Columbia Scientists Discover Genetic Link to Epilepsy

As complex as it is devastating, epilepsy has always been a puzzling disease, rebuffing scientists’ attempts to find a single causative factor. But through a combination of sophisticated analytical techniques and old-fashioned detective work, scientists are finally beginning to understand how subtle genetic factors can lead to faults in the brain’s wiring.

“It is a very complicated area in that there have been so many different approaches that have been tried because nobody knows,” Columbia researcher Dr. Deb Pal said. “Nobody has the winning formula.”

But in a paper published Jan. 28 in an advance online edition of the European Journal of Human Genetics, Pal’s team reports a finding that could change the way scientists look at many developmental disorders. They have discovered that a gene called ELP4 is strongly associated with a mild, childhood form of epilepsy. However, the gene does not seem to be the sole cause of the disorder, and may instead be responsible for some more fundamental neurological problems common to other seemingly unrelated disorders.

For Pal, the paper marks the culmination of years of study on a form of the disorder called Rolandic epilepsy. RE typically strikes young children, causing seizures during which sufferers drool and are unable to speak. The disorder is sometimes considered “benign” because symptoms usually resolve spontaneously during adolescence.

The disorder’s transient nature already made it difficult to study, but RE proved to be even trickier than expected. Scientists checked patients’ DNA for problems near genes known to be critical to brain function, but came up empty or got results that could not be replicated. In 2004, an Australian research team suggested that the evidence for a genetic explanation for the disorder was so weak that scientists should concentrate their research on other factors.

Pal was not convinced. He was studying the disease from another angle. “For me the path is very natural,” Pal said. “I’m a clinician.” Instead of taking shots in the dark by searching for problems with known genes, Pal studied the patients and their symptoms. Pal and his colleagues looked at the cases of 90 tri-state-area children with RE, observing them and their family members. When the scientists began to put the data together, a pattern emerged.

The brains of children who had RE all exhibited a characteristic pattern of abnormal electrical activity, called centrotemporal spikes, or CTS. But this spiky pattern was also found in many of those children’s siblings who did not have RE. In addition, the siblings had other disorders associated with CTS, such as speech problems and attention-deficit hyperactivity disorder, at a far higher rate than that of the general population—about 50 percent, a percentage that is a telltale sign of genetic inheritance.

Armed with the results of this study, Pal’s team took DNA samples from 194 of the children and family members. They used a genetic scan to check whether the unknown gene was near any of 1200 equally spaced locations in the subjects’ genomes, and found a strong association with a region on chromosome 11. Finally closing in, they performed a fine-grained analysis of the region, and discovered a clear link between CTS and ELP4.

ELP4 is a gene that helps cells create the tiny scaffolds that help them move. During development of the brain, in the womb and into early childhood, neurons migrate throughout the brain, linking up with each other to form circuits. A problem with ELP4 could affect the neurons’ ability to migrate, leading to a wiring problem that manifests itself as CTS.

However, this doesn’t explain why some children with CTS develop seizures, while others end up with ADHD or speech disorders or completely unaffected.
The most likely answer is that a problem with ELP4 induces a systematic wiring problem in the brain, but that it is the interaction of this wiring problem with other genes that causes this problem to develop into a full-blown disease.

news@columbiaspectator.com