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The New Genetics
What You Need to Know for Your Practice and Patients

ARTICLE IN BRIEF

Conference chair Dr. Jeffrey Vance highlights the upcoming session on the “new genetics” at the AAN annual meeting in Seattle.

Genetics has undergone a profound change since the average neurologist was in medical school. This is why the Future of Neuroscience conference, scheduled for May 1 at the AAN annual meeting in Seattle, is appropriately titled “The New Genetics.” The daylong session promises to bring neurologists up to speed on what conference organizer Jeffrey Vance, MD, PhD, calls “the future of neurology.” And to hear him tell it, that's no exaggeration.

“Most people were taught the basic genetics of Mendel, that single genes cause single diseases,” most of which are rare, such as Huntington disease, said Dr. Vance, chair of the department of human genetics and director of the Center for Genomic Medicine at the Miami Institute for Human Genetics. “But the genetics that is really going to impact medicine and neurology affects common diseases. That's more complicated.”

The goal of the conference is to “help neurologists understand what this is all about — to understand the importance of the new genetics in the near future, and to be able to talk with patients about the new concepts when they arrive in the office with questions.”

PHARMACOGENOMICS AND RISK GENES

The new knowledge arises out of the continuing avalanche of discoveries about the human genome. The ability to sequence the entire genome, and analyze thousands of small sequence variations among many different people, has led to several key insights that directly impact medicine.

First, there are sequence variants that influence the efficacy and side effect profile of drugs, so-called pharmacogenomics. The metabolism of clopidogrel, for example, is influenced by variants in several genes, some of which reduce the efficacy of the therapy. Specific variants of statin-metabolizing genes can increase the risk of rhabdomyolysis.

Finding such variants is “the low-hanging fruit,” Dr. Vance said, since the payoff in better treatment is high. “A neurologist should probably be determining the genetic status” of a patient going onto statin therapy, “because the potential for harm is so significant.” For other genes, the current economics are not yet as clear-cut.

Second, the risk for most common diseases is influenced by multiple gene variants, each of which contributes only a small amount. “It's like weights,” Dr. Vance said. “Different genes ‘weigh’ different amounts, and the effect is cumulative.” While the full range of genes that influence any condition is not yet known, there has been progress. Based on three or four genes, “we can predict with up to 85 percent certainty whether someone is at risk for age-related macular degeneration.”

The influence of the apolipoprotein E (ApoE) genes on Alzheimer disease is well known, but there is much more to be discovered. “It's going to take a while to get these predictions in place” for other diseases, “but that's what's coming down the pike,” Dr. Vance said. In addition to these small sequence variants, each person's genome also contains multiple duplications and deletions of genes, which may influence disease risk, and may also influence drug response.

“One of the big things we are discovering now is that most of our genome is about regulation of genes,” Dr. Vance said, especially through the actions of RNA, discoveries that were recognized in the 2006 Nobel Prize award. Not that many years ago, “we didn't even know they existed, and already they are looking to be important in infection and cancer,” with neurology likely to be close behind. “Each time you look, there's more of these regulatory elements.”

“The whole idea is to move medicine from reaction, where we only treat people after they get sick, to prevention, where we try to prevent things from happening, or slow them down,” Dr. Vance said.

As with age-related macular degeneration, one could easily imagine a screen for Parkinson disease risk genes, some of which are already known. One would use the gene screen early in life to identify those most at risk, and then image them every few years, starting in middle age. “If they have changes, we would intervene,” he said. For the moment, definitive disease-modifying treatments are not yet in hand, but further understanding of the genetics is likely to identify rational points for intervention as well. “So it's not just genetics — that's one of the tools to move medicine toward preventing disease.”

MAKING SENSE OF THE INFORMATION

Driving the entire field is the plummeting cost of whole-genome sequencing. “The most likely thing that's going to change everything,” Dr. Vance said, “is that in the next five years, there will likely be the ability to sequence a person's entire genome for a thousand dollars. When that happens, medicine is going to change.” As recently as five years ago, it cost 10 million dollars; today, there are companies offering it for only five thousand dollars.

“Genetic information is a different kind of information than what we are used to dealing with as physicians,” he says. Unlike a test for cholesterol, say, whose results vary from week to week, “once you sequence the DNA, it doesn't change. You can use the information not only now, but for the rest of your life,” and the information becomes even more valuable as new discoveries are made.

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DR. JEFFREY VANCE: “Most people were taught the basic genetics of Mendel, that single genes cause single diseases. But the genetics that is really going to impact medicine and neurology affects common diseases. Thats more complicated.”

Currently, the medical system is not set up to handle this information, Dr. Vance said. “People don't know how to use it. Just like everyone had to learn how to use computers, everyone is going to have to learn how to handle this new genetic information.”

And Friday's conference is a great place to get started. Kurt Fischbeck, MD, of the NINDS, will give an overview of the history of the new genetics and why it matters so much to neurology today.

Thomas Bird, MD, professor of medicine, neurology, and medical genetics at the University of Washington in Seattle, will connect the dots from Mendel to the Human Genome Project and beyond. Stephen Zuchner, MD, associate professor in the department of human genetics and director of the Miami Institute for Human Genomics Center for Human Molecular Genomics, will introduce some of the “toys and techniques” of the new genetics, and will look at where the technology is going from here. Other talks will look at regulatory systems and gene-environment interactions. The afternoon is devoted to current applications in neurology, including multiple sclerosis and autism, where new genetic discoveries are having an impact on understanding the disease and its treatment.

The neurologist should come away from the conference not only understanding where the field of genetics is and is going, but also becoming better able to talk with patients who arrive with information on new genetic discoveries. Ultimately, Dr. Vance said, the aim of the conference is to help the neurologist “put that information into context for the patient.”