Blood Matters

by Masha Gessen

  At the root of the symptoms is a mutation at the end of chromosome 4, where a pattern of three bases—CAG—is repeated an abnormally high number of times. In a normal gene, the number of repeats is between ten and thirty-five; a mutation carrier may have over a hundred repeats. The more repeats, it seems, the earlier the person will become ill. Still, geneticists cannot use the number of CAG repeats to predict when symptoms will set in: Even identical twins sometimes come down with the disease as much as seven years apart. People who have between thirty-six and forty repeats are said to fall into the “gray area,” which means they may or may not eventually develop symptoms.

  Rob had forty-one CAG repeats. Given the nature of heredity in Huntington’s disease, his mother probably had the same number: outside the “gray area,” but low as mutation carriers go. She was diagnosed at the age of sixty-three, very late by Huntington’s standards. Her early symptoms were emotional. Her family grew concerned when she began having accidents. “Fender benders, left-hand turns, that sort of thing,” Rob recalled. “Where you have to make a decision.”

  Difficulty with decision making seems to be one of the early typical symptoms of Huntington’s. A person in the early stages of the disease will get hopelessly confused when faced with the need to choose between turning right and going straight—especially if, say, she needs to go to the bathroom at the same time. The options of turning either way or opening the car door and squatting to pee in the breakdown lane may all seem equally valid.

  “They may go, ‘I’m hot, I’ll take my clothes off,’” Rozalia Andrejas, director of the Toronto and Area Resource Centre of the Huntington Society of Canada, described her clients’ logic to me. “‘Need to go to the bathroom? Good spot!’ Trying to reason with the person is futile.” Huntington Society supplies its ambulatory clients with business cards that read, “I have Huntington disease but I am very aware of what is going on around me. Sometimes I may be forgetful, have slurred speech, or have difficulty with my balance. It may take me some time to express my thoughts or answer questions. Thank you for your patience and understanding.” These seem to be helpful in preventing Huntington’s patients’ arrests for public drunkenness or disorderly conduct.

  The errant gene in chromosome 4 has been dubbed the huntingtin gene. It directs the cell to make the huntingtin protein, which performs an unknown function. What is known is that a mutant gene directs the cell to make the huntingtin protein with a higher-than-normal number of consecutive glutamines, which causes the protein to be processed differently and thus to accumulate in the neuron, which somehow leads to the death of brain cells. The exact mechanism remains murky to scientists, but the culprit of bizarre Huntington’s behaviors and dreadful Huntington’s symptoms, or at least most of them, seems to be the part of the brain called the caudate nucleus. This is a structure—two structures, in fact, since there is one in either hemisphere of the brain—that is responsible for transmitting information from different parts of the brain to the frontal lobes. The frontal lobes, in turn, are at least in part responsible for motor function, problem solving, spontaneity, memory, language, initiation, judgment, impulse control, and social and sexual behavior. In other words, for everything we do. A person in the very advanced stages of Huntington’s disease—a decade or two after the initial diagnosis—has basically lost the ability to perform any of these functions. But a person in the early stages, whose caudate has deteriorated but remains largely intact, appears to be controlled by faulty circuitry: Signals flicker, producing the expected effect only some of the time, unreliably.

  Decision making is the first ability to go. People start having trouble organizing their time, setting simple daily priorities. Those who know themselves to be at risk try to prepare by passing time management on to others. Rosie Andrejas described a client of hers, a high-powered lawyer who was still well enough to perform in court but had entrusted the making of his schedule entirely to his secretary. He was also pondering less-demanding fallback occupations—perhaps gardening. Another client, whom she described as “working in entertainment,” was concerned with early signs of movement impairment. “We are not juggling fire and we are not swallowing swords anymore,” Rosie told me quite seriously, looking at me through her round horn-rimmed glasses. “There is also a lot of travel involved, so this client tries to minimize the organizational component.” In his professional activities, he had fallen back mostly on illusion: rope-cutting, card tricks, that sort of thing.

  The early stage of Huntington’s disease, when a patient is considered symptomatic but is still able to live independently and perhaps carry on at least some sort of employment, can last a long time—up to thirteen years. Eventually, though, a person drifts further and further away. “One of the saddest moments I remember is Thanksgiving dinner,” Rob told me. “There were a number of us who were there. We always went out to my grandmother’s. I think there were a couple of my cousins, and I had a couple of friends with me. A bunch of people there for dinner. Mom was still able, helping out with dinner and so on, and being there, but she was obviously affected. And she was still smoking. Her ashtray was a little ashtray with a picture of Bobby Burns, the Scottish poet. And she was stubbing her cigarette out. This little picture on the ashtray, and she was stubbing her cigarette out on his face. Somebody joked about it: ‘Wonder how Bobby Burns feels about that.’ So we all started to laugh. And Mother didn’t get it. And she thought people were laughing at her, or she didn’t understand why they were laughing. And it was a moment for her when she realized that she was out of it, behind a veil there, you know. And she just laughed and then she started to cry. And no one could explain—we tried to explain, but that was when I realized that communication had started to be a problem, because we couldn’t really explain to her. That we were just laughing at Bobby Burns. Laugh with us, you know. Couldn’t do it. Couldn’t comfort her.”

