Thursday, September 13, 2007

One Gene, Curious Outcomes: Lesch-Nyhan Syndrome



Voyeurism is something that one might relate more to art than to medicine. As I learned in my art history course, many artists employ voyeuristic techniques that give the viewer an intimate view of the subject, and thus makes him an observer of distressing, sordid, or scandalous events. In fact, this has many parallels to my entrance into medicine. For instance, during a medical interview, I am privy to information that many would hesitate to otherwise share. Of course, it is medically relevant and important for a proper treatment outcome, but at times of reflection I realize how unique a doctor's role can be. Another aspect of the physician as voyeur, for me, lies in the unique and at times bizzare diseases that we learn about in medical school. In fact, I have a short list of favorite bizzare diseases, which I think are fascinating examples of how the human body is an incredibly intricate machine. One such favorite disease is a congenital enzyme deficiency called Lesch-Nyhan Syndrome. Imagine my surprise, then, when this obscure disorder was the topic of a column by Richard Preston in the New Yorker, titled The Possessed.

Lesch-Nyhan Syndrome is a rare disorder, affecting only one in every 380,000 people worldwide. The disorder is recessive, linked to the X chromosome. Since males only have one X chromosome, it is more likely that they will express the deficiency since they do not have another good copy of the gene, so only rarely has it been reported in females. The gene in question codes an enzyme called hypoxanthine-guanine phosphoribosyl transferase, or HGPRT. It is a lengthy name, but the function of this enzyme is relatively simple. As you may recall, your DNA is made up of little elements called nucleotides; these are divided into two classes, pyrimidines and purines. Normally, purines are recycled in the cell to make new nucleotides for DNA and other functions; this is done by HGPRT. If you lack this enzyme, you have to make new purines from scratch constantly. This means you also need to get rid of the old purines, that you no longer recycle. That process involves breaking them down into uric acid.

Some of the initial symptoms of the disease come form this uric acid accumulation. Babies will often have orange crystals in their diapers, from the crystallization of uric acid in the urine. This is often described as "orange sand." Patients may also present with a variety of neurological disorders. Cognitive function is impaired, with an average IQ of 60 and behavioral disorders. Additionally, there is often spasticity, and these patients display extrapyrimidal dysfunction, which means that the part of the brain which normally coordinates movement (as well as some emotional and impulse control) is not working: it doesn't have enough of the neurotransmitter, dopamine. The part which I find fascinating, however, is that patients with Lesch-Nyhan Syndrome somehow all develop self-mutilating behavior. Little children often present with stubby fingers and chewed up lips, which they have done to themselves in a compulsive manner. What's more, as Preston's description from the above article so vividly describes, the patient seems to be terrified of his hands while at the same time compelled to self-cannibalize them. Those that survive to adulthood (rarely do patients live beyond one or two decades) often have themselves physically restrained, to avoid this bizzare compulsion to "self-sabotage," manifested in these physical as well as strange behavioral acts, such as eating food a patient hates or acting cruelly towards people he loves.

Standard treatment is unfortunately limited to the symptoms of the disease, such as lowering the uric acid content, and most patients succumb to renal failure. However, recently, there has been some very interesting experimental work done with deep brain stimulation, which implants a "pacemaker" for the brain into the dysfunctional basal ganglia. Patients have seen a reduction in their spastic or dystonic movements as well as loss of the self-mutilating behavior. I think this is a fascinating example of how a little enzymatic defect in one gene can manifest as a child who is actually compelled to gnaw at themselves. Perhaps there is a large voyeuristic aspect to the treatment of disease, but this may serve as a reminder of how human physiology is a vast, complicated puzzle.

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Here is a link to more information about the genetics of Lesch Nyhan Syndrome that was prepared by our genetic counselor and which has links to some useful resource for those dealing with this condition: http://www.accessdna.com/condition/Lesch_Nyhan_Syndrome/225. There is also a number listed for anyone who wants to speak to a genetic counselor by phone. I hope it helps. Thanks, AccessDNA

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