Catholic Health Care Advocates Papers

Print Page Print Page
Email Page Email Page

Prenatal Diagnosis: A Catholic Perspective

Paddy Jim Baggot, M.D. And M. G. Baggot M.D.

PRENATAL DIAGNOSIS: METHODS

The goal of prenatal diagnosis is to detect disorders of the fetus. These could be birth defects, chromosomal abnormalities, biochemical genetic disorders or molecular genetic disorders. Popular screening is used to select cases "at risk". " Screen positive" cases then receive diagnostic tests. If a disorder is suspected, abortion maybe be recommended . Population screening can then become a prelude to eugenic elimination of "defective" individuals.

PRENATAL DIAGNOSIS: DISORDERS.

Population screening is often done by alpha-feto-protein (AFP) or triple screen. This is used for maternal population screening. The goal is to reduce the birth of affected children. AFP or triple screen predicts the risk of Down’s syndrome. The alpha-feto-protein (AFP) serum markers are used to calculate a risk estimate for the presence of Down’s syndrome. If the risk is greater than 1/200 then amniocentesis is offered. The decision criterion is 1/200 because 1/200 is the risk of procedural miscarriage (Lynch and Berkowitz, 1992).

Amniocentesis is a procedure which samples the amniotic fluid, which contains amniocytes. About 1% of amniocenteses are positive. In 99% of cases normal babies are subjected to the risk of miscarriage. If the fetus is affected, i.e. has Down syndrome or some other birth defect, then abortion may be offered as ‘her choice.’ As a whole, the program is eugenic-it leads to the elimination of babies with birth defects and genetic disorders.

Chorionic villus sampling (CVS) samples the placenta. Some have raised concerns about a risk of limb reduction anomalies with chorionic villus sampling. Several studies found CVS relatively safe (Simpson, 1991). The risk of procedure-related miscarriage for CVS is estimated to be 1-2% (Lynch and Berkowitz, 1992). CVS is often done at 10-14 weeks, earlier than amniocentesis is performed.

Percutaneous umbilical blood sampling (PUBS) is an acronym for cordocentesis. In this procedure ultrasound guidance is used to place a needle in the fetal umbilical vein. Fetal blood is then sampled. The fetal loss rate is 2-6% (Lynch and Berkowitz, 1992).

The most widely used procedure in prenatal diagnosis is ultrasound. It is widely acceptable. It is inexpensive and is generally considered safe. It is effective for the detection of structural anomalies. Ultrasound detects anatomic birth defects. Examples include spina-bifida, cardiac anomalies, abdominal defects and various forms of urinary obstruction. These can usually be treated surgically after birth.

Cytogenetic disorders may be detected by chromosome analysis. It is generally necessarynnto obtain and grow fetal cells, although some procedures can be applied to non-viable cells. Fetal cells can be obtained from the placenta (CVS) amniotic fluid (amniocenteses) or fetal blood (PUBS). The chromosomes are then analyzed. The chromosomes are first identified and counted. This is usually done for a sample of about twenty five cells. Later more advanced procedures can be performed.

After the chromosomes are counted their structure is assessed by banding techniques. Structural chromosome abnormalities include deletions (the loss of one or more bands from a chromosome), duplications (the presence of additional redundant chromosomal material), and inversions (in an inversion a portion of the chromosome is present in inverse order). Most deletions and duplications have deleterious consequences for the patients. Florescent-in-situ-hydridization (FISH) is a procedure which is a powerful new technique becoming more widely available.

FISH involves the application of DNA probes for the detection of small deletions. A FISH probe is composed of numerous DNA sequences which hybridize to the chromosome of interest. These DNA sequences are tagged with florescent molecules which enable their detection under the microscope. FISH probes have revolutionized cytogenetics. Many disorders whose cause was previously unknown have now been shown to be caused by small chromosomal deletions. In some cases the deletions are too small to be seen with banding techniques but can still be seen with FISH probes.

An example is the DiGeorge syndrome. DiGeorge syndrome is usually caused by a small deletion in the lower or Q portion of chromosome number 22. This deletion can be designated 22q-. DiGeorge syndrome involves absence of the parathyroid glands causing hypocalcemia, and absence of the thymus gland causing a severe defect of the immune system. Since this profound defect in immune function involves both T and B cell function, it is known as severe combined immune deficiency syndrome (SCIDS). It became popularly known as the disease of the ‘boy who lived in the bubble’. The bubble protected him from the plethora of minor bacteria and viruses to which most of us are immune, but which could kill him in a short period of time. He finally died when he ventured outside of his protective environment.

