Alex Deford had been ill almost from the moment of her birth on Oct. 30, 1971. Her frequent colds and ear infections coupled with her small size, despite a healthy appetite, prompted doctors to vaguely diagnose "failure to thrive." When Alex developed double pneumonia at 4 months, it was clear that something was very wrong.

That something turned out to be cystic fibrosis, the most common inherited illness among white people of Northern and Western European ancestry, although it is seen in all ethnic groups. Symptoms include thick, sticky mucus clogging the lungs, impairing breathing and attracting infection; a blocked pancreas that cannot release digestive enzymes, causing pain after eating; stubbed fingers from poor circulation; infertility; salty sweat; and other problems. Patients may have any or all of these symptoms--Alex had quite a list.

When she was diagnosed at Boston Children's Hospital early in 1972, Alex was so ill that she was expected to live only days. She survived eight years, but not easily.

Alex began each day by inhaling a decongestant. Then her parents took turns providing "postural drainage," a 30- to 60- minute pounding and pressing on each of 11 segments of the lungs, to loosen the mucus, which she coughed up. Alex would then take drugs--antibiotics to prevent lung infection and powdered digestive enzymes mixed into applesauce.

Despite this daily regimen, Alex died in January 1980. Her father, sportswriter and commentator Frank Deford, tells her story in his book, Alex, the Life of a Child.

Cystic fibrosis (CF) is inherited and affects 30,000 Americans. In 1989, scientists discovered the gene that causes cystic fibrosis (see accompanying article.) This discovery is enabling researchers to develop new diagnostic tests that will help identify those who can benefit from traditional as well as several new treatment approaches being evaluated by FDA.

How CF Is Inherited

CF is typically passed from parents who each carry the gene, to children of either sex. Carriers have one faulty copy of the gene, which is responsible for the illness, plus one normal copy, which prevents symptoms. Each child of carrier parents has a 1 in 4 chance of inheriting CF; a 1 in 4 chance of being completely free of the mutant gene; and a chance of 1 in 2 of being a carrier, like the parents.

Couples usually learn that they carry CF when they have an affected child. By 1985, individuals who had a sibling with CF could find out if they carried the gene by taking a "genetic marker" (linkage analysis) test that spots a particular family's CF-carrying chromosome, but not the gene itself. Finding the CF gene makes it possible to detect most carriers, even if there are no affected relatives.

The Office of Technology Assessment estimates that 100 million to 200 million people in the United States might want to take a CF carrier test. About 8 million people in the United States, or 1 in 25 whites, may be carriers.

Diagnosing CF

The same gene discovery that has led to development of carrier tests is expected to help to more quickly diagnose CF, whose symptoms resemble those of other illnesses.

The most widely used and best-known CF test is the electrolyte sweat test. It detects the excess sodium, potassium and chloride (charged chemicals called electrolytes) found on the skin of many people with CF. A physician would perform a sweat test in a child with unexplained failure to gain weight, or with very frequent respiratory infections.

The sweat test evolved from the observations made by a physician, Dr. Paul di Sant'Agnese, during a 1953 heat wave in New York City. He was curious why so many children with CF were being brought to Babies and Children's Hospital, where he worked, with heat prostration. The youngsters were unable to cope with the heat because too much salt exited their bodies in sweat. The fact that the sweat of a person with CF contains two to six times as much salt as normal sweat gave him the idea for the sweat test.

The sweat test became widely used by the mid-1950s, and is the only CF test cleared by FDA for marketing. (A forerunner of the sweat test was the observation that a child's brow was salty when kissed. At the turn of the century, this is how midwives identified babies with cystic fibrosis.)

Although the sweat test is a critical part of a CF diagnostic work-up, salty sweat can indicate any of several disorders. Other tests help focus the diagnosis. Some of these tests are based on methodologies developed by reference laboratories, which perform medical tests and send the results to physicians. According to Freda Yoder of FDA's Center for Devices and Radiological Health, methodologies developed in- house have not traditionally been regulated by the agency.

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Explains Tom Tsakeris, director of the division of clinical laboratory devices at FDA, "FDA regulates products, not laboratories. As long as they are not marketing the test itself, we do not regulate the lab." However, he adds, the Clinical Laboratory Improvement Act, signed into law in 1988 but not yet fully implemented, will regulate reference laboratories.

