By Matt Windsor
Patients with neurofibromatosis can find plenty of information about the disease on the Internet. But when they come to UAB from around the world, they're not looking for facts—they're looking for answers. And answers, when it comes to neurofibromatosis, are not so easy to find.
The reason lies in the endless complexity of the disease. Neurofibromatosis type 1 (NF1), the most prevalent form, is characterized by tumors of the nerve sheath, brown spots and freckles on the arms and in the groin, learning disabilities, problems with bone growth, and a host of other complications. Neurofibromatosis type 2 (NF2), which is far more rare, involves superficially similar nerve-sheath tumors that produce different symptoms, particularly in the area of balance and hearing, and are actually caused by mutations in a different gene.
NF1 affects one in every 3,000 people, which makes it "common among the rare diseases," says Bruce Korf, M.D., Ph.D., an internationally recognized expert in neurofibromatosis. "But one in 3,000 means that most affected individuals feel pretty lonely." Patients with NF2, which affects one in 25,000, are lonelier still. And because NF can arise from countless different mutations on the affected genes, many patients have a practically unique version of the disorder.
"The NF1 gene actually is a pretty big target for mutation, being a large gene, and it doesn't take much of a mutation to turn it off," says Korf. "It's like throwing a monkey wrench into a car engine—it isn't hard to make it stop working."
Seeing Through the Static
Diagnosing NF in either form, says Korf, involves "trying to see a picture against a lot of static. The condition is so variable, and the mutations are so diverse, that almost no two are alike." That is why patients fly in from around the globe to see Korf at UAB's Neurofibromatosis Clinic, the only one in Alabama and the only NF clinic in the Southeast designated as an affiliate clinic by the Children's Tumor Foundation.
"The manifestations involve multiple systems of the body, they occur progressively over a lifetime, and they're unpredictable," says Korf. "You can never tell from one moment to another what is going to happen." It helps to have 25 years of experience in caring for NF patients, as Korf does. He traces his interest in the disorder to his student years at Children's Hospital in Boston and Harvard Medical School, where he became intrigued by NF's challenging genetic, neural, and clinical aspects. In 1983, he opened an NF clinic at Harvard that became one of the premier facilities in the world, and he brought a deep reservoir of knowledge with him when he came to UAB in 2003 to serve as the inaugural chair of the Department of Genetics. His arrival helped UAB's existing NF program attract further outstanding clinicians and researchers, including Ludwine Messiaen, Ph.D., who directs UAB's Medical Genomics Laboratory.
The genetic tests developed by Messiaen's lab are some of the most sophisticated available, particularly the NF1 test developed by Messiaen herself, which is the most accurate current model for diagnosing the disease. Korf says that UAB receives samples daily from physicians around the globe searching for a definitive diagnosis for their patients.
"You're looking at a gene with 60 segments, where mutations could be anywhere," Korf explains. "It's like proofreading a 1,000-page book, looking for something as subtle as one misplaced letter." But the test that Messiaen developed is a "big step forward," says Korf. "Dr. Messiaen is a master at devising practical genetic tests for extraordinarily complex genes. Thanks to her work, we can now at least confirm a diagnosis and offer counseling on that basis—things we could not do in the past."
Even after patients receive a diagnosis, it may be months before they can get an appointment to see a specialist. So Korf has developed Understandingnf1.org , a Web site that features a videotaped counseling session with a real patient. "The counseling visit is when most people learn about NF," Korf says. "We tell patients about the diagnosis, where they fit in the NF spectrum, what they can expect in the future, and then what management options exist and where the state of the research is. Because patients may not get access to that kind of visit right away, we've developed this unique counseling resource."
While Korf and his team devote much of their time to helping patients manage NF, they are also looking for new treatments. Surgical removal of tumors is the only current option for most patients, but intriguing alternatives are being studied. UAB recently received a $5.7-million grant from the Department of Defense to coordinate the study and testing of new NF treatments at a consortium of nine institutions.
"Clinical trials so far are mainly looking at drugs that target the pathway in the cell, of which the NF1 gene product is a part," says Korf. "They're looking at ways of bypassing the step that is now missing because of the damage to the NF1 gene."
Korf says his team's regular visits with patients keep them focused on their mission. "These patients place enormous hope in the medical research community. Neurofibromatosis has existed throughout history, but it's only in the last decade that there's been any reason to hope that treatments would become available. That is very sobering as you go to work each day—whether it's urgent for you or not, it's urgent for a lot of people."
Even as he shares his decades of experience with patients, Korf says he learns lessons of his own: "Chronic conditions like this amplify the inner personality. If a patient is inclined to be optimistic, they're more so now. I've had patients who were completely and totally covered with tumors, so that there was no way to fail to notice that the first time you saw them. But as you listen to them talk about their lives, after a few minutes you forget all that and see the person inside."