Panic in Level 4: Cannibals, Killer Viruses, and Other Journeys to the Edge of Science (29 page)

H. A. J
INNAH
, a neurologist at Johns Hopkins Hospital, has been studying Lesch-Nyhan syndrome for more than fifteen years. “This is a very horrible disease, and a very complex brain problem,” he said to me one day in his office. “It is also one of the best models we have for trying to trace the action of one gene on complex human behavior.”

A child born with Lesch-Nyhan syndrome seems normal at first, but by the age of three months has become a so-called floppy baby, and can’t hold up his head or sit up. His diapers may have orange sand in them, and his body begins a pattern of writhing. When the boy cuts his first teeth, he starts using them to bite himself, especially at night, and he screams in terror and pain during these bouts of self-mutilation. “I get calls in the middle of the night from parents, saying, ‘My kid’s chewing himself to bits, what do I do?’” Nyhan said. The boy ends up in a wheelchair, because he can’t learn to walk. As he grows older, his self-injurious behaviors become subtle and more elaborate, more devious. He seems to be possessed by a demon that forever seeks new ways to hurt him. He spits, strikes, and curses at people he likes the most—one way to tell if a Lesch-Nyhan patient doesn’t care for you is if he’s being very nice. (He wishes you would go away, so the Lesch-Nyhan part of him tries to keep you near him.) He eats foods he can’t stand; he vomits on himself; he says yes when he means no. This is self-sabotage.

A few hundred boys and men alive in the United States today have been diagnosed as having Lesch-Nyhan syndrome. “I think I know most of them,” Nyhan said. A boy known as J.J. whom Nyhan found in a state institution, where he’d been considered spastic and mentally retarded, ended up living in Nyhan’s research unit for a year. He was a lively, gregarious child whose hands seemed to hate him with a demonic precision. Over time, his fingers had gotten into his mouth and nose, and had broken out and removed the bones of his upper palate and parts of his sinuses, leaving a cavern in his face. He had also bitten off several fingers. J.J. seemed happy most of the time, except when he was injuring himself.

J.J. died in his late teens; in the past many Lesch-Nyhan patients died in childhood or their teens, often from kidney failure. (Both Morlen brothers died young.) Nowadays they may live into their thirties and forties, but they often die from infections like pneumonia. Occasionally, a man with the disease flings his head backward with such force that his neck is broken, and he dies almost instantly.

A Lesch-Nyhan person may be fine for hours or days, until suddenly his hands jump into his mouth with the suddeness of a cobra strike, and he cries for help. People with Lesch-Nyhan feel pain as acutely as anyone else does, and they are horrified by the idea of their fingers or lips being severed. They feel as if their hands and mouths don’t belong to them, and are under the control of something else. Some Lesch-Nyhan people have bitten off their tongues, and some have a record of self-enucleation—they have pulled out an eyeball or stabbed their eye with a sharp object such as a knife or a needle. (The eye is a soft target for the hand of a Lesch-Nyhan person.) When the Lesch-Nyhan demon is dozing, they enjoy being around people, they like being at the center of attention, and they make friends easily. “They really are great people, and I think that’s part of the disease, too,” Nyhan said. Some Lesch-Nyhan people are cognitively impaired and others are clearly bright, but their intelligence can’t be measured easily. “How do you measure someone’s intelligence if, when you put a book in front of him, he has an irresistable urge to tear out the pages?” Nyhan said.

