Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.
Dept. of Pediatrics, Tokyo Women's Medical College, JAPAN
The Human Genome Project is now actively being carried out with international collaboration. In the future, clarifying individual genomes will no longer be a dream. Along with the right to know one's genome, individuals will also be guarantied the right not to know. I would like to introduce some present conditions here in Japan which must be considered in weighing the benefits and demerits of having this knowledge.
Firstly, genetic counseling should contribute to solutions for genetic problems, and facilitate early diagnosis and treatment. The main focus should be the individual. It is possible for scientific progress to be harmful to individuals if the available information is incomplete or has been carelessly manipulated and if support systems from people being given bad news are inadequate. These factors must be considered even though progress is generally the gospel for humanity.
Having long been involved in clinical care and genetic counseling for patients with neuromuscular disease, I will discuss genetic counseling of progressive muscular dystrophy, focusing on carrier diagnosis and prenatal diagnosis.
Case 1: I would like to discuss one illustrative case. In 1986 a couple came to visit me, the woman being nine weeks pregnant. Her brother had died at age 20 of muscular dystrophy, but detailed information was not available. She had read that muscular dystrophy was an X-linked recessive genetic disease and that while her son could be afflicted her daughter would not be. She had knowledge, through mass media, of the possibility of sex selection by artificial insemination, so she wanted to abort and use artificial fertilisation to have a girl. At that time neither DNA analysis nor dystrophin testing for Duchenne muscular dystrophy (DMD) had been applied to her brother. Furthermore, in a family like this with a sporadic case, DMD is the most probable type based on family history. We could not, however, confidently rule out the possibility of autosomal recessive inheritance. It is known that two thirds of DMD carriers have elevated creatine kinase (CK) when tested in a non-pregnant state but, unfortunately, this woman had never had her CK tested. I discussed the possibility of the fetus being a girl so she decided to continue the pregnancy, using amniocentesis to check the sex of the fetus. The fetus was a girl, and the baby was delivered successfully.
1) The impact of informing individuals of carrier status
We must discuss how best to inform people that they are carriers a serious genetic disease. The case which I have presented here illustrates many issues. The individual should be well prepared before being informed of carrier status/ One can make up strategy when informed of carrier status. The woman whose case has been discussed here knew that she had a chance to be a carrier through the mass media and was understandably very worried. But, before visiting me, she had never been, and did not know how to be, evaluated. She sought genetic counseling after becoming pregnant. She had read about the possibility of sex selection using artificial fertilisation, a very timely topic in the newspaper, but available at very few hospitals. Furthermore, although the possibility of attaining the desired gender is high it is not 100%. Mass media have grossly over-inflated the capabilities of this technique. If she had not visited me, and had discontinued her first pregnancy she would not have been able to have had her daughter. This lady was intelligent, active and acted positively with a specific purpose in mind. She had experienced strong anxiety fearing that her son might have muscular dystrophy. based on the fact that she went from hospital to hospital, we can assume that she was not satisfied with her hospital care.
In the past, carrier detection for DMD yielded only positive results: we could not guarantee that someone was negative. In recent years, however, for certain families we have been able to diagnose some people as carriers and assure others that they are definitely not carriers. A female with a positive family history might be eager to be evaluated in hopes that she will be proven not to be a carrier. If, however, the result is positive she might suffer more upon being informed that she is a carrier.
2) Care and strategy used for informing individuals of carrier status
a) Thoughtfulness is essential in informing someone of their carrier status
Information must be presented accurately. People need and have a right to know as much as they are prepared to understand. They should be informed of the limitations of prenatal diagnosis and carrier testing and what may be possible in the future, based on scientific progress. In cases in which people have obtained incomplete or inaccurate information through the mass media, it is essential to provide realistic expectations and establish individual support systems.
The progress of medical science continues to be steady. There is however, a time lag between top scientific breakthroughs and practical accurate application of the newly discovered information. This clinical application requires financial as well as skilled human resources. On the other hand, as the body of medical information increases, it becomes increasingly difficult for doctors to understand and put into practice significant medical breakthroughs which are beyond the scope of their own speciality.
As the Human Genome Project proceeds, genetic information increases and more people who thought that genetic problems were beyond their concern may discover that they have the possibility of being a carrier. We have to consider carefully how best to present this information and how to provide good follow up. We must protect the individual's privacy. We also need to promote an enlightened attitude toward genetic disease as an issue that everyone should be concerned about, and we need to reduce the psychological impact as much as possible.
At present, genetics is not adequately covered by medical school curricula in Japan. Currently, there is an urgent need for doctors who can adequately provide accurate genetic information. It is essential for physician training to include such aspects of genetic counseling as reducing people's anxiety, helping them devise strategies for coping with the disease and fully understanding its impact. It is thus absolutely essential to establish a genetics department at each medical school which can provide a comprehensive genetics curriculum.
1) Response of a mother whose son was diagnosed as having an intractable disease
When a woman meets someone with whom she shares a special feeling, gets married and becomes pregnant, the couple await their baby with expectation and anxiety. The genome of that woman and her husband are combined in one cell, the DNA replicates doubling the amount, then the cell divides in two, ultimately producing a new human by repetition of cell division. The baby, a new life, represents eternal life for humans as animate creatures. The mysteries of the beginning of a new life are beyond our scientific understanding. At the moment of birth, parents hope their child will be healthy, just as they wish for its happiness. Rather than a "healthy and talented child" they hope for a child who will enjoy good health.