One test developed by reference labs measures the amount of the protein trypsinogen in a newborn's blood. Trypsinogen is manufactured by the pancreas and sent to the intestine, where it is snipped to a shorter form, trypsin, which helps digest proteins. If the pancreas is clogged by the sticky mucus of CF, trypsinogen levels are elevated, because the longer protein cannot be cut down to size.

In one study conducted by researchers at the University of Colorado School of Medicine and Children's Hospital in Denver, the trypsinogen test identified 95.2 percent of infants with CF who did not have the earliest sign, a greenish discharge called meconium ileus indicating intestinal blockage. But in the study there were many false positives--of 96 infants who tested high for trypsinogen on two tests, only 31 had CF. So, although the trypsinogen test alone is not perfect, combined with a sweat test and observing symptoms, it can begin to paint a portrait of CF.

Another test detects the level of certain fetal intestinal enzymes in the amniotic fluid (the liquid surrounding the fetus). Amniotic fluid is collected for testing by a procedure called amniocentesis (see "Genetic Screening: Fetal Signposts on a Journey of Discovery" in the December 1990 FDA Consumer). In a fetus with CF, these enzymes are decreased. Again, however, other disorders besides CF can produce this finding, and therefore it is not a specific disease marker. Researchers have turned to the genetic material to develop a definitive CF test.

Enter Genetic Testing

Developing a test to detect the gene that causes CF would provide a definitive diagnosis, because this mutant gene is the only cause of the disorder. The first step was to find out where the gene behind CF lies among the 23 pairs of chromosomes.

By 1985, several research teams had narrowed the search to a part of chromosome 7 (the seventh largest chromosome). Until the CF gene itself was isolated and characterized in 1989, relatives of patients could take an indirect test that uses linkage analysis. Because of the complexity of test interpretation, these tests are primarily performed at academic centers.

A genetic linkage test tracks a known DNA sequence (a genetic marker) that, within a family, always occurs in people with CF, and never in those who do not have the illness. A genetic marker and the gene responsible for the disorder behave like two inseparable friends. If you see one at a party, you know the other is nearby. Genetic linkage testing is based on the observation that genes carried close together on the same chromosome tend to be inherited together.

Ray White at the Howard Hughes Medical Institute at the University of Utah in Salt Lake City and Robert Williamson of St. Mary's Hospital Medical School in London each found a marker, one on either side of the CF gene. Using these two markers, a couple who already had a child with CF could have fetal chromosomes tested in a subsequent pregnancy. If the two markers on the two chromosome 7's in the fetus matched those of the affected child, then it, too, has likely inherited the disease.

A major limitation of linkage tests is that they only work on families known to have CF. Because people can carry CF without having symptoms, a disease-causing gene can be in a family without anyone in recent memory being ill. Finding the CF gene itself, however, may make possible a test useful on anyone, so that carriers could be detected in families where no one has CF.

Like other genetic tests, CF tests can be performed on any type of tissue, because all human cells (except red blood cells) contain two copies of all of the genes, and sperm and egg have one copy of each. The first CF tests used white blood cells. Then Williamson's group in London came up with a pleasanter alternative--a mouthwash! After swishing a saltwater solution in the mouth, the person spits into a bottle. The CF gene can be spotted in cells dislodged from the inside of the cheek.

Taking a cue from London, Genzyme Corp. (Cambridge, Mass.) developed a cheekbrush test for CF, which is investigational. A patient swabs cheek cells onto a brush, and the physician sends the sample to Genzyme. The presence of both normal and mutant CF genes indicates carrier status. If only mutant genes are there, CF is indicated.

To Test or Not To Test?

A carrier test provides information to couples who are not ill but whose children are at high risk of inheriting the condition.

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Many experts predict that the day of universal CF screening is approaching, with several companies developing CF tests that simultaneously screen for several CF mutations.

Two factors contribute to the sensitivity of a CF carrier test. The first is the number of mutations that can be detected. The more mutations tested for, the more carriers will be spotted.

Ethnic background is the other important factor, says Marisa Ladoulis, a genetic counselor at Collaborative Diagnostic Services in Waltham, Mass. For example, a 12- mutation test that spots 84 percent of whites with a Northern or Western European background will detect 92 to 95 percent of Ashkenazi Jews, and the 16-mutation test finds 96 to 98 percent of them.

