, even though they may themselves be carriers, is
called X- linked or sex-linked recessive inheritance.
Mutations
Sometimes the gene defect has not been present in any previous member
of the family, not even in the mother. The defect in the dystrophin
gene has arisen because of an error in the copying of this particular
gene during the formation of the X chromosome which went into the egg
cell from which the boy was formed. This is called a mutation. Many
other diseases are also caused by genetic mutations. It is thought that
we all carry mutations of some of our genes but serious effects are
prevented by a normal gene being present on the second of a pair of
chromosomes.
Rarely there are children with disability similar to that seen in Duchenne
dystrophy but where the disease is not Duchenne dystrophy and there
are quite different genetic implications. When a boy is diagnosed as
having Duchenne muscular dystrophy, it is important to determine whether
the mother is a carrier. If the mother is a carrier there is a risk
that she could have another affected boy in a future pregnancy. It also
raises the possibility that the mother's daughters, sisters or other
female relatives could also carry the defective gene.
Laboratory
Tests
It may be obvious that a woman is a carrier because of her family history.
For instance, a woman who has a brother and a son with Duchenne muscular
dystrophy must be a carrier. However, when a woman has just one boy
with Duchenne muscular dystrophy and there is no family history of the
disease, it can be very difficult to determine whether she is a carrier
without sophisticated laboratory testing. There are several methods
of determining whether a female is a carrier of the Duchenne muscular
dystrophy gene.
Creatine kinase (CK) test
CK is an enzyme (protein) that is important for energy production in
muscle fibres. If a fibre is damaged by a disease process such as muscular
dystrophy, some of the CK leaks out into the blood. Normally there is
a small amount in the blood but in Duchenne muscular dystrophy there
may be 10 to 100 times the normal amount. This excessive amount of CK
in the blood does not cause any extra damage but it does give us a way
of detecting muscle problems. Because carrier females have some muscle
fibres that have degenerated there may be a slightly greater amount
of CK leaking out of muscle into the blood and this can be detected
by doing a CK blood test.
Because the amount of CK in carriers may be only slightly more than
normal, and because things such as exercise may increase the amount
of CK in the blood in people who are not muscular dystrophy carriers,
the test is usually done on three separate occasions with restriction
of physical activity prior to the blood being taken. If the mother or
sister of an affected boy, or a female relative (on the mother's side),
has consistently abnormal CK tests she would be regarded as a carrier.
Unfortunately the CK test is positive in only about 60-70% of known
carriers and hence if a female has normal CK tests this does not prove
that she is not a carrier.
DNA
testing
Laboratory testing to examine the structure and inheritance of genes
is called DNA testing because genes and chromosomes are made from the
chemical molecule called deoxyribonucleic acid (DNA). In the case of
Duchenne muscular dystrophy, DNA testing specifically looks for abnormalities
in the structure of the dystrophin gene of the X chromosome. Testing
can be done on a blood sample.
At the present time laboratory tests can detect a deletion (piece of
DNA missing) in the region of the dystrophin gene in about 70% of boys
with Duchenne muscular dystrophy. The Duchenne muscular dystrophy gene
is very large and small deletions may occur in many different areas
of the gene. the ideal would be to identify, if possible, the deletion
in the affected boy and then try to identify a deletion in the same
area of any female relatives who seek information about their carrier
status. Unfortunately, identifying a deletion in a female is difficult
at present and the results are not reliable enough for routine use.
One major advantage of the DNA tests is that they can be used to determine
whether a male fetus is affected in the very early weeks of pregnancy.
This allows families with a carrier female the option to choose to have
a normal boy . If a deletion is not detected in the affected boy there
are still some other ways to use knowledge of the Duchenne muscular
dystrophy gene and its relationship to nearby neighbours on the X chromosome
to determine if a female is likely to be a carrier or if a male fetus
is affected. Inheritance of the Duchenne muscular dystrophy gene can
sometimes be deduced by knowing the pattern of inheritance of the neighbouring
genes. This type of testing called linkage analysis is more cumbersome
and less accurate than if a deletion can be detected, and may not be
possible in all instances However, it is still sometimes useful to have
this type of testing to fall back on if a deletion cannot be detected.
Other methods
Electrical tests of muscle function (EMG), measurement of the level
of certain enzymes other than CK and muscle biopsy have been a few of
the methods sometimes used to detect carriers. These methods would be
used only rarely now.
