Cystic Fibrosis : Advances and Stumbling Blocks

by Food and Drug Administration (FDA)

(Page 4 of 4)

The symptoms of CF were first described in medical journals in 1938. The malady was attributed to a defect in the channels leading from certain glands — a remarkably accurate description, it would turn out. But the disorder was recognized before it was given a name, as illustrated by the 17th century English saying, "A child that is salty to taste will die shortly after birth."

In 1960, a CF patient rarely lived past the age of 12. By 1970, only half lived to see their 18th birthdays. In the 1970s, when postural drainage began to be implemented and FDA approved enzyme replacement and antibiotic therapy, the average lifespan began to creep upwards. Today, it is 29 years, according to the Cystic Fibrosis Foundation. New, more targeted therapies may raise survival age higher.

Cystic fibrosis researchers marked a medical milestone on Oct. 8, 1989, when Science magazine published a report by Francis Collins and his co-workers at the University of Michigan at Ann Arbor and Lap-chee Tsui at the Hospital for Sick Children in Toronto on precisely how a specific gene disrupts a certain protein to cause CF.

The researchers named the protein the "cystic fibrosis transmembrane conductance regulator," or CFTR for short. CFTR is normally manufactured inside cells lining glands in the respiratory passages, small intestine, pancreas, and sweat glands. The protein travels to the cell's surface, where it controls the flow of salt in and out of the cell like a gateway in the cell membrane.

In the disorder, CFTR protein is abnormal in a way that prevents it from reaching the cell's surface. Without the gateway in the membrane, salt is trapped inside cells. Following a natural chemical tendency to try to dilute the salty interiors of cells, moisture is drawn inside them through other gateways. This dries out the surrounding secretions, causing symptoms. In most people with CF, the protein is missing just one amino acid building block out of 1,480 — a tiny, but devastating, glitch.

Almost as soon as Collins and Tsui described the mutation that causes CF, dubbed delta F508, a difficulty arose. Delta F508 was not the only way that the gene could be altered. (A gene consists of sequences of four types of building blocks. Just as a sentence can have an error in any of its letters, a gene can be altered in many ways. A person with CF inherits two abnormal forms.)

But within days of the publication of the Science report, several biotechnology firms were already devising carrier tests for delta F508. A test for the disease-causing gene variant became available on an investigational basis by November 1989. But on Feb. 1, 1990, Collins, Tsui, and several others reported in The New England Journal of Medicine that only 75.9 percent of white CF patients of Northern and Western European backgrounds had the delta F508 variant. How useful would a test for delta F508 be, researchers worried, if this wasn't the only variant responsible for CF? At current count, more than 200 variants of the gene are known.

The multiple guises of the CF gene meant that a test to spot delta F508 would miss about 24 percent of Northern or Western European descended whites in the United States who do carry a CF gene. This, in turn, meant that the test would find only about half the couples in the United States who risk passing CF to a child (this figure is derived by multiplying the chances of each parent having delta F508). But it would be too costly to develop a test for more than 200 different mutations, when only a few of them are common.

Adding to the complexity is that different populations have different proportions of the CF gene variants. For example, delta F508 occurs in only 35 percent of African- Americans and Jews of Central and Eastern European ancestry (called Ashkenazi) who carry CF, making the test for this mutation even less valuable than it is for non-Jewish whites. For Hispanics and Italians, the frequency of delta F508 is 50 percent.

The potential powder keg of a carrier test for a common genetic disease that would, at best, only work three-quarters of the time set off a flurry of statements by professional medical organizations. On Nov. 13, 1989, the American Society of Human Genetics urged caution in carrier testing until a greater percentage of the CF-carrying population could be identified, calling for pilot programs to test the tests. Meanwhile, they suggested the test only for those with a close affected relative.

In early March 1990, a panel of physicians, geneticists, genetic counselors, and attorneys met at the National Institutes of Health in Bethesda, Md., to develop guidelines for CF carrier testing. This group echoed the earlier call for pilot programs, adding that widespread testing should wait until tests could detect 90 to 95 percent of carriers.

In December 1992, the American Society of Human Genetics reevaluated their 1989 statement, in light of the ability to detect many CF mutations. Their advice remains unchanged — for now, CF testing should be offered only to those with a relative who has the disorder. The organization also calls for informed consent and genetic counseling, confidentiality of results, and quality control of the laboratory performing the test.

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