All CF Mutations Are Not Equal

Checking for an errant CF gene may be easy, but interpreting the results may not be. Researchers are finding that different CF mutations cause different degrees of sickness. Alex Deford probably had two copies of delta F508, the most common and one of the more serious mutations that can cause CF. But a researcher in the laboratory of Francis Collins, the co-discoverer of the CF gene, has a milder case of CF because he inherited the delta F508 mutation as well as a different one.

This young man must perform postural drainage on himself and take antibiotics and digestive enzymes, but he also plays the trumpet, bikes, and sings. Still, a respiratory infection can send him to the hospital for a week or longer. Clinicians are finding that some people who have frequent bouts of pneumonia and other respiratory infections actually have CF.

Some people with CF may not even have lung or digestive symptoms. Aubrey Milunsky, D.Sc., Director of the Center for Human Genetics at the Boston University School of Medicine, found that some men who were referred to him because they were having difficulty fathering a child actually had CF. In examining x-rays that had been taken as part of a standard fertility work-up, Milunsky noticed the men lacked the vas deferens, the paired tubes that deliver sperm from the body. Knowing this is a symptom in 90 percent of men with CF, Milunsky tested their genes and found they had inherited CF.

"Cystic fibrosis is not a simple single mutation to look for," says Margaret Wallace, Ph.D., assistant professor in the division of genetics in the department of pediatrics at the University of Florida in Gainesville. "There will be a lot of problems in doing the diagnosis and giving an idea of what it means," she adds.

Treating CF

CF symptoms are controlled with a number of drugs. Antibiotic drugs combat infections to which CF patients are prone, including Pseudomonas aeruginosa bacteria, a type of microbe that is attracted to the sticky mucus in the lungs. The combination of animal enzymes, called Viokase, that Alex Deford took regularly is still used today by CF patients. It is approved as a prescription digestive aid for CF patients and others with pancreatic insufficiencies. Combined with a high-calorie diet, this enzyme preparation aids digestion, helping the patient to maintain weight.

Many patients also take anti-inflammatory prescription drugs, such as ibuprofen (Motrin and others), prednisone (Deltasone, Winpred, Orason, and others), and naproxen (Anaprox, Naprosyn and others).

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The drug amiloride (Midamor, Moduretic), introduced in 1967 and approved as an adjunct to treatment with some diuretic drugs, is now being tested as a treatment for CF. Scientists believe amiloride thins lung secretions by blocking sodium uptake by lung cells. Clinical studies are under way to assess amiloride as a CF treatment alone, and in combination with the biological products adenosine triphosphate (ATP) and uridine triphosphate (UTP). (ATP and UTP are components of the nucleic acids DNA and RNA.)

Other investigational products are aimed at tempering the body's immune response to lung infection, which can be excessive. One such product is deoxyribonuclease. The March 19, 1992, New England Journal of Medicine reported that in a pilot study, this protein biologic given in an aerosol helped clear the lungs of 16 adult CF patients. It is being tested in 900 CF patients at 50 medical centers in the United States.

Gene Therapy

FDA has designated recombinant cystic fibrosis transmembrane conductance regulator (the gene's protein product, abbreviated CFTR) as well as gene therapy as orphan products. This gives their sponsors special incentives because they are developing products for a condition affecting relatively few people.

The first human gene therapy study of CF got under way last April 17 at the National Heart, Lung, and Blood Institute after FDA gave the go-ahead the previous day. An engineered cold virus (adenovirus) was introduced into the cells lining the nose and airways of a 23-year-old man with CF. The virus was altered to carry the normal CFTR gene and lacks the genes to cause a cold and to replicate.

The research was the first use of gene therapy for a common genetic disorder and the first use of a cold virus to transport genes. The study includes 10 patients age 21 or older who have mild to moderate CF symptoms.

Previous experiments in rats indicated that replacing the CF genes in just 10 percent of the lung lining cells improves lung function. However, because the genes go to the patients' lungs but not their sex cells, CF can still be passed to the patients' children.

New knowledge of CF is coming so fast that the goals of carrier screening may change even before the tests are cleared for marketing.

Soon, detecting the gene for CF may be a way of finding who needs treatment, as early as possible, just as is presently done for high blood pressure and elevated blood cholesterol. Says Wallace, "CF research is moving so quickly, with a lot of hope for treatment in the near future. It will be treatable, and possibly easily."

For more information, contact The Cystic Fibrosis Foundation, 6000 Executive Blvd., Suite 510, Rockville, MD 20852; telephone (1-800) FIGHTCS.

FDA / FDA Consumer