for slowing the disease. Most people die fifteen to twenty years after they start to show symptoms.
The problem with the repeats in the instructions is that they cause the huntingtin protein to be built wrong. “It spoils the shape of the protein, and this has a functional effect of some sort,” says Craufurd. If the language sounds vague, that’s because our understanding of how that malformed protein wreaks havoc on the body and the brain isn’t clear. “There are twenty-five different theories about what the problem is,” says Karen Anderson, “but there is no good solid answer as to what is really going on, which is why we’ve had so much trouble targeting it with the treatment trials.”
Although the mechanism isn’t obvious, the effects are: the busted protein somehow causes muscles to waste away. The liver and the spleen suffer, Craufurd says. HD patients burn calories at a rapid rate, “which sounds wonderful until you realize they also have swallowing problems,” says Anderson. “They can’t possibly eat what most of us eat in a day, let alone enough food to burn four thousand calories in a day, which some of them easily can.”
The brain, however, is the main target of the illness. It shrinks. Brain cells die, and the brain atrophies. One area that suffers the most is the basal ganglia—particularly, the caudate, a primitive section buried deep within the brain. The cerebral cortex also thins out, Craufurd says. “It’s really quite widespread. It’s not uniform throughout the brain. There are some areas where there’s more atrophy than others. You can see that cortical atrophy starts quite early.”
Like a domino effect, when one area of the brain dies, the connections from that area to other places die as well. Karen Anderson says, “As a result of the caudate dying, all of these connections to the frontal lobe and other parts of the brain also die off.”
Brain-imaging techniques such as PET (positron emission tomography) scans and fMRI (functional magnetic resonance imaging) are helping researchers unravel just how the brain deteriorates. If the progression of the disease in the brain could be understood, it’s possible that a symptom like irritability could be tied to particular brain circuitry. At this point, researchers are far from being able to make those connections. “I think that in ten years, we might have a really good answer to that question,” says Karen Anderson. “Right now, we don’t know enough about the progression of brain changes in Huntington’s to be able to answer that.” Anderson says it’s likely that different patients will exhibit different patterns of cell death. “My thought is that there are some groups where the frontal cortex—the areas that control motivation—die out more. In others, there’s circuitry that affects irritability, and those may die out more.”
This is consistent with how the disease manifests. HD affects different people in different ways. Not all patients are irritable. Chris’s grandfather, for example, didn’t seem to show signs of irritability.
Chris went back to West Virginia when he was twenty-eight. When he walked into the house, “it looked like a tornado had hit,” he says. Food-encrusted plates and cups of milk that had been sitting out for days littered the counters. Cigarette burns pocked the carpet. A woman was lying limply on the couch. Her cheeks were sunken. Her hair was a mess. Her body was skeletal. She wasn’t moving. Chris wasn’t sure whether she was breathing. He walked into the kitchen to look for his mother. When he walked back into the living room, the woman on the couch opened her eyes and smiled at him. He left the house and broke down.
Chris also brought a video camera on this trip. He had the idea to do a documentary on Huntington’s disease, although, he says, “I had no idea what I was going to shoot, until I got there.” Chris couldn’t bring himself to film the house when he first got home. He regrets that. He did set up a “makeshift studio in one part of the garage” and used it to do self-interviews. He shot twenty hours of footage in the two months that he stayed with his mom. During the last fifteen years, he has relived that period of his life again and again while editing the tape. As you might suspect, he says, “It is painful to watch that footage over and over.”
Chris’s mom, despite the severe chorea, refused to admit that she had the disease. She had told Chris that if she ever started to show signs of the illness, she would kill herself. So Chris never got to talk to his mom about the disease. The denial also complicated the filming—“I couldn’t just say to her, ‘Hey, Mom, I’m doing a documentary on Huntington’s disease,’ because she never admitted that she had it, and any time I would bring up Huntington’s disease, she would start talking about suicide. That was a conversation I never wanted to have with my mom.”
