Tuesday, August 17, 2010

Lesch-Nyhan Syndrome

Medical Meanderings 15 August 2007


“I take you where you want to go / I give you all you need to know / I drag you down, I use you up / Mr. Self-Destruct…” - Nine Inch Nails, “Self Destruction”

In 1964, a pediatrician named Dr. William Nyhan and his medical student assistant, Michael Lesch, published a report bearing the esoteric title: “A familial disorder of uric acid metabolism and central nervous system function.” In it, they described a horrifying disease affecting little boys that caused them, around 6 months of age, to move spastically, twitching and involuntarily jerking their limbs. Then, as the disease progressed, these little boys would develop self-mutilating behaviors. Their hands would fly to their mouths, where they would bite off parts of their fingers, all the while screaming for help, unable to stop. They would bang their heads into walls, stab themselves, burn themselves, unable to stop.

In earlier times, such horrifying behavior would have doubtlessly been attributed to demonic possession or witchcraft. But Lesch-Nyhan syndrome, as it is now known, is due to the buildup of a simple chemical in the areas of the brain that control movement, the basal ganglia. The culprit is uric acid, a byproduct of the metabolism of DNA in our diet. Uric acid is familiar to anyone with gout—it is this chemical that builds up and crystallizes in the joints, causing inflammation and pain.

When Drs. Nyhan and Lesch discovered the uric acid was the cause of the bizarre syndrome, they attempted to treat affected children with allopurinol, a medication used to lower uric acid levels in gout patients. However, this medication, and no medication so far, has been able to change the course of the disease. As it turned out, the high uric acid levels and the self-mutilating behavior are both symptoms of a separate underlying problem.

That problem is a misspelling. Patients with Lesch-Nyhan syndrome are born with one letter misplaced in one gene in their entire genetic program. That gene, which is carried on the X chromosome, codes for an enzyme, hypoxanthine-guanine phosphoribosyltransferase (HPRT). Since boys have only one X chromosome, while girls have two copies, this abnormal gene and thereby the disease, shows up predominantly in boys.

What does it mean that a single gene can cause a person to chew off his own fingers against his will? How can any of us believe in “free will” (whatever that means) if a random, simple DNA misspelling can make someone destroy his own life if left unrestrained? Lesch-Nyhan syndrome raises interesting questions, not just about the brain and our body’s complex chemistry, but also about our easy assumptions about our behaviors and choices. Do we control our brains, or do our brains control us? Does that question even mean anything?

Dr. Nyhan, now 81 years old, still works with patients affected with the disease at the University of California – San Diego. His younger colleague, Dr. Lesch, is now Chairman of the Department of Medicine at New York’s St. Luke’s-Roosevelt Hospital. The disease named for them is fortunately rare, affecting only a few dozen people worldwide. But the questions about human nature it raises affect us all.

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