  If a cruel deity set out to concoct the most punishing disease imaginable, it might have come up with Huntington’s. The disease goes on for a long, long time. It gets worse slowly, inexorably, but unpredictably. And for much of its progression, the person trapped inside is aware of mounting losses, even if he or she cannot control them, grasp them, or, eventually, express emotions about them. It probably feels like a protracted bad dream, the kind where you try to run but cannot, try to scream but cannot, try to reach a target but cannot. What could be more horrible than that?

  What could be more horrible than that would be to go down that long, darkening path after having watched someone you love go down it. Huntington’s is hereditary: The vast majority of people who develop it have seen a parent succumb to it, and many are watching their siblings struggle as well. In this sense, Huntington’s is like all other genetic conditions, including hereditary cancers: a person’s fears and expectations stem from the parents’ experience. But, perfect punishment that it is, Huntington’s is also different. It is the only known human genetic disease that is what scientists call “truly dominant.” A person who has two mutant copies of the huntingtin gene—one inherited from the mother and one from the father—will fare no differently from a person with just one bad copy. By contrast, people with two mutant copies of one of the BRCA genes are not born: Whatever the gene does wrong keeps the embryo from being viable. In a person who has a cancer-causing mutation, the healthy copy of the gene does its job for some time—possibly even well into old age—so that some mutation carriers never develop the cancer. The presence of one copy of a mutant huntingtin gene with forty or more CAG repeats is a 100 percent guarantee that the person will develop the disease: Such is the nature of “true dominance.”

  Fittingly, Huntington’s was the first genetic disease for which a predictive test was developed. In 1983 a group of scientists located the huntingtin gene at the end of chromosome 4. In 1986 a test using linkage analysis became available. Starting in 1993 laboratories were able to offer a more precise and definitive direct gene test. The search for the gene was a family quest, initiat
ed by a Hollywood psychoanalyst whose wife was succumbing to the disease. Their neuropsychologist daughter ultimately managed the search, and a second daughter, a history professor, movingly documented it in a book. Huntington’s was the perfect test case for genetic testing: a disease that is fatal, incurable, and basically untreatable, but also “truly dominant.” Each child of an affected person has a 50 percent chance of testing positive. A positive result tells a person he or she will definitely develop the disease and die from it, but it contains no information on when the symptoms will hit, or what they will be—whether it will begin with depression or aggression, with involuntary movements or with balance problems.

  Recent research suggests that years before clinical symptoms become apparent enough for a diagnosis, the disease process has begun. One study examined 260 “at-risk persons”—meaning those who did not know their gene status, only that they had a 50 percent probability of having inherited the mutation. They were given various tests of cognitive abilities. When researchers went back to their test subjects two years later, 70 of them had been diagnosed with Huntington’s; these were the people who had scored worse on the tests. In other words, they had been losing crucial brain cells and mental capacity long before a clinician would have diagnosed them with Huntington’s.

  Another study looked at the brain scans of mutation carriers who were considered presymptomatic, and concluded that visible changes were occurring, in the caudate as well as in other areas of the brain. Rob may have been in that study. “My neurologist got me into a couple of research programs,” he told me. “They flew me down to Long Island three times. New York City, yes. North Shore Jewish General Hospital in Long Island. They were looking at whether they could see changes in PET scans before there were clinical symptoms. They wouldn’t tell me, no, no. They gave me my scans. They were very colorful. I could see there were changes. Something is happening there, for sure.”

  I listened to Rob’s clipped sentences on my recorder. His diction was also a little off—not disturbingly so, but as if he were sucking on a piece of candy. Had Rob always talked like this? Did he know he was talking like this now? Did he think he was showing symptoms?

  “I think I have some little subtle things that only I know about,” he told me. “Sometimes I lose my balance when I turn around. And I’ve always been a little bit disorganized, but, I mean, time management now. I have problems getting hold of my time, getting motivated. But that’s always been my way.” Here were the same questions again: Were Rob’s symptoms actual symptoms, or just the normal expressions of speech habits, character, blood-sugar levels? And did the answers to these questions matter if he knew that sooner rather than later he would develop clinical symptoms of Huntington’s, as everyone who carries an abnormal huntingtin gene does? Finally, did this knowledge itself matter if, even at the age of fifty-seven, having prepared himself for the onset of the disease that took his mother, Rob would be unable to know when it actually came? Indeed, one of the particular cruelties of his predicament was that the certainty of his diagnosis—made on the basis of clinical manifestations rather than gene status—would come just at the point when his ability to understand the meaning of events began to erode. Virtually his entire adult life, from the moment he learned of his mother’s diagnosis, when he was twenty-four years old, Rob’s understanding of how Huntington’s affected him personally was always and would always be slipping away from him.

