The Frontal Cortex


There is wonderful, disturbing, and extremely graphic article in last week’s New Yorker (not online) about Lesch-Nyhan syndrome, a mysterious disorder characterized by excessive amounts of uric acid and a dangerous tendency to injure oneself. In its bleakest incarnation, Lesch-Nyhan turns victims into their own worst enemy, as their can’t help but chew off their lower lip, or bite of their own fingers, or curse at a loved one. (For Lesch-Nyhan patients, aggression and hateful speech are a sign of love.)

What biological mistake could cause such a tragic behavioral disorder? The problem results from a minor stretch of DNA (only 657 base pairs long), which codes for HPRT, an enzyme that helps recycle DNA inside cells. Nobody knows how this glitch leads to such self-destructive tendencies, but reduced levels of dopamine seem to be implicated. According to one study, Lesch-Nyhan brains contain eighty-percent less dopamine than normal brains in the basal ganglia.

But here’s what so odd: Parkinson’s patients also have drastically reduced dopamine levels in the basal ganglia, a result of the death of dopamine neurons. And yet, as Richard Preston notes, Lesch-Nyhan manifests itself as a very different set of symptoms:

In some ways, Lesch-Nyhan syndrome looks like Parkinson’s disease reversed. People with Parkinson’s have trouble starting physical actions, and are said to hypokinetic. Lesch-Nyhan people start actions too easily, and can’t stop an action once it starts; they are said to be hyperkinetic. Because Parkinson’s is also associated with a deficiency of dopamine in the basal ganglia, scientists have looked to each disease for clues to the other.

Diseases like Lesch-Nyhan are a bleak reminder of how much remains to be learned about the brain. We know so little, and understand even less.

Read the whole article. It’s another Richard Preston gem.


  1. #1 DavidD
    August 14, 2007

    HPRT is not an obscure enzyme. 30 years ago when I was a medical student I gave up some blood to a lab that was studying HPRT. They were looking at partial deficiencies of HPRT among young people with gout from overproduction of uric acid, which I had. My HPRT was fine, so if my leukocytes are still frozen in that lab, they’re labeled “control”. There aren’t that many of our 20,000 genes where I know for a fact mine are normal, like this one. Later this century, such knowledge will be much more common.

    Lesch-Nyhan is a disease where the X-linked recessive gene defect and the direct effects of that are very well understood. I’m not sure how the increased uric acid and other effects of that gene deficiency translate into decreased dopamine. I assume there’s some cellular toxicity from the altered metabolism that affects certain cells more than others.

    I don’t find it surprising that low dopamine in Lesch-Nyhan kids doesn’t make them look like patients with Parkinson’s. It’s not just a problem of dopamine in Lesch-Nyhan. It’s not just a problem of a single neurotransmitter in any disorder. It’s a problem of cells and the entire biology of the brain. Lesch-Nyhan kids have compulsions, as patients with Tourette’s or OCD do, but they’re different from those other sorts of compulsions. I understand some frustration about knowing the ultimate cause of the disease very well, yet not knowing how that turns into something as distinctive as self-mutilation vs. some other compulsion.

    Yet to me, that uncertainty isn’t discouraging, but a sign of order in the brain that we haven’t worked our way to understanding yet. Those 20,000 genes we will know everything about later this century won’t just tell us about genetic disease. It will also identify all the players in the biology of the brain. It is silly even now to expect single neurotransmitters to explain disease, without knowing what cells are doing with those neruotransmitters, but there are many more players in this game than we know even now, all of which are connected to some protein that makes them, which connects to some gene that makes the protein. The complexity of all that may drive some people to oversimplification now, but I don’t think it will be that way much longer. Both genetics and neuroscience will change a lot this century, and how they will change is just a matter of working through all our genes and what those genes affect. It’s just work, like I was sure my quantum mechanics final in college was when I first looked at it, not knowing how to solve any of the problems at first. The solutions just required applying what I know. Neuroscience today requires the same thing. It’s not a hopeless mystery. It’s just that a decade is not enough, maybe several decades.

    If in a hundred years, there are big parts of brain function that makes no sense, maybe then will be a time to rethink our ability to understand the brain. Today I am very hopeful about that.