Possible
Outcomes if a Female is a Carrier
If a female is a carrier of the Duchenne muscular dystrophy gene she
has a one in four chance of having a child with Duchenne muscular dystrophy.
How does this come about? The genetic material (DNA) of both parents
combine in such a way that a child receives half the number of his or
her chromosomes from the mother and half from the father. This is how
we inherit various characteristics from our parents.
If a mother is a carrier of Duchenne muscular dystrophy, one of her
two X chromosomes will carry an abnormal dystrophin gene. Hence there
is a 1 in 2 (1/2, 50%) chance that she will pass the chromosome with
the abnormal gene onto a child, and a 1 in 2 chance that the child will
receive the normal chromosome (with a normal dystrophin gene). Similarly
, there is a 1 in 2 chance that the child will receive the father's
X chromosome and a 1 in 2 chance that the father's Y chromosome will
be inherited. When the sex chromosomes (X and Y) from parents combine
there can be four different outcomes, with equal liklihood, as follows:
1. An egg containing a healthy X chromosome can pair with a sperm
containing an X chromosome and produce a healthy girl.
2. An egg containing a healthy X chromosome can pair with the Y chromosome
of a sperm and produce a healthy boy.
3. An egg containing the defective X chromosome can pair with a sperm containing
a normal X chromosome to produce a girl who is a carrier. She carries
the defective X chromosome but her normal X chromosome prevents her
from developing muscular dystrophy.
4. An egg containing the defective X chromosome can pair with a sperm containing
a Y chromosome to produce a boy who has Duchenne muscular dystrophy.
Y chromosomes do not have the dystrophin gene and hence there is no
normal dystrophin gene to control the body's production of dystrophin.
Of the four possible outcomes, only one will produce a child with Duchenne
muscular dystrophy. Thus, if a female is a carrier of the Duchenne muscular
dystrophy gene there is a 1 in 4 chance of giving birth to a child with
Duchenne muscular dystrophy.
What
does a Risk Factor mean?
It was shown in the above section that if a woman is a carrier she has
a 1 in 4 (25%) chance or risk of having a child with muscular dystrophy.
This risk figure applies to each pregnancy that she has irrespective
of whether any previous children have muscular dystrophy or not. Some
carriers are fortunate and have several boys who are normal while others
have several boys in a row who all have Duchenne muscular dystrophy.
This is like flipping a coin or rolling a dice.
Some families in whom it cannot be determined for certain whether or
not a female is a carrier will be given a estimate of their risk of
having a boy with muscular dystrophy. This might be, for instance, 1
in 10 (10%) based on blood test results and knowledge of the family
tree. A risk of 1 in 10 means that if 10 couples are told that they
will not have a child with muscular dystrophy, this information will,
on average, be wrong for one of the couples and they will have an affected
child. The problem is that it is not possible to tell which one of the
couples will have the affected boy. Risk figures mean different things
to different people. Most people would regard a risk of 1 in 10 of having
a boy with muscular dystrophy as fairly high, particularly if they have
had personal contact with somebody with the condition. A risk of 1 in
100 would usually be considered reasonably low particularly as a couple
face a risk higher than this of having a child with other serious birth
defects.
It is important to be clear about whether a risk figure is referring
to a female being a carrier or to the risk of an affected child being
born. A 1 in 10 risk of being a carrier means a 1 in 40 risk of having
an affected child because if the person does turn out to be a carrier
she still has only a 1 in 4 chance of a child being affected.
Couples need to consider their situation realistically. Doctors can
give them the best available information on their risk of having an
affected child but it is up to the couple to interpret those risks into
their own network of knowledge, concerns and desires.
Who
should be tested for Carrier Status?
It is thought that in about one third of boys with Duchenne muscular
dystrophy the condition has arisen in the boy by a genetic mutation
(see above) and his mother is not a carrier. For the remaining two thirds
the mother and therefore possibly other female members of her family
may be carriers. When a boy is diagnosed as having Duchenne muscular
dystrophy all females on the mother's side should be considered at risk
of being carriers although some will have a much higher risk than others.
Whether carrier detection studies are initiated depends on many factors.
For instance, if the affected boy has no sisters and his mother has
no sisters, and the parents are not considering having more children,
there is little practical value in knowing if the mother can be identified
as a carrier. The obvious situations in which women wish to know about
carrier status are where:
a
mother has one son with Duchenne muscular dystrophy and she would like
to have another child.
the sister of a mother with an affected boy wants to start a family.
the sister of a boy with Duchenne muscular dystrophy wishes to have
a child.