As a pediatrician, I treat children with neuromuscular disorders including muscular dystrophy. As parents come to realize that their child is suffering from an untreatable disease, they are overwhelmed by grief and often refuse to accept the diagnosis, going from hospital to hospital searching for some possibility of cure. As time passes, they become increasingly able to accept the disease and begin to contemplate how to achieve the best quality of life for their child. Sometimes, parents become tired and depressed. The child may also develop these feelings of hopelessness and despair as they become aware that the disease is progressive and untreatable. For a parent, the realization that this is a genetic disease that the child has inherited from them, is devastating. Parents feel tremendous guilt. In cases in which one parent is clearly a carrier the spouse may reject this individual. Knowing that everyone has several harmful genes can help the spouse to accept the carrier. Some parents feel that they will never have other children for fear of passing on the disease again. Some want to let their baby be born even though it will suffer from an intractable disease.
Most parents are thankful for their child's existence, feeling that their lives have been enriched by many experiences they could never have enjoyed without their child. But in cases in which the child is suffering from an X-linked recessive disease, mothers worry about whether their daughters are carriers, hoping that their daughters will not experience what they themselves have gone through in raising a handicapped child with a terminal illness. It is out of these concerns that the demand for prenatal diagnosis arises.
The gene responsible for muscular dystrophy is located on the short arm of chromosome X (Xp21.2). If a woman is a carrier and had abandoned the idea of having a healthy child, prenatal diagnosis can offer her the possibility of having a healthy baby. However, at present, we must consider the limitations of medical science and intrinsic ethical issues.
Technically speaking, chorionic villi sampling can induce some spontaneous miscarriages and misdiagnoses because of mistaken maternal tissue sampling, as shown in the second case presented above. In using amniocentesis we can collect fetal tissue accurately, but there is a time limitation even though it can be done earlier with PCR.
As clinicians we are faced with challenges stemming from inadequate knowledge and limitations in prenatal diagnostic techniques. When using RFLPs, the possibility of misdiagnosis due to recombination must be kept in mind. Using cDNA only 60% of DMD cases can be detected, far short of the 100% we would like to be able to offer our patients. As in the case reported by England et al. (1990), the severity of the DNA abnormality, a large cDNA deletion in this case, may not predict outcome as clinical features were very mild. The possibility of germline mosaicism (Boileau et al. 1989), in which a normal fetus was aborted on the basis of RFLPs without considering germline mosaicism, presents another difficulty in making an accurate diagnosis. Another possibility is an affected female (Isaacs et al. 1987). One of their cases was a carrier who opted to continue her pregnancy after genetic counseling because the fetus was female. Unfortunately, the infant girl had muscle weakness and was diagnosed as having muscular dystrophy.
In the case of a woman who is pregnant and wants an abortion because she is afraid of having an afflicted child, prenatal diagnosis is valuable even when no DNA deletion has been detected in the patient. Having this information allows us to rescue a female fetus or a normal male fetus. Negative results do not, however, guarantee a normal boy.
If no familial DNA abnormality is detectable, prenatal sex determination is available even though prenatal diagnosis is not possible. RFLPs will be applicable to these families but we cannot confidently rule out the possibility of recombination.
Prenatal diagnosis is valuable for patients in whom a familial DNA abnormality has been confirmed because, we can not only rescue a female or normal male fetus, but also provide psychological support and reassurance for the pregnant woman. At our hospital, prenatal diagnosis is permitted only under the last condition. Still, even in these families no one feels perfectly justified in aborting in the case in which prenatal diagnosis is positive.
Prenatal diagnosis can allow them to avoid abortion and to have a child. A woman will be very disappointed to discover that abortion is the only way for her or her daughter to avoid having a child with an untreatable disease. No one can determine with certainty that abortion is a reasonable procedure under these circumstances. Most are never relieved of the guilt feelings that follow termination of a pregnancy. Complicating these difficult and painful personal decisions are the possibilities of incorrect prenatal diagnosis and inducing abortion as a result of these procedures. These limitations in diagnostic procedures present special problems and challenges for physicians offering genetic counseling.
Based on a top news story that we can diagnose DMD prenatally, the general public believes that prenatal diagnosis for DMD is infallible. At present, most scientists agree that the detection rate for DMD is 60% but it took time to reach this consensus. The number of diagnosable diseases or abnormalities will increase as the human genome project proceeds. As this information becomes available, we must be increasingly cautious as to how we utilize it.
Suppose all the medical issues are solved and we have 100% precision in diagnosis, would that be the end of all the problems? Some people say the carrier state is unacceptable, they can not tolerate the condition of Becker muscular dystrophy.
When does the conceptus come to have rights as a human being? What constitutes the dignity of life? What is the definition of a human being, and what constitutes the right to control one's own body? Some people, like Fletcher, say that quality control is a more important issue than to only maintain life. Then what is the quality of life?
I would like to conclude by introducing a poem written by a 17-year old girl suffering from congenital muscular dystrophy - a disease with intellectual impairment and muscular dystrophy. She wrote this one week before her death. Later her mother found this in her notebook, and sent this poem to me.
The ends of the leaves are extended,
they are prickly when I touch them.
They are prickly, they hurt me when I touch them
The shadows of the leaf are gone now ...
New green buds will turn into a new leaf,
how nice it is,
I hope to see it again.
Boileau, C. et al. (1989) "Misdiagnosed normal fetus owing to undetected germinal mosaicism for DMD deletion", J. Medical Genetics 26: 790-2.
England, S.B., et al. (1990) "Very mild muscular dystrophy associated with the deletion of 46% of dystrophin", Nature 343: 180-182.
Isaacs, H. et al. (1987) "Female carriers of Duchenne muscular dystrophy: a dilemma", Clinical Genetics 31: 288: 296.
pp.173-178 in Human Genome Research and Society. Proceedings of the Second International Bioethics Seminar in Fukui, 20-21 March, 1992, eds., N. Fujiki & D. Macer (Eubios Ethics Institute, 1992).