Epilepsy is a lonely disease.
When the woman at the computer terminal burst into tears, she flabbergasted Dr. Jeffrey Noebels.
As the first person to enter information into a database of families affected by epilepsy, she had seemed excited about the prospect.
She was, she assured the concerned Baylor College of Medicine epilepsy expert.
"It's just that I'm so happy and excited that you are doing research to cure this disease," she told the BCM professor of neurology.
When Noebels responded that hundreds of scientists around the world were working night and day on that very task, she replied,"Yes, I know, but they are not working on my family."
Epilepsy is a lonely disease. The fear of seizures separates those who have the disorder and those who do not understand it. Often, no one knows why one person has epilepsy and another does not or why it suddenly crops up in a family where it has never been seen before.
Most, like the woman at the computer, want answers about the disease that affects them. Until now, the answers were fairly generic. Now, however, Noebels and a host of experts in genetics, neurology and gene sequencing at Baylor College of Medicine will be looking for more specific answers as they attempt to find genes associated with epilepsy in people who are the first in their families to have the disease.
"In the vast majority of epilepsy cases, the disease affects one individual. There is no family history," said Dr. Dan Burgess, a BCM assistant professor of neurology. "Does that mean it's not genetic? People used to think that. Now we know we may have to look at more than one gene. When we started to clone genes for epilepsy, about one-third of them were ion channel genes. This study that focuses on these particular kinds of genes provides us with an excellent opportunity to find some answers."
Noebels, Burgess, Drs. Alica Goldman and Susan Leal are collaborating with Dr. Richard Gibbs and the Baylor Human Genome Sequencing Center to find answers for those people who have epilepsy for which there is not a known explanation.
Epilepsy is an old disease with many causes. Seizures can occur for many reasons including tumors, imbalances of sugar or sodium, head injury, drug abuse, alcohol withdrawal, stroke with bleeding in the brain and injuries to the brain at birth. Genetic mutations can also cause the disease or at least predispose a person to developing it.
Many people are told that the cause of their epilepsy is unknown. It is an unsatisfying explanation.
Changes in nerve cells can produce brief disturbances in the normal electrical discharges in the brain. These alterations are called epilepsy. Epilepsy is a generic term for everything from the generalized seizures that most people associate with the term to absence or petit mal episodes that cause a person to stare blankly into space for less than a minute. In another form of the disorder, a person seems awake but is actually in a fugue state and can be irascible or non-compliant.
To identify the genes associated with epilepsy, the BCM researchers plan to sequence 250 genes in each of 500 people with epilepsy and 500 who do not have the disease.
"We don't need to look at all their genes," said Noebels. "We are looking at the genes for their ion channels only."
These tiny pores in the membranes of nerve cells govern the release of charged chemicals such as sodium and potassium. These ions are key to the production of electrical impulses in the brain. When the channels are malformed and the ion release is not controlled, electrical impulses occur out of sync and a seizure results.
Finding these tiny defects is a task for computers. Every gene is made up of DNA. DNA consists of bases called thymine, adenine, cytosine and guanine. A single misprint - an "A" where a "C" should be or a similar substitution - and there could be a defect in the ion channel and a problem that leads to epilepsy.
One genetic misstep may not be enough. A person may have to inherit a genetic defect in an ion channel from one parent and another mutation from the other. Together, it might be enough to cause the seizure disorder. Environment or disease could contribute. The task is monumental, however, this study is a start.
"It is as if we are looking at every letter in a word of a book for a typo," said Noebels, "only we don't know which typos are important enough to change the meaning of the word."
In a few rare instances, epilepsy can run in families. More commonly, however, the disease occurs as a new phenomenon.
"These are people for whom genetics has not come up with any solution," said Noebels. "The only way to attack this is to look at all their genes involved with ion channels."
When he took the problem to Gibbs, the BCM professor of molecular and human genetics and director of the sequencing center got out his calculator. As the numbers climbed, he turned to Noebels.
"Piece of cake," he said. "We can do that."
The Baylor Human Genome Sequencing Center was one of only three in the nation designated to perform the task of rapidly sequencing the human genome - a task completed in 2001.
"The reason we got into this whole business was because of human genetics," said Gibbs. "The sequencing center is another tool in the process of doing human genetics."
While the task seems monumental to Noebels, "it's actually not much compared to what we've done in the other organisms," said Gibbs. The BCM Center has participated in sequencing not only the human genome, but that of two types of fruit flies, the rat, the cow, the honey bee and the chimpanzee, among others.
"It's a slightly different flavor from the human or the rat," he said. "Then we didn't know what the sequence was. Now we know what we are looking for and we have a reference sequence to test it against. We do a patient's sequence and compare it to a known sequence."
If there is a difference, there is either an error in the sequencing or a real error in the genetic code. If it is truly a genetic error, then the sequencers can look for that error in other samples.
"Epilepsy is very attractive because these ion channel genes are clearly involved," he said. That limits the numbers of genes that have to be sequenced. In other diseases, the entire genome might have to be sequenced. Currently, finding the differences in all 25,000 human genes would be difficult, but "it will get to that point," said Gibbs.
BCM provides a rich infrastructure for this kind of study, said Burgess. Experts such as Noebels and Goldman see many patients with epilepsy. The genome center provides the expertise for unraveling the genetic code in the ion channel genes. Once the most likely gene mutations are identified, Burgess will clone them and put them into cell culture to determine if that actually causes the disturbance in electrical activity that can cause seizures.
"I will put a normal version of the gene in a cell culture and measure the current that goes through the channel. Then I will take the variant and see if the cell culture works in the same way. If it will not let one of the ions (sodium, potassium or calcium) through, then it is a good candidate for causing epilepsy."
"Until now, no one has had the capacity to do this kind of thing," said Burgess. "We are fortunate to be here in a place where we can ask these sorts of questions."
It is fortunate for patients that BCM is also the kind of place to find answers, said Goldman, also an assistant professor of neurology. Her job is to find the 1,000 subjects who will participate in the research. Half will have epilepsy and half will not.
"Finding these genes will help us understand the disorder better," she said. "Once we have a better grip on what's going on, we can tailor medications for the patients and minimize the side effects that disrupt their lives. We will become better doctors for them."
Medication provides little or no relief for an estimated 30 percent of people with epilepsy. Understanding the genetic cause may enable the development of new drugs that target the actual cause of their disorder.
"People like to know the source of their disease," Goldman said. "If we can help them understand their disorder, they can take better care of themselves. For those whom medication cannot help, surgery may be helpful. This may help us better understand the benefits of both."
Now she is honing the system for finding subjects, determining if they fit the criteria of the study and performing the activities necessary to enter them into the study. "I envision that within a year, we will have fine-tuned our process. It will take four to five years to collect enough patients."
She hopes that the findings in this study will help resolve some of her patients' frustrations as well as her own.
"It is very frustrating for the patient and also for me as a physician," she said. "I don't know why they don't respond to the medicine or why they have a bad reaction. It is frustrating for me when I cannot find the right medicine to control the seizures."
"I hope we can find the answers. They may take a long time to find, but we had to make a start."