Medicine: Do They Really Want to Know?

As a scientist, Nancy Wexler always thought she would want to know. Since watching her mother die in 1978 of Huntington’s disease, the 41-year-old Columbia University neuropsychologist has wondered if she too will develop the untreatable and fatal brain disorder. She was all too aware that a child with a Huntington’s parent has a 50% chance of contracting the inherited disease, usually between the ages of 35 and 45. Now the answer is hers for the asking, thanks to a complex chromosomal test Wexler herself helped devise.

Last month that test was given for the first time to two young adults at the Johns Hopkins Hospital in Baltimore. Both tested positive, and must now live with the grim certainty of developing the disease, which causes progressive dementia and loss of body control. And suddenly Nancy Wexler is no longer sure she wants to know her fate. “Before the test, you can always say, ‘Well, it can’t happen to me,’ ” says Wexler, who is president of the Hereditary Disease Foundation. “After the test, if it’s positive, you can’t say that anymore.”

Wexler is not alone in her dilemma. More than 100,000 Americans with a family history of Huntington’s live with the knowledge that they may have inherited the defective gene. Like Wexler, many have decided not to have children, and are likely to be ambivalent about taking the test once it is no longer experimental. Recognizing how devastating a positive test result could be, Johns Hopkins, Columbia University and Massachusetts General Hospital are conducting a three-year study to determine the emotional impact of early diagnosis. “We’re trying to find out what type of psychological care these people will need,” says Jason Brandt, a Johns Hopkins neuropsychologist. “Will their families break up? Will they be unable to concentrate on their jobs?”

Small-scale studies have shown that people who know they are at risk have a high rate of depression and behavior disorders, and that 25% of those who are diagnosed with early symptoms of the disease attempt suicide. Says Brandt: “We’ll stop doing the test if we see we’re doing more harm than good.”

Huntington’s strikes about one in every 20,000 people eventually killing so many cells at the center of the brain that a gaping hole is created. But the first symptoms, such as irritability and depression, are often subtle. “We just thought it was an extreme mid-life crisis,” says Wexler, recalling the onset of her mother’s illness. “We blamed it all on Betty Friedan.” Next come the neurological and motor effects that are often mistaken for drunkenness: slowed thought processes, slurred speech, impaired memory and problem-solving abilities. In the later stages of the disease, the patient is seized by uncontrollable jerking movements.

To learn whether someone will develop a genetic disease, scientists must confirm the presence of a particular defective gene in his or her chromosomes. Using genetic “scissors” called restriction enzymes, researchers cut the DNA strands taken from body cells into distinctive fragments. Then they compare fragment patterns from different family members, some of whom have the disease. Eventually scientists can identify those fragment patterns that serve as disease “markers” because they come from regions of the DNA close to the defective gene. But identifying such markers is a time-consuming, hit-or-miss affair: because there are a hundred thousand genes along the DNA strands. When Wexler’s Hereditary Disease Foundation gathered researchers in 1979 to hunt for the Huntington’s marker, even optimists guessed the search would take ten years.

But one of the scientists, James Gusella, director of neurogenetics at Massachusetts General Hospital, got lucky. While studying an American family with Huntington’s, he located an apparently reliable marker after just eleven comparisons of the family’s DNA. Still, he needed a much larger family for confirmation. That was provided by Wexler, who had traveled to Venezuela to study a huge clan on the shores of Lake Maracaibo, descendants of a woman who died of Huntington’s disease a century ago. Using basic Mendelian principles to chart a family tree of 5,000 area villagers, Wexler documented more than 600 cases of Huntington’s. When Gusella examined DNA samples from affected family members, he found that all carried the same pattern of the marker. In 1983 Gusella and Wexler published their results in the journal Nature.

The test they made possible usually requires comparison of the participant’s DNA with that of healthy and afflicted family members and involves drawing only a few blood samples. Will there be many takers? Of six people who originally volunteered to take the test in Boston, three have changed their minds. “Some people don’t really want to know,” says Gusella. “For many, that’s a reasonable judgment.”

The test raises difficult ethical and legal questions. Employers and insurance companies may try to require the test for people at risk. It may sometimes be difficult to safeguard the right of certain people not to know–for instance, a husband with a family history of Huntington’s whose pregnant wife decides to test her unborn baby for the gene. “That’s kind of a double whammy,” explains Wexler, “because if the fetus has it you know the at-risk parent does too.”

Wexler is still pondering her own decision: “I wonder if I would really be that much happier if I knew I wouldn’t get the disease.” Yet she is tantalized by the chance to know. “When my sister and I both decided not to have children,” she says wistfully, “neither of us ever expected anything to happen in our lifetime that might change that.” –By Joe Levine. Reported by Robert Ajemian/Boston and Christine Gorman/New York