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FACT SHEET
WHO IS AT RISK?
by Sean Phipps
The Purpose of Genetic Counselling
Parents often are uncertain about the purpose of genetic counselling
and what it entails. In the case of Duchenne muscular dystrophy, the
basic purpose of counselling is to help a couple understand the
hereditary nature of the disorder and the probable risk for them and
other family members of having a dystrophic child. Couples are then
able to make informed decisions about future childbearing.
It should be stressed that the genetic counselor will not tell, or even
advise, a couple as to whether or not they should have children. This
decision is a personal and private one that a husband and wife must
make for themselves.
About the author : Sean Phipps, M.S., is a genetic counselor who has
worked extensively with the families of Duchenne muscular dystrophy
patients. He has served as a genetic counselor on the staff of the MDA
clinic at the University of Wisconsin Hospitals and Clinics in Madison
and as coordinator of genetic counselling services at the Milwaukee
Children's Hospital Birth Defects Centre.
Genes & Chromosomes
X Linked Recessive Inheritance
Carriers & New Mutations
Carrier Status
CK Test - Alternatives
Prenatal Options
Genetic Counselling
Duchenne Muscular Dystrophy
The most common and severe type of muscular dystrophy is called
Duchenne Muscular Dystrophy (DMD), after the French neurologist who
first described it in 1861. This muscle-wasting disorder, which affects
boys almost exclusively, typically has its onset between the ages of
two and five and progresses rapidly. Few patients survive their early
twenties. There is no known cure, and no medication has yet been
shown to be of value in arresting the disease.
Among the first symptoms of DMD are difficulty in climbing stairs and
rising to a standing position, a waddling gait, and frequent falls. The
wasting of muscles usually begins in the lower trunk and calves,
progresses to the upper trunk and arms, and eventually involves all of
the major muscle groups. DMD is sometimes referred to as
pseudohypertrophic muscular dystrophy because it characteristically
results in a seeming enlargement of the calf muscles, which look
abnormally big because fat and connective tissue have replaced
degenerating muscle fibres.
Like the other muscular dystrophies, DMD is inherited - it is a genetic
condition. Unlike most of the other dystrophies, it is transmitted by an
altered gene on the X chromosome in an "X-linked" (or "sex-linked")
recessive pattern of inheritance. When a disorder is transmitted in this
way, only males are affected. Females, who rarely show any
symptoms, may be carriers of the defective gene and pass on the
disease to their sons and, indirectly, to their grandsons through
daughters who are carriers. the same inheritance pattern is seen in
hemophilia and colour blindness.
One other type of muscular dystrophy - Becker muscular dystrophy - is
also X-linked. Becker muscular dystrophy is similar to DMD but has a
later onset and is considerably less severe. Because they share the
same X-linked inheritance pattern, much of the information in this
booklet applies to Becker as well as Duchenne muscular dystrophy.
Genes and Chromosomes
All of our inborn traits, from the colour of our eyes to our blood types,
are determined by our genes - chemical bits of information that are the
basic units of hereditary. Genes are carried on the rod-like structures
known as chromosomes, which are found in every cell nucleus in our
bodies. Except for sperm and egg cells which contain twenty-three
chromosomes, human cells have forty-six chromosomes, half of them
contributed by the mother and half of them by the father. Normally,
forty-four of the forty-six chromosomes occur in pairs, with both
members of a pair carrying genes for the same trait. For every trait
there are two genes, one on each chromosome of a pair, in
corresponding positions.
Although the two matching genes carry instructions for the same trait,
they may or may not call for identical versions of it. For practical
purposes, one may use as an example the trait of eye colour. An
individual might have two genes for brown eyes, or perhaps one gene for
brown eyes and one gene for blue eyes. In either case, he or she has
brown eyes. This is because the gene for brown eyes is dominant and
the gene for blue eyes is recessive. Only one dominant gene is needed
in order for its version of a trait to show up. On either other hand, two
recessive genes must be present - a double dose - before their form of
the trait is expressed. Only if you have two genes for blue eyes, will
your eyes be blue.