  “My parents told my brother and I together. It was quite a shock to everybody. It was a devastating moment for everybody, my mother’s diagnosis, especially for her, poor duck. But for me—I was twenty-four, young enough that it seemed like something—I knew I was at risk, we knew about Huntington’s disease, my parents, my mother was a social—well, both my parents were social workers, they’d encountered it in their own awareness, and they talked. I remember talking to them about it many, many years before my mother was diagnosed.” A few minutes later, Rob picked up the lost thread: When he first learned of his mother’s disease, “it was something I didn’t have to worry about right now. I often thought about it over the years, especially after the test became available, and I was online discussing it with other people and families, and I spent a lot of time answering e-mail on the mailing list.” Rob actually put up one of the first Web sites devoted to Huntington’s disease, so he found himself in the position of amateur virtual counselor to many people at risk for the disease.

  “Young people who were teenagers—a lot of them wanted to be tested, and I couldn’t—at that time I was already forty-something, and I couldn’t imagine a young person facing that test. I always counseled them carefully, because you didn’t want to say—I wasn’t an expert or anything, but my advice always was, ‘No, don’t. Wait. If you wait, then you’ve got the choice. If you take the test, then you don’t have the choice anymore.’ If the test had been available when I was twenty-four, I might have wanted to have it too. Immediately, you get the news that you are at risk, the test: Let’s find out. What would it have done to my life? I think it might have destroyed me. Because I think in some ways I overreacted once I got the test, even though I was an adult.” Just then lunch was ready, and Rob halfheartedly pleaded with me to take a break from the interview: “I make soup noises when I eat. I slurp.” A lot of Huntington’s patients in the early stages are embarrassed to find themselves unable to eat neatly any longer, because of decreasing muscle control. Then again, I forgot to ask Rob whether he had always slurped his soup.

  Rob actually took the test twice. He pushed the idea of Huntington’s to the back of his mind through his twenties and thirties, even as his mother slowly deteriorated. But after his fortieth birthday, Rob suddenly became obsessed with his risk. It seems to work like that with Huntington’s: The fear kicks in on its own schedule. The French journalist Jean Baréma, who wrote a book about his own decision to take the test, described it this way: “That particular weekend, eighteen years after my mother’s death, fear suddenly coursed through me, jolting me awake.... Quick—get the information!”

  Rob’s awakening to the fear coincided perfectly with the advent of the first predictive test for Huntington’s. The early linkage test required blood samples from both parents, to attempt to determine whether the person had inherited the mutant gene from the affected parent. Even then, the results were not always conclusive: The test looked not for the mutant gene itself but for markers, signposts in the neighborhood that would indicate that the bad huntingtin gene was there. Rob’s father was reluctant to give blood because, said Rob, “he was just in denial; he always would say, ‘Oh, Robert, don’t be stupid, you are not going to get Huntington’s disease.’” Obtaining a blood sample from Rob’s mother presented a different sort of problem: “She was fairly advanced in the symptoms, and it was kind of like an intrusion—you were never really sure if she understood what this blood sample was for. The trip to the doctor was a little bit sort of intruded on her space in ways that were not respectful necessarily.” Ultimately, Rob got both samples and got the test. The results were inconclusive.

  The direct gene test became available a couple of years later, in 1994. “I phoned them right back and started on a program to get that,” he recalled.

  If that makes it sound like a long-term, comprehensive undertaking, that is because it was. The first laboratories that offered genetic testing for Huntington’s approached the task with grave responsibility—as though they were the first humans to attempt foretelling the future. The rules required that the person getting tested come with a partner, notify all at-risk relatives of the intention to get tested, and continue with counseling even after blood was drawn. The lab held on to the blood until the counselor gave the go-ahead for testing—usually about three months after the person’s first genetic counseling session. The work itself took time too: The early linkage test occupied two lab technicians for two weeks, testing family samples and the sample from the potentially affected person, and then duplicating the study to confirm the result
s. It was not long before clients began to protest the process as excruciating and patronizing—and eventually guidelines began to relax—but Rob found the process reassuring. “I thought, Hey, they are taking care of me!”

  Rob went to the counseling sessions with Bill, who had been his partner for about three years by that point. Rob showed me a picture from the early 1990s: two smiling bearded gay men, one a bit older, the other a bit heavier, sitting on a stone ledge, their legs hanging in the air. “He is fifteen years younger than I am.” Rob smiled. “Poor baby. A lot to cope with.”

  It was Bill who burst into tears when the genetic counselor gave Rob the news. Rob was taken aback—not so much because it should have been his moment in the tragic limelight as because he felt compelled to take care of his distraught partner before he could deal with the knowledge he had just gained. “I don’t think he ever recovered,” Rob said. “He just pulled away afterwards.” They stayed together for another ten years, and there is, of course, no telling whether they may have lasted longer if it had not been for the genetic test. But as with Huntington’s, the signs of a relationship’s disintegration seem clear in hindsight, and seem to reach far into the past.