The
Options For Carriers
Having established that a woman is a carrier these are the options couples
face.
1. They can decide not to have any more children.
2. They can decide to have a child but elect to terminate the pregnancy
if the fetus is shown to have a defective dystrophin gene. Analysing
the DNA material of the fetus, to see if there is an abnormal dystrophin
gene, can be done in two ways. The commonest is by taking a small sample
of tissue from the placenta (chorion) and is called chorionic villus
sampling. It is done at about 10 weeks into the pregnancy. The other
test, amniocentesis, involves taking a specimen of fluid that surrounds
the developing baby at about 16 weeks. Ammocentesis is performed less
frequently now that chorionic villus sampling is available.
3. Parents can decide to accept the risks and accept the outcome.
For many women who are at risk of carrying the gene for Duchenne muscular
dystrophy it is possible to tell whether or not they are carriers. For
the others it is possible to give a risk figure for being a carrier.
Doctors can provide the available facts but it is up to the people affected
to interpret the information and use it as they see fit. It is vital
for all family members at risk to seek information before planning a
pregnancy or as early as possible in any unplanned pregnancy.
MEDICAL
RESEARCH AND THE HOPE FOR A CURE
In recent years our knowledge of the cause of muscular dystrophy has
led to a major research effort to find a cure. In this section the current
position is discussed but it is inevitable that in the near future the
level of understanding will improve and what seems the latest information
today will become "old information". For this reason it is important
for you to seek up to date information from your medical adviser. Research
for a cure for muscular dystrophy is going on throughout the world.
The Muscular Dystrophy Association of America allocates millions of
dollars each year to research into muscle diseases. The scientists they
support, along with many others throughout the world, share their research
findings to achieve one common goal - an effective treatment for muscular
dystrophy.
The amount of money available for research in Australia is not large
by world standards but important research work is going on in several
centres across the country. The results give cause for optimism in the
search for an effective treatment for Duchenne muscular dystrophy. The
most promising results have recently come from experiments with mice
which have various forms of muscular dystrophy. One type of treatment
being studied is called myoblast transfer therapy. Myoblasts are immature
muscle cells. When muscles are diseased or injured, repair (regeneration)
begins with small cells in the muscle, called satellite cells. These
change into myoblasts, which ultimately join together to form ordinary
muscle cells. It is possible to remove a small piece of muscle from
a healthy individual and grow these myoblasts in a laboratory.
Myoblasts from healthy animals have been injected into the muscles of
mice with muscular dystrophy and there has been very significant recovery
of muscle function. This was because the myoblasts from the healthy
animal joined with the myoblasts from the dystrophic animal to produce
mature muscle cells that were part normal and part abnormal. In an earlier
chapter it was noted that muscular dystrophy results when dystrophin
is missing from muscles. In the mice, recovery occurred because the
injected normal myoblasts brought with them the normal genetic message
to allow production of dystrophin and this resulted in the formation
of muscles containing some dystrophin.
These experiments show that dystrophin
can be replaced in muscle, the ultimate aim in the treatment of Duchenne
muscular dystrophy.
The next step was to see if these same results could be achieved with
humans. Human trials are currently under way, but at the time of writing
it is too early to know whether myoblast transfer therapy will be useful.
There are many practical problems facing researchers trying to develop
this form of therapy. For instance, they must work out ways to grow
enough myoblasts in the laboratory to enable injection of all important
muscles. If successful, myoblast transfer therapy will be applicable
not only to Duchenne muscular dystrophy, but also to other conditions
in which a genetic defect leads to muscle weakness. No attempts have
been made to apply myoblast transfer to other forms of muscle, such
as the heart. At present, only limb muscle is potentially treatable.
Application of this technique to heart muscle will have to wait until
results from extensive research are available. Myoblast transfer therapy
is still highly experimental. Scientists working in this field cannot
guarantee that what has worked on mice will work on humans. However,
they are genuinely optimistic, and feel they have moved from a situation
where they could offer no hope of a cure, to a situation where there
is definitely some hope. It is impossible to predict how, when and if
these research challenges will be overcome. Some research workers feel
that myoblast transfer therapy may not be the answer and many are looking
for other possible treatments. Medical scientists work with the hope
that a young child diagnosed with Duchenne muscular dystrophy today
will, in the not too distant future, be offered an effective treatment
that will prolong life and greatly improve the quality of life.
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