For better or for worse, who we are has always been rooted in what our parents gave us, both genetically and psychologically. Inevitably, we pass along to our own kids more of the bad than we might choose. Yet the exact nature of what we pass on has been apparent mostly on the surface of things: dad's hair, grandma's eyes. What the gene revolution has quickly done is start making explicit the inventory of flaws that we inherit and pass on. New knowledge about our genes is coming so quickly that we sometimes don't know how to deal with it. Sometimes, even medical regulators can't keep up.
Wes Lange, of Turlock, Calif., and his son got swept up in that revolution recently when UCSF researchers discovered that both carry a gene that can lead to sudden death from a heart attack. They are living a future that all of us may experience someday soon, when our fatal flaws are diagnosed, and perhaps treated, due to advanced genetic technologies being developed now.
Lange got an introduction to the future of medicine last year, as he was driving home from Sacramento. He began to feel flushed and nauseated as he drove and felt that he was about to pass out. Lange managed to navigate his car safely to the roadside and call 911. The paramedics who responded could barely find a pulse.
Ultimately, he ended up at UCSF Medical Center, where cardiologists told Lange that he had a dangerous thickening of the heart muscle that should be treated right away. As he prepared for treatment, Lange received a much worse blow. His 3-year-old son's pediatrician thought he heard something strange in the boy's heart. The pediatrician referred Garrett to a pediatric cardiologist at a UCSF outreach clinic in Modesto, who found a slight thickening of the heart muscle. The cardiologist told Lange about genetic research being conducted at UCSF on mutations that affect heart muscle.
Lange and his son went to see UCSF researcher Dr. Amy Sehnert, a pediatric cardiologist who has done a great deal of research on genetic mutations that cause heart disease. Two years ago, she identified a mutation in a common heart gene in zebrafish, which led to an important discovery about how contractile proteins function normally in beating hearts. Sehnert took blood samples from father and son and then subjected the samples to an advanced genetic analysis. She found that both of them tested positive for a genetic defect known to cause heart problems and sudden death.
Lange, who has known he had some heart abnormalities since he was young, doesn't feel that his own condition is a terrible curse. "But the idea that I had passed this along to my son, that I was responsible for his condition, that was tough," Lange says.
Hypertrophic cardiomyopathy (HCM) afflicts one in 500 people and is the most common cause of sudden death in otherwise healthy people. In a normal heart, the two ventricles, the power-stroke chambers of the heart, are separated by a thin wall of muscle called the septum. Normally, we think of building muscle mass as a healthy thing. Athletes commonly have thicker, stronger muscles in the heart as well as other parts of the body.
But this is not always good. When the muscles in the septum grow too much (hyper means over, and trophic means growth), it causes various problems for the heart. For one thing, the thickened septum makes the chamber in the ventricle smaller, shrinking the volume of blood that can be pumped with each heartbeat. Worse, the muscle often grows so much that it impinges on the valves, ruining valve function or blocking the flow of blood. Many people may not have any symptoms, but if they do, they might feel irregular heart beats, experience shortness of breath, have chest pain or feel faint.
Another side effect of the gene mutation is that the muscle cells in the heart don't grow neatly aligned in the same direction, as they should. Instead, they grow in a disorganized fashion, so that when the muscle cell contracts they pull against each other, making the heart pump inefficiently. This disorganization is also believed to disrupt electrical conduction in the heart, leading to dangerous heart rhythm disorders,(arrhythmias). At any time, Wes' heart might start beating so hard that it ceases pumping effectively, burns out its own oxygen supply and goes into cardiac arrest.
Almost 15 years ago, researchers discovered that HCM could be caused by a mutation in a gene that makes a protein called cardiac beta myosin heavy chain. This protein is part of the coglike machinery that pulls interlocking filaments together to make muscle cells contract. Since that time, scientists have discovered over 250 different mutations in 13 specific genes that can cause the muscle thickening and disorganization found in HCM. Together, these genes are thought to account for at least half of all cases of the disease, which runs in families and can be passed along from one generation to the next. Heart muscle thickening can also be caused by more common conditions such as obesity, high blood pressure or thick heart valves.
"What we've found is that some of the mutations in the genetic form of the disease are likely to cause cardiomyopathy at an early age, while others tend to cause it much later in life," Sehnert says. "Some mutations make cardiomyopathy show up in the 60s or 70s, when physicians might think it is secondary to other health and aging issues and not recognize it as a genetic problem. Others show up in newborns or very young children."
