Who Is At Risk? The Purpose of Genetic Counseling

This information is intended for use as a supplement to genetic counseling. Because each family situation is different, there is no substitute for individual counseling.

Parents often are uncertain about the purpose of genetic counseling and what it entails. In the case of Duchenne muscular dystrophy, the basic purpose of counseling 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 counseling services at the Milwaukee Children’s Hospital Birth Defects Centre.

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 fibers.

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 chromosomes; 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 chromosome 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 non-carrier. 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 counseling 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 counselor 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 counseling can often help to alleviate some of the distress that parents naturally feel.

What Happens in Genetic Counseling

Before appropriate counseling can be given, an accurate diagnosis must be obtained. Generally, the diagnostic workup has been completed by the time of referral for genetic counseling. In that case, the genetic counselor 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 counselor 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 counselor can be especially helpful. The counselor will not only provide the facts but also offer help in interpreting them.

The genetic counselor 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 counselor 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 counseling 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.

Reproduced with kind permission MDA USA. by Sean Phipps