J.J., one of the earliest Lesch-Nyhan patients diagnosed by William L.
Nyhan. His fingers pulled out the bones of his upper palate and sinuses, while his teeth removed several fingers. The bumps at the top of his ear were caused by gout; they are deposits of uric acid crystals known as tophi. J.J. was an outgoing child, very popular with his caregivers. He may be smiling in this picture, and he seems to have closed his eyes in anticipation of the camera flash.
William L. Nyhan

I
N
1967, J. E
DWIN
S
EEGMILLER
, a scientist at the National Institutes of Health, and two colleagues discovered that in Lesch-Nyhan patients a protein called hypoxanthine-guanine phosphoribosyl transferase, or HPRT, which is present in all normal cells, doesn’t seem to work. The enzyme is especially concentrated in deep areas of the brain, around the brain stem. The job of this enzyme is to help recycle DNA. Cells are constantly breaking DNA down into its four basic building blocks (represented by the letters A, T, C, and G, for adenine, thymine, cytosine, and guanine). This process produces compounds called purines, which can be used to form new code. When HPRT is absent or doesn’t work, purines build up in a person’s cells, where they are eventually broken down into uric acid, which saturates the blood and crystallizes in the urine.

In the early 1980s, two groups of researchers, one led by Douglas J. Jolly and Theodore Friedmann, decoded the sequence of letters in the human gene that contains the instructions for making HPRT. It includes 657 letters that code for the protein. Researchers also began sequencing this gene in people who had Lesch-Nyhan. Each had a mutation in the gene, but, remarkably, nearly everyone had a different one; there was no single mutation that caused Lesch-Nyhan. The mutations had apparently appeared spontaneously in each affected family. And in the majority of cases, the defect consisted of just one misspelling in the code. For example, an American boy known as D.G. had a single G replaced by an A—one out of over three billion letters of code in the human genome. As a result, he was tearing himself apart.

The HPRT gene is found on the X chromosome, which is the female sex chromosome and carries information that makes the person female. Women have two X chromosomes in each cell, and men have an XY pair. Lesch-Nyhan is an X-linked recessive disorder. This means that if a bad HPRT gene on one X chromosome is paired with a normal gene on the other X chromosome, the disease will not develop. A woman who has the Lesch-Nyhan mutation but carries it on only one of her X chromosomes doesn’t develop the syndrome. Any son she has, however, will have a 50 percent chance of inheriting the syndrome (if he gets the bad X chromosome, he will have the disease; if he gets the good one, he won’t), and any daughter will have a 50 percent chance of being a carrier. (Examples of this type of X-linked recessive disease include hemophilia and a form of red-green color blindness. Queen Victoria was a carrier of the hemophilia gene, but she didn’t have hemophilia. Some of her male descendents had it.)

Other genetic mutations have been associated with profound behavioral changes. Rett syndrome, which affects mostly girls, is caused by a mutation in a gene that codes for the MeCP2 protein. People with the syndrome compulsively wring their hands and rub them together as if they were washing them. Children with Williams syndrome have an elfin appearance, an affinity for music and language, an extreme sensitivity for sound, and are very sociable. Williams syndrome is caused by a deletion of a bit of code from chromosome 7.

There is still great uncertainty about how much of a role genes play in major, common conditions such as depression or bipolar disorder. One wonders where obsessive-compulsive disorders come from, or such behaviors as compulsive hand-washing, compulsive neatness. Do some people suffer from OCDs that are caused by misspellings in their code? What about borderline personality disorder? How many mental illnesses are the result of errors in the code or certain combinations of errors? No one knows. It seems quite evident that a lot of human behavior is affected or governed by the blueprint of a person’s DNA. Even where there is evidence of a family history of disease, scientists are unsure how a single gene could choreograph a suite of behaviors. There are roughly twenty-five thousand active genes in the human genome, each with about a thousand to fifteen hundred letters of code. The human genome could be thought of as a kind of piano with twenty-five thousand keys. In some cases, a few keys may be out of tune, which can cause the music to sound wrong. In other cases, if one key goes dead the music turns into a cacophony or the whole piano self-destructs.

The havoc that the Lesch-Nyhan mutation causes cannot easily be undone. Early on, Nyhan tried giving his Lesch-Nyhan patients allopurinol, a drug that inhibits the production of uric acid. The drug is effective with gout. It lowered the concentration of uric acid in Lesch-Nyhan patients, but it didn’t reduce their self-injurious actions. The uric acid, it seemed, was another symptom, not a cause of the behavior.

