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Saturday, Nov. 1, 2008 | Dr. William Nyhan’s young patients have slugged him, kicked him and thrown his eyeglasses across the room. But they mean him no harm: Defective genes rob them of control over their bodies, causing them to chew on themselves and hurt others.
Nyhan, a longtime pediatrician at the University of California, San Diego, has spent more than four decades trying to unravel the mysteries of metabolic conditions like this one, known as Lesch-Nyhan syndrome in honor of him and a colleague.
While Nyhan has managed to find a cure for one rare metabolic disesae and treatments for others, Lesch-Nyhan syndrome remains largely untreatable, dooming many of its victims to short and difficult lives. No one can explain how a genetic malfunction makes kids involuntarily turn violent.
But Nyhan hasn’t given up. At the age of 82, Nyhan continues to work full time and treat children from across Southern California with a variety of metabolic diseases.
In an interview at his La Jolla home, Nyhan talked about his research and his 53-year career as a pediatrician.
How did you discover the condition that came to be known as Lesch-Nyhan syndrome?
A boy about 6 years old came to the (Johns Hopkins University) emergency room, and he was admitted because those guys thought he had a disorder that produces kidney stones. My first contact was when the resident asked me to analyze the amino acid from his urine.
I started the analysis, and (medical student) Mike Lesch and I went down and saw the kid. He had bandages on his hands that were so fully wrapped that they looked like boxing gloves, and there was a loss of tissue in his lip.
We unwrapped his hands, and his hand went immediately to his mouth, but I grabbed it before he could chew on it.
The children with the condition will chew on their lips and hands and cause severe damage, but their actions are involuntary, correct?
They don’t want to injure themselves. If they succeed in biting themselves, they cry. I think they’re driven to do it by something bigger than they are.
Have the patients hurt you?
I’ve been hit, kicked, had my eyeglasses thrown on the floor.
If they succeed in hurting you or doing something bad to you, they’ll be as remorseful as they are if they do it to themselves.
What are some of the other symptoms of Lesch-Nyhan syndrome in children?
They get an extreme degree of developmental delay. None of these kids has ever walked, and they can’t even sit without support. And then they have this neurological disease which gives them a variety of involuntary movements.
At the same time, it’s maddening because their cognitive development isn’t nearly so bad, and some are cognitively normal.
Despite having all these problems, the kids who have this disease — they’re almost all boys — tend to be quite cheerful.
They almost have two sides to their personality. They’re often very engaging kids and fun to be with, have a good sense of humor. And yet they’re driven to do these awful things to themselves and to others if they can get away with it.
What happens in the brains of these kids?
Back in those days, we thought it was going to be easy (to figure out), but it turned out not to be. We still don’t know what’s going on.
It’s maddening because some, of course, have died. Their brains have been studied and they look absolutely normal.
Is it possible for these children to live very long?
Until we developed the treatment we have now, they all developed early-stage kidney disease, sometimes as early as their first birthday but almost always by the tenth year. [The condition causes an increase in the production of uric acid, which can lead to kidney problems.]
Now, we have some who are in their 40s.
Do you think we’re near a cure for Lesch-Nyhan syndrome?
I don’t have any immediate hopes, but we’re doing some negotiations with a pharmaceutical company to see if we can develop a drug treatment that has some promise.
Besides its bizarre symptoms, what makes this condition unique?
When we first saw those kids, I thought “Wow, we’ve got a biochemical explanation for behavior.” Behavior has always been a mystery to man. To have a clue that in some way a distinct chemical can cause a recognizable pattern of behavior, that’s a big deal.
Why is it unusual to have that kind of link?
It’s never turned up before. That’s probably the reason this disease has caught the imagination of so many people.
Don’t people today think brain chemistry is related to things like depression?
They think that, but they don’t have the chemical explanation in hand. People talk about abnormal chemistry and schizophrenia or manic depression, but the evidence isn’t there.
How many kids come down with metabolic disease? (Metabolic diseases are caused by mutated genes and affect enzymes in the body.)
Most inherited metabolic diseases are rare, but not always. PKU is a common metabolic disease and occurs in one in every 10,000 births. That was the disease that started the world taking the drop of a blood (for diagnosis purposes) from a newborn’s heels before he gets out of the hospital.
What happens when a child gets a metabolic disease?
It depends on the gene and the enzyme it affects.
The spectrum is enormous. Some diseases can be lethal within the first weeks of life if they’re not diagnosed and vigorously treated.
How far have we come in treating these disease?
It seems to me that we’re getting better and better at pinpointing the area of metabolism that is abnormal and finding the enzyme that’s defective, and more and more now we’re finding mutations in the gene.
What has been slower is finding keys that would permit treatment. There’s been a lot of real advances, and we’re even able now to treat some diseases by infusing the enzyme that’s defective. But maybe 15 years ago I would have thought that by now there would be ways to treat the gene.
You mean manipulating the gene that causes the disease?
Or taking someone with a defective gene and somehow inserting a normal gene. That would fix them. We can do this in test tubes, but not in living people or animals. That’s one of the real challenges.
You’ve been a pediatrician since 1955 and were the founding chair of the UCSD Department of Pediatrics. How has being a pediatrician changed over the years?
Dealing with kids has changed enormously over the years, even in the time since I’ve been in San Diego (since 1969). The whole spectrum of what kids get sick from has changed.
(In the past), all our hospitals were full of kids with meningitis, some of whom died of it, and some of whom became neurologically impaired because of it. And those things have almost disappeared because of immunization.
I think of kids desperately sick of complications from chicken pox. Now, (thanks to a vaccine), nobody gets it.
The other big thing is that happened in all of our lives is the newborn screening. It’s been with us for many years now for PKU, but until two years ago in California that drop of blood only permitted us to diagnose two different metabolic diseases.
Now, the advent of tandem mass spectrometry permits us to diagnose 30 different metabolic diseases with the same drop of blood. Virtually all of them are treatable.
Is that used in all hospitals?
It’s the law in California, and it’s spreading throughout the U.S.
What are you future plans? Do you plan to keep working?
Sure. I’m 82 years old, and I’m still working full time. This is what I do.