Genetic Screening

by Food and Drug Administration (FDA)

A worldwide effort to understand all our genes is well under way. Along this journey of discovery, tests are being developed to identify both healthy people who can pass a genetic disorder to a child (carriers) as well as those, including fetuses, who will actually develop symptoms.

In the past few years, scientists have identified the genes responsible for several major disorders, including cystic fibrosis, Duchenne's muscular dystrophy, and a few inherited cancers. Applying this new and complex information to the practice of medicine will require education of health professionals, patients, and their families.

How will physicians, medical consumers, and, ultimately, the Food and Drug Administration deal with this coming avalanche of information? Fortunately, experts can turn to past experience with genetic screens to guide them in planning the programs of the future.

Urine Clues to PKU

The age of genetic screening dawned in 1934, when a mother of two retarded children in Oslo, Norway, commented to a relative who was a chemist that her children's diapers had an odd smell. The curious chemist analyzed the urine and found too much of one biochemical yet none of another, an enzyme (a protein that speeds a biochemical reaction).

The children had an "inborn error of metabolism" called phenylketonuria (PKU), each inheriting a defective gene from each carrier parent. The combined deficit blocked production of the enzyme (phenylalanine hydroxylase) that normally breaks down phenylalanine, a protein building block. This genetic roadblock caused the mental retardation.

Knowing precisely what a faulty gene does (or doesn't do) is half the battle in conquering an inherited disease. The story of PKU indeed has a very happy ending. In 1963, a test was approved to detect the enzyme deficiency at birth, making it possible to prevent retardation if the child follows a very low phenylalanine diet for the first 8 years. Thanks to the observant mother, today every newborn in the United States is tested for PKU, and often other inborn errors, such as sickle cell disease, hypothyroidism, galactosemia, biotinidase deficiency, and homocystinuria.

Even though PKU is rare (affecting 1 in 14,000 whites and 1 in 300,000 blacks), genetic screening makes economic sense?it costs $3.3 million a year to screen newborns, but $189 million to care for the PKU patients who would be retarded if not for the screen.

PKU screening got off to a rocky start. In the early 1960s, a few children who had transiently high levels of phenylala-nine, but not PKU, were inappropriately placed on the diet. Some of them died. But PKU testing and treatment have since been perfected.

Sickle Cell Confusion

Another genetic screening program was initially disastrous. In the early 1970s, mass screening of blacks to identify carriers of sickle cell disease, a painful inherited anemia, began in earnest. (Although sickle cell disease affects other populations, notably Arabs, in the United States, it is overwhelmingly predominant among blacks.)

Semantics led to mass misunderstanding. Sickle cell disease carriers are referred to as having "sickle cell trait," although these people in fact have no symptoms. Quite understandably, people told they had sickle cell trait feared they would develop symptoms?and also often did not understand the genetic odds their children would face. If two carriers have a child, the child has a 1 in 4 chance of having full-blown sickle cell disease, a 1 in 2 chance of being a carrier like each parent, and a 1 in 4 chance of being completely free of the sickle cell gene.

Discrimination against carriers was widespread. In Massachusetts, black children had to be screened for sickle cell trait before they would be admitted to public school. In New York, the test was mandated when applying for a marriage license. Carriers were denied health and life insurance and entrance to the U.S. Air Force Academy. As geneticists began to recognize in the late 1970s that being a sickle cell disease carrier does not adversely affect health, these restrictions were lifted.

Newborn screening is useful when early diagnosis is coupled with treatment. Screening newborns for sickle cell disease is now mandatory, because it is known that daily penicillin can ward off life-threatening infections (see "New Hope for Children with Sickle Cell Disease" in the March 1989 FDA Consumer).

Marilyn Gaston, M.D., deputy chief of the sickle cell disease branch of the National Heart, Lung, and Blood Institute, explains, "Infection is what kills kids with sickle cell disease. A fever can progress to death in under nine hours, and we can't treat an infection that moves that fast. But we can diagnose the disease at birth, and then give oral penicillin daily. The test is easy, it's quick, it works, and it's cheap." Blood taken for the PKU test is used.

Adds Kenneth Pass, Ph.D., and director of the newborn screening program in New York, "With early diagnosis and prophylactic penicillin, mortality can be reduced to zero."

Tay Sachs Success

Ironically, at the same time that the sickle cell carrier screening program was causing unwarranted panic, another screen for a genetic disease Tay Sachs was quite successful.

In a child with Tay Sachs disease, a missing enzyme (hexosaminidase) leads to buildup of fat on nerve cells, destroying the nervous system. The child begins to lose developmental skills from about the age of 6 months, and by 2 years of age can no longer see or hear. Death comes by age 4. Like PKU and sickle cell disease, a Tay Sachs child usually comes as a surprise to two healthy parents who each carry the gene.

Tay Sachs disease is 100 times more prevalent among Jewish people of eastern European descent than in other populations. In this ethnic group, 1 in 3,000 newborns has the disease, and 1 person in 27 is a carrier. A pilot screening program in the early 1970s searched for carriers among the Jewish community in the Washington, D.C., area, and other programs followed. Because most couples found to be at risk of having a Tay Sachs child (that is, both parents were carriers) chose not to have children, the number of children born with Tay Sachs disease has since dropped by 90 percent.

The secret to the success of Tay Sachs screening, experts agree, was education. Community and religious leaders were first informed by the physicians in charge, and they informed the public. Testing was widely available on college campuses and in synagogues, community centers, and shops, and offered at times convenient for young people.

About the Author

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