These rules apply only to traits carried on the twenty-two pairs of
corresponding chromosomes known as the autosomes. With the two
remaining chromosomes, the situation is different. These are the ones
that determine whether an individual is male or female and therefore are
known as the sex chromosomes, X and Y. In addition to the forty-four
autosomes, females have a pair of X chromosomes. males, on the
other hand, do not have a matching pair of sex chromsomes; they have
one X and one Y which carry different genes. The defective gene in
DMD is carried only on the X chromosome.
As mentioned previously, all of the body's nucleated cells contain
forty-six chromosomes except the sperm and egg cells, which have
twenty-three, half of the usual number. Every egg cell contains one
each of the twenty-two autosome pairs plus an X chromosome, while
sperm cells contain twenty-two autosomes plus either and X or Y
chromosome. Consequently, the mother always contributes and X. The
father will determine whether the child is a girl or boy by passing on
either and X, which will result in a female, or a Y, which will result in a
male.
X-Linked Recessive Inheritance
To repeat, the gene for DMD is located on the X chromosome. Since
the defective gene is recessive, a female with the DMD gene on one of
her two X chromosomes will not develop muscular dystrophy. The
normal gene on her second X chromosome masks the effects of the
defective gene. Such a woman is called a "carrier". Male offspring,
however, have only one X chromosome, and there are no equivalent
genes on the Y chromosome. Consequently, in males the
X-chromosome genes have no "partners". Therefore, a male with the
DMD gene on his X chromsome will be affected with the condition
because he has no normal gene to counteract the effect of the
abnormal one.
Each time a DMD carrier mother has a child, there are four possible
outcomes, each with an equal probability of happening. Thus, the
chance of producing an affected son is one in four, or 25 %. If we
breakdown the risk further according to the sex of the child, it follows
that there is a 50% chance that each son will be affected. All daughters
will be unaffected, but each has a 50% chance of being a carrier like
her mother.
It is important to point out that unaffected sons of carrier mothers do
not have the DMD gene, and therefore, cannot transmit DMD to their
offspring. The same is true for those daughters of carriers who have not
inherited the DMD gene. If circumstances should allow a male affected
with DMD to reproduce, and if his wife was not a carrier of DMD, then
all of his sons would be unaffected and free of the gene but all of his
daughters would be carriers.
The Luck of the Draw
The odds in the transmission of DMD work in exactly the same way
they do when you pick a playing card from a full deck. Let us consider
that red cards represent males and black cards represent females.
Then, let us assume that hearts represents a male with DMD,
diamonds are unaffected males, clubs are a carrier female, and spades
a female noncarrier. Now, we thoroughly shuffle the deck and draw a
card. Because there are equal numbers of cards in each suit, the
chance of drawing a heart is one in four. However, if you pick a red
card(a boy), the chance of its being a heart is 50%, because there are
only two red suits. If you pick a black card (a girl), there is a 50%
chance that it will be a club (a carrier).
Keep in mind that "chance has no memory" -if the card is replaced and
the deck is reshuffled after each draw, the probability of picking a
particular suit is unchanged. Thus, in a serious of four draws, you may
pick four spades, or you may pick no spades. The fact that you picked
spades in the first three times does not alter the one-in-four probability
of picking a spade on the fourth draw. In other words, the probabilities
remain with the same for each child born in a family. If the first is
affected with DMD, there is no guarantee that the next three will be
unaffected.
Carriers and New Mutations
The mother of a boy with DMD may not be a carrier. The DMD gene
she transmits may have becomes defective as the result of a
spontaneous change in the particular egg cell that joined with a sperm
cell to develop into a child. Such a change in a gene is known as a new
mutation and is a possibility to be considered when DMD occurs in
families where there is no previous family history of the disease.
Mutations are accidents of nature for which it usually is not possible to
pinpoint a specific cause.
