San Diego School of Medicine. “I love working with kids, but dealing with pediatric cancer was depressing, saddening, and, in truth, maddening,” he said. Nyhan ran some tests on Matthew’s urine, using the equipment he had designed. The crystals weren’t cystine or any sort of amino acid. They proved to be uric acid.
A high concentration of uric acid in a person’s blood can lead to gout, a painful disease in which crystals of uric acid grow in the joints and extremities, particularly in the big toe. Gout has been known since the time of Hippocrates, when ancient doctors recognized that it occurs mainly in older men. Yet the patient here was a little boy. Nyhan had a medical student named Michael Lesch working in his lab, and together they went downstairs to have a look at the boy with “gout.”
Matthew lay in a bed in an open ward on the second floor of the Harriet Lane Home. The ward was filled with beds, and most of them were occupied by sick children. Matthew was a spot of energy in the ward, a bright-eyed child with a body that seemed out of control. The staff had tied his arms and legs to the bed frame with strips of gauze, to keep him from thrashing, and they had wrapped his hands in many layers of gauze. They looked like white clubs. Nurses hovered around the boy. “He knew I was a doctor and he knew where he was. He was alert,” Nyhan recalled. Matthew greeted Nyhan and Lesch in a friendly way, but his speech was almost unintelligible: he had dysarthria, an inability to control the muscles that make speech. They noticed scarring and fresh cuts around his mouth.
They inspected Matthew’s feet. No sign of gout. Then the boy’s arms and legs were freed, and Lesch and Nyhan saw a complex pattern of stiff and involuntary movements, a condition called dystonia. Nyhan had the gauze unwrapped from the boy’s hands.
Matthew looked frightened. He asked Nyhan to stop, and then he began crying. When the last layer was removed, they saw that the tips of several of the boy’s fingers were missing. Matthew started screaming, and thrust his hands toward his mouth. With a sense of shock, Nyhan realized that the boy had bitten off parts of his fingers. He also seemed to have bitten off parts of his lips.
“The kid really blew my mind,” Nyhan said. “The minute I saw him, I knew that this was a syndrome, and that somehow all of these things we were seeing were related.”
Lesch and Nyhan began to make regular visits to the ward. Sometimes Matthew would reach out and snatch Nyhan’s eyeglasses and throw them across the room. He had a powerful throw, apparently perfectly controlled, and it seemed malicious. “Sorry! I’m sorry!” Matthew would call, as Nyhan went to fetch his glasses.
The doctors persuaded Deborah Morlen to bring her older son to the hospital. Harold, it turned out, had bitten his fingers even more severely than Matthew and had chewed off his lower lip down into his chin, at the limit of the reach of his upper teeth. Both boys were terrified of their hands and screamed for help even as they bit them. The Morlen brothers, the doctors found, had several times more uric acid in their blood than normal children do.
Nyhan and Lesch visited the Morlen home, a row house in a working-class neighborhood in East Baltimore, where Matthew had been living with his mother and grandmother. “He was a well-accepted member of his little household, and they were very casual about his condition,” Nyhan said. The women had devised a contraption to keep him from biting his hands, a padded broomstick that they placed across his shoulders, and they tied his arms to it like a scarecrow. The family called it “the stringlyjack.” Matthew often asked to wear it.
Nyhan and Lesch also discovered that they liked the Morlen brothers. Lesch, who became the chairman of the department of medicine at St. Luke’s–Roosevelt Hospital, in New York City, said, “Michael and Harold were really engaging kids. I really enjoyed being around them. I got beat up once by Matthew.” He had leaned over the boy and asked him how he was feeling, and Matthew had slugged him in the nose. Lesch had staggered backward holding his nose while Matthew said, “Sorry! I’m sorry!”
TWO YEARS AFTER meeting Matthew Morlen, Nyhan and Lesch published the first paper describing the disease, which came to be called the Lesch-Nyhan syndrome. Almost immediately, doctors began sending patients they suspected of having the disease to Nyhan. Very few doctors had ever seen a person with Lesch-Nyhan syndrome, and boys with the disease were, and are, frequently misdiagnosed as having cerebral palsy. (Girls virtually never get it.) Nyhan himself found a number of Lesch-Nyhan boys while visiting state institutions for developmentally disabled people. When I asked him how long it took him to diagnose a case, he said, “Seconds.” He went on, “You walk into a big room, and you’re looking at a sea of blank faces. All of a sudden you notice this kid staring at you. He’s highly aware of you. He relates readily to strangers. He’s usually off in a corner, where he’s the pet of the nurses. And you see the injuries around his lips.”
WILLIAM NYHAN was eighty-one, a tall, fit-looking man with sandy-gray hair and blue eyes. He ran marathons until he was about seventy, half marathons after that; he was now the top-seeded tennis champion in his age class in southern California. He had a laboratory overlooking a wild canyon near the U.C. San Diego Medical Center. One day when I visited him, the Santa Ana wind was blowing in from the desert, and the air had an edgy feel. Two red-tailed hawks were soaring over the canyon, tracing circles in the air. The distinct movements of the hawks revealed a pattern of flight engraved in the birds’ genetic code.
In the years since he had identified Lesch-Nyhan, William Nyhan had discovered or codiscovered a number of other inherited metabolic diseases, and he had developed effective treatments for some of them. He had figured out how to essentially cure a rare genetic disorder called multiple carboxylase deficiency, which could kill babies within hours of birth, by administering small doses of biotin, a B vitamin. Lesch-Nyhan, however, had proved to be more intractable.
Decades after the discovery of Lesch-Nyhan syndrome, it is still mysterious. It is perhaps the clearest example of a change in the human DNA that leads to a striking, comprehensive change in behavior. In 1971, William Nyhan coined the term “behavioral phenotype” to describe the nature of diseases like Lesch-Nyhan syndrome. A phenotype is an outward trait, or a collection of outward traits, that arises from a gene or genes—for example, brown eyes. Someone who has a behavioral phenotype shows a pattern of characteristic actions that can be linked to the genetic code. Lesch-Nyhan syndrome seems to be a window onto the deepest parts of the human mind, offering glimpses of the genetic code operating on thought and personality.
H. A. JINNAH, 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