Nyhan experimented with simple treatments, such as soft restraints, which seemed to relax patients and made them feel safer from themselves. Matthew Morlen had frequently asked to be tied into his stringlyjack. Nyhan also began recommending that Lesch-Nyhan children have their upper teeth removed, so that they couldn’t bite off their lips and tongues as easily. “I’m profligate with those upper teeth,” he said. This led to arguments with dentists. Some dentists would refuse to extract healthy teeth, even when the Lesch-Nyhan syndrome was explained to them.

I was visiting Nyhan in his office, and there was a lull in the conversation. He sat back in his chair and looked at me. I couldn’t tell what he was thinking. Outside the window, the hawks were still riding thermals over the canyon. We had come to the end of knowledge about Lesch-Nyhan. The disease remained as mysterious and frightening as it had seemed on the day when Nyhan and Lesch had first seen it, nearly forty years earlier. But I had never seen it. “I can’t imagine what it’s like to have Lesch-Nyhan,” I finally said to him.

“You could ask someone who has it,” he replied.

I
MET
J
AMES
E
LROD
and Jim Murphy one winter day not long afterward. They were living next to each other in rented bungalows in a somewhat marginal neighborhood in Santa Cruz, California. James Elrod was then in his early forties, and Jim Murphy was just over thirty. They were close friends, except when their Lesch-Nyhan symptoms annoyed each other. (Murphy died in 2004; Elrod, who is fifty as I write this, became one of the oldest living people with Lesch-Nyhan.) The men were clients of Mainstream Support, a private company contracted by the state of California to help people with developmental disabilities live in community settings. Before he came to to Santa Cruz, James Elrod lived for eighteen years in a state institution in San Jose called the Agnews Developmental Center. Jim Murphy had spent all of his adult life in a California state institution in Sonoma. Mainstream employees, called direct-care staff, stayed with Elrod and Murphy around the clock, to help them with daily tasks and to make sure they didn’t harm themselves. Elrod and Murphy had the authority to hire and fire their assistants and direct their work, though an assistant could refuse an order if he thought it would put the client in danger.

At the time, Mainstream was run by two business partners, Andy Pereira and Steve Glenn. “James and Jimmy are real down and gritty guys,” Pereira said. “They are not sweet types. They’re into fast cars and women.” Steve Glenn confessed that he still had difficulty seeing into the labyrinth of Lesch-Nyhan. “There are these Lesch-Nyhan moments when you feel like you’ve kind of got it,” he said. “James and Jimmy are pretty good at telling you when they think they’re in danger of hurting themselves, but whenever they’re doing something, you always have to ask, Is this James or Jimmy, or is it Lesch-Nyhan?”

James Elrod had a square, good-looking face, which was marked with scars, and he had brown, hyperalert eyes. His shoulders and arms were large and powerful, but the rest of his body seemed slightly diminished. One day at the Agnews Developmental Center, before he was with Mainstream, an attendant left him alone at a dining table for a few minutes. To his horror, his left hand picked up a fork and used it to stab his nose and gouge it out, removing most of his nose and permanently mutilating his face. “My left side is my devil side,” he told me. When I met him, he wore black leather motorcycle gloves that had been reinforced with Kevlar. If he thought his left hand was threatening him or someone else, he would grab it or swat it with his right hand. He owned a pickup truck, and his assistants drove him around in it. He had a job working at a recycling facility. He also used to sell flowers on the Santa Cruz pier. He carried business cards explaining that he had a rare disease that compelled him to hurt himself. “I have injured myself in many ways including my nose, as you can see,” the card said. “I will even try to hurt myself by getting into trouble with others.” One day, a man bought some flowers from Elrod and said, “God bless you.” “Eat shit,” Elrod replied, and handed the man his business card. While crossing a street in his wheelchair, Elrod had been known to suddenly roll himself straight into oncoming traffic, yelling, “Slow down, you morons! Don’t you know it’s Lesch-Nyhan?” His assistants wrestled him to safety.