A year after that visit, when Chris was twenty-nine, he decided to get tested for Huntington’s. “I just felt like I needed to know what direction to go in my life. I felt like I was stuck. I felt like the best thing to do was to find out if I had inherited the gene. I’m working on this documentary, and I’m about ready to find out my test results. I thought, ‘I hope I get some good news, but it would be great for the film if I got bad news.’” It was bad news.
Now, at age forty-three, Chris is showing mild chorea and says he’s a little more forgetful and words are harder to retrieve. His documentary is almost entirely shot, and he’s holding annual fund-raisers to bankroll the production of the rest of it. He makes regular speaking appearances to educate people about Huntington’s. For the last nine years, he’s been working with mentally ill adults—mainly, schizophrenics—who live in something like an assisted-living home, only it is for people with mental illness. The residents can come and go as they please, but there are always caretakers like Chris around. Chris says that he would like to see the same model of care for people with Huntington’s disease.
Care of HD patients is a challenge that often falls on family members, until the burden becomes too much. One of the main reasons people with Huntington’s are put into nursing homes, according to some studies, is irritability.
Psychiatrists such as Karen Anderson say that they spend a lot of time educating the families of HD patients. “A lot of it is teaching people that this loved one or this patient who used to be a reasonable person five or ten years ago is not the same,” Anderson says. “You can’t reason things out anymore because that part of the brain is not working the way it should.”
Although the symptoms can’t be traced to exact circuits, general brain regions are implicated in regulating irritability. Psychiatrist Jon Silver points to the frontal lobes. “Data have shown that irritability and aggression are correlated with frontal lobe lesions,” Silver says.
Silver specializes in treating patients with traumatic brain injury (TBI). The most commonly injured parts of the brain are the frontal and temporal lobes (mostly due to car accidents and falls)—which means there is some overlap between the brain areas affected in TBI patients and Huntington’s patients.
Irritability in Huntington’s patients and TBI patients manifests in a similar way: a short fuse that ends in a giant explosion. This is how Silver describes it: “If you’re crossing the street in Manhattan, and a car comes close to you as a pedestrian, what do you do? What do you do to the driver or the car? You don’t scream at him, you don’t hit the car. Right? My patients do.”
Your frontal lobes are thought to be the brakes for your most basic wants. Think of the frontal lobes as the gatekeeper for your limbic system. The limbic system—which includes the hippocampus, the amygdala, the anterior thalamic nuclei, and the limbic cortex—is your primal urge center. Do you feel hungry? It’s your limbic system telling you. Do you want to have sex? It’s your limbic system knocking. The idea is that without your frontal lobes to regulate your desires, you’d simply do these things without worrying about the consequences.
When you have a disease that affects your frontal lobes, Silver says, “You can’t inhibit your responses and deal with the stressors as well as you can when your frontal lobes are working well. What we’re saying is that the frontal lobe is in charge of inhibiting the limbic system.” Although many areas of the brain can play a role in anger and aggression, Silver believes that the frontal lobes play perhaps the most important role in regulating irritability.
If true, this suggests that getting annoyed over minor provocations is an inhibition problem. In other words, we all have this capacity for extreme responses, but most of us have frontal lobes that tamp down the annoyed reaction. Mark Groves puts it simply: “Our frontal lobes help inhibit inappropriate responses or impulsive responses. And our patients who have damage to these circuits lose their ability to inhibit those behaviors.”
Irritability is one of the earliest symptoms of Huntington’s, according to a study conducted by David Craufurd.{44} He found that HD patients were irritable five to ten years before motor symptoms appeared. As the HD progresses and more of the brain dies, however, irritability is overcome by indifference. Groves says, “One symptom that you see in basal ganglia disease is apathy. The more damage, the more apathy in Parkinson’s and Huntington’s.” One interpretation is that the basal ganglia—which is primarily associated with motor function—also helps us decide between different actions. In any given moment