Sehnert discovered that Wes Lange had a mutation in the beta myosin heavy chain gene, the first of the 13 genes already found to be associated with HCM. But this discovery had a catch to it. In a sign of how fast basic research is moving into the clinic, Lange's surgeons, cardiologists Dr. Thomas Ports and Dr. Jeffrey Olgin, couldn't directly use the genetic information in deciding on a course of treatment. The test that Sehnert did was still classified as research, she explains, and no diagnostic laboratories have yet been certified to report these gene mutations in a clinical setting. "By law, we are forbidden from letting our knowledge of the genetic test affect our clinical decision making," Olgin says.
As it happened, even without letting the genetic results enter into the clinical evaluation, Lange had many of the hallmarks that made him a good candidate to receive an implanted cardiac defibrillator. This device senses when the heart goes into ventricular fibrillation, the most common cause of cardiac arrest. When the heart is beating normally, the muscle cells work together to make the heart clench rhythmically, like the hands of a dairyman milking a cow. During fibrillation, however, the heart muscle cells fire independently, making the heart quiver like a bag of worms. Ports and Olgin decided that the best option would be to implant a defibrillator, which would sense when Lange's heart was going into cardiac arrest and shock it back into the right rhythm.
"It used to be that we would only implant a defibrillator if the patient had already had one heart attack," Ports explains. "Of course, they had to survive that first one." Ports and Olgin decided that Lange qualified for the implanted defibrillator partly based on information gleaned from a large, multi-center trial in which UCSF participated. That trial demonstrated that if patients met certain other criteria, like having a low volume of blood pumping through the heart, patients could benefit from an implant-able defibrillator even before the first heart attack.
Lange's son, meanwhile, will be watched yearly as he grows older and may benefit from future discoveries to mitigate the severity of his disease. With the combination of a slight thickening of the heart muscle and a positive test for the genetic mutation that afflicts his father, there is a high likelihood that he will also develop HCM.
In the meantime, Sehnert looked deeper into the family tree and wondered if others might also be carrying the beta myosin heavy chain mutation. Neither of Lange's parents had known heart problems, but his grandfather on his mother's side had died of a heart attack. So Lange's mother, Patricia, was tested. She too has the mutation. Although she has never been diagnosed with HCM, she is now going back to her doctors to insist that they do more extensive tests. She is also urging her own brothers to get tested so that they know whether they or Patricia's other grandchildren might also be at risk.
"I've seen these sorts of gene mutations weave through families, and it can really have a major impact on them," Sehnert says. One mother told Sehnert that she might have made different decisions had she known before she had children that she was carrying an HCM gene mutation. When the mutation is present, there is a 50% risk of passing it along.
In the future, many people might be making different decisions after consulting their own gene profiles or those of potential spouses. With over 250 known mutations in 13 cardiomyopathy genes (and probably many more undiscovered genes) floating around the population, the chances are not negligible that one might turn up in you or someone you know.
Similar gene mutations, yet undiscovered, probably underlie the risk of contracting other disorders like diabetes, atherosclerosis or cancer. Aging itself may be the collected action of hundreds of small gene defects that we cannot detect now but will be able to detect in the future.
Even when such genetic problems are discovered, there is often no cure for the diseases. As the number of known mutations multiplies and tests become more widely available, we may all face dilemmas already faced by those who, for example, have to decide whether or not to get tested for Huntington's disease, a deadly neurological disease for which there is no cure. Some people in this situation simply do not want to know whether they carry a particular genetic risk.
And though there is no cure for Lange's condition yet and he is not glad that he carries the beta myosin heavy chain gene mutation, he is glad to know that he does. Such information can allow him to make better decisions about the course of his life and his son's. "At one point I was thinking about working for myself, but now I know that will never be a possibility, because I could never get health insurance," Lange says. "I imagine my son will eventually have similar issues."
Although the doctors couldn't directly use the existence of Lange's gene defect to craft his treatment plan, it provided an answer as to the cause of his heart problem and raised awareness among his relatives. The knowledge also factored into Lange's own decisions, such as whether to get the implantable defibrillator.
One morning a short time ago, while he was getting ready for work, Lange's choice paid off with a bang. His defibrillator, sensing a dangerous heart arrhythmia, shocked his heart. "It knocked me back," Lange says. "It was like touching a live wire, but it went through my whole body."
A quick analysis at the hospital demonstrated that the device had done its job correctly. Lange's heart had been going into arrest. The defibrillator had cut short the heart attack that might otherwise have ended his life.
"I'm really grateful for having the defibrillator now, because it worked," Lange says.
Story first published in UCSF Magazine, December 2004
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