Biochemical genetic disorders are usually caused by deficiency in the function of a biochemical enzyme. The deficiency is caused by an alteration in the gene which codes for the enzyme. Some alterations have no effect on the enzyme and these alterations are called polymorphisms. Alterations which affect the enzyme’s function are called mutations. A deficiency may be caused by absence of the enzyme or by the presence of an enzyme which is defective and therefore does not function. Disorders where the enzyme is absent usually result from mutations in the control regions of the gene. Since the control region of the gene determines when the enzyme is synthesized, and how much enzyme is synthesized, mutations in the control region impair enzyme synthesis. Mutations in the portion of the gene which codes the amino acid sequence result in an alteration of the protein structure of the enzyme. These mutations result in enzyme which is present but has defective function.

Enzymes are proteins which catalyze chemical reactions. Those reactions often involve small molecules such as sugars, amino acids, fats and/or fatty acids, organic acids. etc. When an enzyme is deficient, the small molecule it supposed to metabolize may then accumulate. The product of the enzyme will also be in short supply. Disease may be cause by the absence of a product, by the accumulation of a toxic metabolite or by the metabolism of the accumulated metabolite by an alternate pathway to another metabolite which may be toxic. These disorders frequently effect neurologic development.

In some cases molecules accumulate which cannot be broken down. Since these molecules cannot be processed they are stored by the cell. Such disorders are then called storage disorders. Tay-Sachs is an example of a disease which is caused by the storage of products which cannot be broken down. Storage disorders often are not evident until the amount of stored material rises, which may happen sometime after birth.

Some mutations involve changes in the portions of the enzyme which binds to vitamin or mineral co-factors. If the enzyme binds a vitamin co-factor weakly, then enzyme function will be defective. This situation can be corrected by the administration of large amounts of the vitamin, which may enable the defective enzyme to achieve more normal function. This treatment may be possible for enzymes which are deficient due to structural abnormalities. This type of treatment will not be effective for mutations in the control region of the gene.

The archetype of biochemical genetic disorders is phenylketonuria (PKU). Children with PKU are unable to metabolize phenylalanine one of the twenty amino acid building blocks of proteins. Excessive levels of phenylalanine are toxic to brain development and as a result these children previously had mental retardation. They can be treated with phenylalanine restriction diet. If these children are detected at the time of birth and treated shortly thereafter, they can have normal intelligence (Scott and Cedarbaum, 1990). This disorder can be detected prenatally either by measuring phenylalanine and amniotic fluid or by culturing fetal cells and assaying their ability to metabolize phenylalanine. There are about 700 -1000 biochemical disorders, most of which are very rare. About seventy have treatment. The overall frequency of all these disorders taken together is about 1/200.

Molecular genetic disorders result from an error or misspelling in the DNA sequence. All biochemical disorders are also molecular disorders. In usual parlance, molecular disorders refer to those molecular genetic disorders which are not diagnosed by biochemical methods.

Molecular genetic disorders are caused by misspellings in the DNA sequence of a particular gene. Theoretically all biochemical disorders are also molecular genetic disorders. Molecular genetic disorders usually refer to disorders which are not also biochemical disorders.

One archetype of a molecular genetic disorder is cystic fibrosis (CF), which is a respiratory disease (McGrae & Williams, 1990). As in many molecular genetic disorders, the disease is caused by malfunction of a protein. Mapping and cloning of the cystic fibrosis gene was pioneered by Francis Collins now director of the Human Gene Project.

Cystic fibrosis was initially known as mucoviscidosis. It was given this name because children with this disease were unable to excrete their pancreatic enzymes into the intestines because the pancreatic ducts were blocked by viscous accumulations of mucoid secretion. As a result these children died of malabsorption in the first one or two years of life. These children could be treated by pancreatic enzyme replacement, vastly increasing their lifespan. Now these children develop severe chronic respiratory disease. Until recently their life spans were cut short in the teens and twenties due to chronic progressive lung disease. Many new treatments are being developed for cystic fibrosis which are again extending their lifespan. As in the pancreas, the airways in children with cystic fibrosis are often blocked by viscous mucoid secretions. These secretions contain degenerating cells. Within these degenerating cells are nuclei and within the nuclei are chromosomes which are composed of long filaments of DNA. One reason for the high viscosity of these secretions is the presence of numerous long strings of DNA. This situation can be treated by the application of an enzyme which chews up DNA, known as DNAse. In ideal climates where lung infection is minimized, some patients with cystic fibrosis survive past the age of fifty.

