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.

Hypertension and Heart Failure

I was sitting around the other day, just waiting to bite down into my deep-fried, salt-laden, double bacon cheeseburger sub sandwich, when a little medical school angel appeared on my shoulder and chirped, "wait Andy, what about your blood pressure? It's going to skyrocket!!"

Of course, at this point the little devil on my other shoulder retorted, "blood pressure? So what? Everyone has high blood pressure. What's the worst that this delicious bite of instant gratification could do?"

Luckily, it was cardiology section and the little medical school angel knew just how to answer such a health dilemma. We have all heard of the dangers of high blood pressure, and yet far too many of us carry the diagnosis; in 2003 there were more than 35 million doctor's visits for hypertension. I find that in order for me to want to change a behavior, such as the food that tastes so good but that I vaguely know is bad for me, I have to know why. Why is it so important that I keep my blood pressure normal?

First, let's look at circulation. I think that the circulation is most easily envisioned as a big loop, with a pump, the heart, propelling blood through progressively smaller tubes, arteries and arterioles. These eventually narrow into capillaries to distribute oxygen and nutrients and then expand again as veins to carry away waste and return to the lungs for more air. The tubes have a certain amount of resistance, especially as they get narrower, and hypertension occurs when the relationship between the output from the heart and the total peripheral resistance is altered. High blood pressure can injure many organs when the pressurized blood damages the vessels, including those of the retina (which may result in vision damage), the kidneys, and the brain (which may cause stroke). As we are in cardiology, however, I am worried now about the damage that hypertension inflicts on the heart.

The heart is a fairly simple pump. Blood flows into the right atrium, is contracted into the right ventricle, then sent into the pulmonary, or lung, circulation where it becomes oxygenated. It returns from there and enters the left atrium, is "kicked" into the left ventricle, and this, the strongest chamber of the heart, contracts to send fresh blood to the body. The principle behind this directional flow is that pressure must always decrease from one chamber to the next. Thus, pressure in the atrium is lower than in the veins, and pressure in the ventricle, when it is relaxed, is lower or equal to pressure of the atrium. When the ventricles contract, they increase the blood pressure so that it can perfuse the body, return to the heart, and the cycle begins again. When the heart contracts, this is called systole and the pressure produced is your systolic blood pressure. When it relaxes, this is diastole, and the pressure that remains in the vessels is diastolic blood pressure. This is higher in the vessel than in the heart because there is a valve that closes after the heart contracts. This means that the heart can relax and refill, while the vessels remain pressurized and able to go forward.

For such a simple pump, many things can go wrong. If the left ventricle is trying to pump against high blood pressure, as in hypertension, the ventricle will have to work harder to expel its blood. Recall that blood must go from high pressure to low; the ventricle has to work harder to overcome the high pressure in the aorta. Just like any other muscle, the heart will "get jacked" and you see hypertrophy, or increased size, of the ventricle. This bulking up means that less blood can get into the ventricle chamber, and so you might begin to experience heart failure. The problem is that since the circulation is a big loop, blocking one step results in backing up all the others. So, less blood pumped through the ventricle means blood, and pressure, builds up in the atrium, which then backs up in the lungs. This can result in congestive heart failure, where fluid can actually build up in the small alveoli of the lungs because of the pressure forcing it out of the small, weak capillaries. Pressure can continue back, so that you may get the right side of the heart involved, and even the venous return. So it is that the failure of your left heart to pump past the high blood pressure in your aorta can result in pulmonary edema (swelling with fluid) and right heart failure.

So, when my little medical school angel on my shoulder is confronted with a deep-fried, salt-laden, double bacon cheeseburger sub sandwich, it can fight back, knowing that since the circulation is one big loop, pumping up the pressure in one part will cause the rest of it to try and compensate. Heart failure (and maybe more) just isn't so appetizing.

P.S. Here is a very fun story of hypertension presenting as a medical mystery, from the New York Times.

Big Hearts