It is not certain what proportion of DMD cases results from new
mutations, but estimates run as high as one-third. In cases where a
boy is affected with DMD due to a new mutation, the risk to future
offspring is very small. A new mutation is a rare event, unlikely to
happen again in the same family.
It must be emphasized, however, that absence of a family history does
not mean that a case of DMD has resulted from a new mutation. It may
be that the mutation has been in the family for a number of generations
and has not shown up before, just by chance. Or, the mutation may
have occurred in a family member only one or two generations earlier.
In any event, the mother of a child who is the only family member with
DMD may or may not be a carrier. It is a major goal of genetic
evaluation to determine whether or not she is.
Determining Carrier Status
How can the genetic counselor determine whether the mother of a child
with DMD is a carrier or a new mutation is involved? The first step is to
examine the family history. A history, or "pedigree", showing several
male family members affected with DMD may indicate that certain
female family members are clearly carriers and that others are at risk of
being carriers. If there is no previous history of DMD, or if the family
history leaves carrier status uncertain, the second step would be to
investigate females for carrier status by means of various laboratory
tests.
There are a number of different carrier tests in use. The one most
widely utilised measures the blood serum level of the enzyme creatine
kinase (CK, sometimes referred to as CPK, or creatine
phosphokinase). In DMD, the membrane surrounding the muscle cell is
altered. Normally, the membrane allows waste products to pass out of
the cell but keeps in essential substances such as enzymes. When
the membrane loses this selectivity, enzymes that should be retained
are released and are usually found in blood serum in elevated amounts.
Serum CK levels are greatly elevated in the early stages of DMD and
are also considerably above normal in a most DMD carriers.
Elevated CK levels are found in approximately two-thirds of known
carriers. A positive CK test indicates with reasonable assurance that
the mother of a child with DMD is, in fact, a carrier. However, a negative
CK test does not totally rule out that possibility; many known carriers
have CK results within the normal range.
Because CK levels can show day-to-day variations in the same person,
it is generally recommended that the test be performed on at least
three separate occasions to increase the reliability of the results.
Another consideration is that this carrier test is more definitive in
younger females. It is advantageous, therefore, for daughters and other
female relatives of known or suspected carriers to be tested before
reaching childbearing age.
Alternatives to the CK Test
Researchers have been seeking alternatives to the CK test that may be
more effective in carrier detection. Many procedures have been
investigated and some are currently in use. They include tests for
serum enzymes other than CK, the measurement of various other
substances in the blood, and analysis of the structure and functioning
of blood cells. There are also tests that involve microscopic
examination of muscle cells. Such an examination is done on a muscle
biopsy, a small specimen of muscle tissue that is removed surgically.
Couples getting genetic counselling sometimes ask about the so called
lymphocyte capping test, which received considerable attention when it
was originally reported in 1987. Subsequent work with the test in
several laboratories has produced varying results. There is also some
question about the test's practical value. It is still under and generally is
not used in diagnosis.
Finally, a major improvement in the reliability of carrier detection in
DMD is expected to result from ongoing research to locate the defective
gene on the X chromosome. Molecular geneticists in ten different
laboratories are searching for the gene with recombinant DNA
techniques in an intensive effort supported by the Muscular Dystrophy
Association.
The goal of carrier testing is to look at women with some probability of
being carriers and differentiate between those who actually are carriers
and those who are not. Unfortunately, in some cases it may be
impossible to determine carrier status with certainty. This is particularly
true in families where there is only one boy affected with DMD. In these
families, it is very important to document the number of unaffected boys
in the family when obtaining the family pedigree. This information can
be used in determining the probability of carrier status.
In computing the risk of a woman's being a carrier, the geneticist takes
into account her carrier test results, the results (if available) on her
mother, sisters, and daughters, and the number of unaffected sons and
brothers that she has. Once her carrier probability is established, the
rick of any male offspring's being affected can be calculated.
