Led by Dr. Ruth Ottman, a group of Columbia investigators identified the gene, called LGI1, by extensively studying five families in which some members had an uncommon type of epilepsy characterized by auditory hallucinations and other symptoms. During a seizure, affected individuals often hear sounds that are not real.
The findings were published Jan. 28 in the online version of Nature Genetics and will be published in the March issue of the journal. Dr. Ottman is professor of epidemiology in the Mailman School of Public Health and deputy director of research at the Gertrude H. Sergievsky Center. Two significant collaborators on the project at the Columbia Genome Center were Sergey Kalachikov, associate research scientist, and Dr. T. Conrad Gilliam, professor of genetics and development and director of the genome center.
Researchers have not yet identified the genes associated with most forms of epilepsy, a chronic medical condition that affects at least 2.3 million Americans. People with epilepsy have repeated seizures, caused by temporary changes in the electrical function of the brain that can affect awareness, movement, and sensation. Scientists study rarer familial forms of the disease to get genetic clues about the more common cases.
"Most people with epilepsy do not have family members who are also affected, but unusual families that have multiple affected people can help scientists find genes associated with the disease," Dr. Ottman says. "Discovery of these genes can tell us a lot about the basic processes that lead to seizures."
Scientists previously found eight genes that predispose people to other rare forms of "idiopathic" epilepsy, or unexplained epilepsy that occurs without other serious neurological problems. But those genes allow chemical signals in and out of brain cells and function differently than LGI1. While the function of LGI1 has yet to be determined, some evidence suggests it plays a role in brain development.
"The discovery that LGI1 causes epilepsy with auditory symptoms points to new avenues for studying the causes of all types of epilepsy," Dr. Ottman says. "The gene seems to play a role in how nerve cells migrate during development and create faulty wiring."
In the study, Dr. Ottman and colleagues looked at the pattern of inheritance of the auditory epilepsy in the families. They collected blood from 108 members of five families and analyzed the DNA from 85 of them. They knew from prior studies of one family that a gene associated with epilepsy with auditory symptoms was on chromosome 10.
In the Nature Genetics paper, the researchers report identifying the gene by studying the DNA from the first family and four other families and finding mutations in affected individuals. Inheriting a mutated copy of the LGI1 gene does not guarantee getting epilepsy, the researchers found. The disorder will develop in 70 percent of individuals who have mutations in the gene.
Identification of the gene was one of the largest successful positional cloning efforts in the world to date. It required the complete DNA sequencing of 4.2 million base pairs of DNA, identification of 28 full-length genes, and systematic re-sequencing of 21 genes to identify the disease alleles.
LGI1 had been characterized before, but by other scientists doing cancer research. They found that loss of both copies of the LGI1 gene promotes the progression of certain types of brain tumors. The Columbia research has found no evidence for an increased risk of brain cancer in people carrying a mutant copy of the gene.
The Columbia scientists are now studying how the gene works during brain development and how it may relate to other forms of epilepsy.
"Our finding is quite interesting in that while one mutant copy of LGI1 leads to this rare form of epilepsy, two mutant copies apparently lead to glial tumor progression," Dr. Gilliam says. "Comparative genomic analysis suggests that LGI1 may play a role in neuronal cell migration and neuronal growth-cone guidance, consistent with its presumptive role in both epilepsy and tumor metastasis."
The research was supported by grants from the National Institute of Neurological Diseases and Stroke and by funds from the Columbia Genome Center.
Arthur Barrett, a 71-year-old retired businessman from New Jersey, was the first patient in the United States to receive robot-assisted coronary artery bypass graft (CABG) surgery without a chest incision of any kind.
The Jan. 15 operation was performed by Dr. Michael Argenziano, assistant professor of surgery and director of robotic cardiac surgery, and Dr. Craig Smith, professor of surgery and chief of cardiothoracic surgery, as part of a clinical trial sanctioned by the Food and Drug Administration.
Until this point, coronary artery bypass surgery required open-chest surgery, which involves an 8- to 10-inch incision made in the chest. Robot-assisted surgery requires only three pencil-sized holes made between the ribs. Through these holes, two robotic arms and an endoscope gain access to the heart, making surgery possible without opening the chest.
This historic operation follows the successes of other robotic-assisted surgeries at New York-Presbyterian Hospital. Cardiac surgeons have performed more than 40 robotic cardiac operations including internal mammary artery harvests, mitral valve repairs, and the first robot-assisted atrial septal defect repair in the United States. The surgical robot, Intuitive Surgical's da Vinci Surgical System, has been approved by the FDA for a number of clinical trials.
Heart disease is a leading cause of death in the United States. Approximately 375,000 CABG surgeries are performed in the United States each year, making it the most common "open heart" operation.
Studies show that patients who have minimally invasive operations get out of the hospital one to two days earlier than patients recovering from conventional cardiac surgery. Dr. Argenziano, who is the principal investigator for the first robotic coronary artery bypass surgery clinical trial in the United States, says, "Other advantages of minimally invasive surgery can include quicker patient recovery times, less pain, and dramatically less scarring than traditional open-heart operations."