Molecular genetic disorders can be either autosomal recessive or autosomal dominant. Autosomal dominant disorders result when a single mutation on either the maternal or paternal copy of the gene is sufficient to cause the disease. For an autosomal dominant disorder each child has a fifty percent risk of inheriting the disease from an affected parent. Most biochemical genetic disorders are autosomal recessive. If either the maternal or the paternal copy of the gene can produce a functional enzyme, then the patient is usually clinically normal. The patient who has one normal gene and one defective or diseased gene is known as a carrier. The parent who is a carrier will randomly pass either the normal or the diseased gene to each child. If both parents are carriers each child has a one-fourth chance of being affected by the disease (McGrae & Williams, 1990).

Molecular genetic disorders are diagnosed by tests which depend on the DNA sequence of the affected gene (Simpson, 1991). The DNA sequence can be copied millions of times by a process known as the Polymerase Chain Reaction (PCR). After amplification the sequence can be tested for the presence of mutations.

Maternal screening for cystic fibrosis has been suggested by some. Molecular generic techniques can be used to determine if a mother is a carrier. Screening of all pregnant women has been proposed. If the mother is screened positive then the father can be tested. If both mother and father are carriers, then fetal genetic material can be obtained by amniocentesis. Diagnosis of cystic fibrosis in a fetus could then lead to other the termination of pregnancy. This should be characterized as a eugenic program to reduce or eliminate the birth of babies with cystic fibrosis. Unfortunately, the rapid strides being made in the treatment of cystic fibrosis have not yet eliminated the desire for such a eugenic program.

The field of genetics is making very rapid, scientific progress. Many conditions which were previously of unknown origin are now being understood and their causes determined. Through the application of these methods to the fetal period, the ability to diagnose fetal diseases is rapidly increasing. These changes are fundamentally good. Some are using these scientific advances to further prenatal diagnosis. A growing problem is that diseases can be diagnosed but treatments have not been developed. This will likely lead to ever expanding eugenic programs for selective termination of ‘defective’ fetuses.

The diagnoses based on new genetic methods tend to strongly suggest clues for the development of treatments. When the biochemistry of a problem is specified, treatment options suggest themselves. If a toxic metabolite is produced, can it be neutralized? Can it be excreted?nnIf a diagnosis is based on molecular genetics, there can also be suggestions for treatment options. Often the gene has been sequenced or will be soon. Once the gene is sequenced, the three- dimensional structure of its protein can be predicted from computer programs. If a zinc binding site is hindered, zinc supplementation might be helpful. Perhaps the correct protein could be produced by bacteria and given to the patient.

In conclusion, the capabilities of prenatal diagnosis are rapidly expanding due to the human genome project. This can be both good and bad. It is good in that new knowledge will suggest new treatments. It can be bad because the ability to conduct eugenic programs will be greatly increased.

What must be done? The solution suggested here is that new treatments should be developed as fast as possible. In order to stem the rapidly expanding tide of eugenic abortion, we must try to develop treatments for new diseases almost as quickly as the diagnostic methods are developed. This is of course a tall order, but nonetheless still necessary. For those disorders which are treatable, an offer of selective termination could be countered with an offer of a new treatment.

As more treatments become available, people may gradually develop faith in the science which is coming but not yet here. If a child were born today with Cystic Fibrosis, it is not really reasonable to base his prognosis on the life span of CF adults today. When today’s adults with CF were born, their prognosis was much more dismal. As a result of scientific progress, they do much better now than they were expected to do when they were born. There is no reason to expect that scientific progress will come to a screeching halt tomorrow. As long as scientific progress continues, it is reasonable to hope that the prognosis for a disease will improve over the course of a child’s lifetime. Thus it is reasonable to encourage parent to keep their babies, avoid termination, and hope that things will turn out better than expected. What cliché is more worn than the baby with a disease who does better than he/she was expected to do?

ACKNOWLEDGMENT

The assistance of Mrs. Suzanne Baggot is gratefully recognized. Part of this work was done at the Pope Paul VI Institute in Omaha NE, which is directed by Dr. Thomas Hilgers.

REFERENCES