Prenatal Options
What are the options for parents of a child with DMD - or for other
at-risk couples - with regard to future childbearing? One option, of
course, is to accept the risk and have more children. Remember, even
when the wife is a definite carriers, there is a three-in-four, or 75%,
chance that in any pregnancy the child will not be affected.
Nevertheless, many couples may feel that, in view of what is at stake, a
one-in-four risk is too high. Some may consider adoption. Their
physician or genetic counsellor can provide such couples with
information about adoption and refer them to appropriate agencies.
Since Duchenne muscular dystrophy does not affect female offspring,
some couples at risk who are expecting a baby wish to know the
child's sex before birth. This can be determined with amniocentesis, a
procedure for removing a small amount of the amniotic fluid surrounding
the fetus. Fetal cells that are floating in this fluid are grown and their
chromosomes studied. Aminocentesis is generally performed in the
sixteenth week of pregnancy. If the test shows a female fetus, the
parents can be reassured that their daughter will not have DMD. If the
test shows the fetus of a carrier to be a male, there is a 50% probability
that the couple will have an affected son. Some parents faced with the
risk elect to terminate the pregnancy at this point; others choose to
assume responsibility for the possible birth of a child with muscular
dystrophy.
Nobody Is to Blame
After learning that their son has DMD, parents are often overcome by
sorrow, anger, or guilt. Many hold themselves responsible, laying the
blame for their child's illness on such factors as diet during pregnancy,
life styles, or even "punishment" for some previous thoughts or actions.
It must be stressed that whether or not a child will be affected with
DMD is determined by the genetic composition of the fertilised egg and
is not related to any parental action (or lack of action) either prior or
subsequently to the pregnancy.
Some mothers feel that the child's condition is their fault because they
may have transmitted the defective gene to him. Muscular dystrophy is
nobody's fault. We have no Control over our genetic makeup. We all
have many thousands of genes, which inevitably include some that are
abnormal. Only rarely are these expressed, and most of us are never
aware that we carry abnormal genes capable of producing serious
disorders. By explaining these facts, genetic counselling can often help
to alleviate some of the distress that parents naturally feel.
What Happens in Genetic Counselling
Before appropriate counselling can be given, an accurate diagnosis
must be obtained. Generally, the diagnostic workup has been
completed by the time of referral for genetic counselling. In that case,
the genetic counsellor would begin by obtaining a detailed family
history and arranging whatever carrier tests are called for.
This information is used to determine the likelihood of carrier status and
to estimate recurrence risks. The findings are then discussed with the
family. If much of the workup and testing has already been done, a
single visit with the genetic counsellor may be sufficient. Otherwise, a
number of visits may be required in order to obtain the necessary
information and to discuss its implications.
As mentioned previously, the answers are not always yes or no; some
degree of uncertainty is to be expected. For example, the couple may
be told: "From our findings, we calculate that your probability of being a
carrier is about 20%, and therefore your overall risk of having an
affected child is about 5%". It is often more difficult for couples to deal
with uncertainty than with the knowledge that the wife is definitely a
carrier. This is where discussion with a genetic counsellor can be
especially helpful. The counsellor will not only provide the facts but also
offer help in interpreting them.
The genetic counsellor will not tell, or even advise, a couple as to
whether or not they should have children. This decision, and others,
such as whether or not to have amniocentesis, are personal and private
ones that a husband and wife must make for themselves. The genetic
counsellor will try to ensure that such decisions are based on
understanding of accurate information and will offer the couple
sympathetic support in whatever decision they make.
At the present time, while there is no cure for Duchenne Muscular
Dystrophy, supportive measures, such as physical therapy and
bracing, can help to slow down some of the crippling symptoms of the
disease and improve the quality of life for the patient and his family. In
the Muscular Dystrophy Association's worldwide research program,
many hundreds of scientists continue to work intensively to find a cure
or effective treatment for DMD. In the meantime, genetic counselling
can help families at risk to understand and deal with the decisions they
must make. It is difficult to answer in a single pamphlet all the
questions you might have about a complex genetic disorder such as
DMD.
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