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Christopher A. Walsh Laboratory 

Harvard University Gazette - April 24th, 1997

Epilepsy Genes Reveal Brain-Cell Migration

By William J. Cromie

Marie Brown is, by all appearances, a woman who leads the good life. She graduated from a highly respected college, holds a fast-track job, and lives with her husband in an affluent suburb of Boston.

Outwardly she looks healthy, but inside her head is a troubled brain.

She had her first epileptic seizure as a freshman in college. For a while, the seizures didn't hamper her studies or social life. But at age 30, they have begun to interfere with her work.

Brown (not her real name) went to see a neurologist, who used magnetic resonance imaging (MRI) to take pictures of her brain. The pictures were surprising. They showed that chunks of cells that should have moved to the highest parts of her brain during development lay stalled in a deeper part of the organ.

"In patients like her, brain cells form normally before birth, but their migration to the cortex is arrested somehow," says Christopher Walsh, assistant professor of neurology at Harvard University. "That leaves her with clusters of brain tissue in the wrong place." The right place is the cortex, the thin cap of cells on the top of the brain where memory, reasoning, and other higher functions are centered.

In this month's issue of the journal Human Molecular Genetics, Walsh and his research team link such brain malformations with specific genes that result in two types of epilepsy. The team is also close to identifying the gene responsible for the disorder from which Brown suffers, periventicular heterotopia, or PH, as well as another gene for a similar condition known as double cortex.

"By identifying such genes and understanding how they work, we can learn not only about treating the diseases they cause, but about how a normal brain develops and functions," Walsh notes.

Electrical Brainstorms

The PH gene that causes Brown's problem is one of 13 known genes linked to epilepsy. "There's probably dozens of others that haven't been identified yet," admits Walsh, who is also chief of neurogenetics at Beth Israel Deaconess Medical Center.

Normally, your brain crackles with well-organized electrical signals that guide your hand when you lift a hot cup of tea to your lips, or steer a car. But in epilepsy, such activity becomes chaotic. Uncontrolled electrical storms interrupt normal awareness and behavior. Some seizures pass almost unnoticed. But "grand mal" seizures cause wild jerking of the arms and legs, and loss of consciousness.

The federal government calculates that the disease costs $3.5 billion a year in medical expenses and lost productivity. For individuals, costs are measured in lost jobs, physical handicaps, and embarrassment.

Anywhere from 2 million to 10 million Americans suffer from epilepsy, Walsh says. "The best estimates at this point, and they're only estimates, put those cases with a strong genetic component at 50 to 75 percent of the total." That comes to at least a million people.

Epilepsy without a genetic connection can be caused by blows to the head, stroke, infection, tumors, and drug or alcohol abuse. Anticonvulsive drugs control seizures in many, but by no means all, epileptics. Such drugs, of course, do not cure the disease, and they are not without side-effects.

"Until 1994, the drugs we used were found randomly, or by the long process of screening promising compounds in animals," Walsh says. "But recent advances in knowledge raise the hope of designing drugs to hit specific targets in the brain known to participate in the electric brainstorms. To do this effectively, we need a better understanding of the genes involved and the exact role they play in the disease."

That turns out to be a lot more difficult than it sounds. Genes, known and unknown, can perform in confusing concert.

"Depending on which combinations of genes people inherit, some of them will be more susceptible to epilepsy than others," Walsh comments. "But these genes do not make epilepsy inevitable."

In some families, seizures occur in newborns during the first week of life. Then they just go away and usually don't come back. Many of the genes cause seizures in the temporal lobes, the brain area between the temples where learning, memory, and smell are housed. People who undergo this sort of seizure experience bizarre memories, or smells that no one else can detect.

One genetic-based epilepsy causes uncontrollable movements just after the onset of sleep. Others trigger violent muscle jerking.

A woman treated by Walsh hears voices every time she has a seizure. A stern male voice speaks to her but, like a forgotten dream, she doesn't recall what he said when the seizure is over. The woman realizes that the voice is a manifestation of her disease and not a communication from aliens or spirits.

Blocked Migrations

The type of epilepsy suffered by Marie Brown - PH - has been traced to a specific location on a single gene. In such families, anyone who inherits that gene will always have abnormal neurons and go on to develop epilepsy.

Another gene studied by Walsh causes a second cortex, or abnormal layer of cells, under the normal cortex. Like PH, double cortex (DC) stems from the failure of cells to migrate to their proper place in the brain. Both maladies may produce mental retardation in addition to epilepsy.

Both genes occur on the so-called X chromosome. Females have two X chromosomes; males possess an X and a Y. According to Walsh, women with mutant PH and DC genes have brains with a mosaic of normal and abnormal cells. The normal cells come from genes on the unaffected X chromosome, whereas abnormal cells express mutant genes from the affected chromosome.

Such women will have a shortage of sons and an excess of daughters, half of whom will have epilepsy. Although relatively rare, PH and DC affect thousands of women in the U.S. alone, and there is no cure for either disease.

Males are worse off. If their single X chromosome has either mutant gene, their brains are so severely affected they die in the womb or shortly after birth.

Working at the Beth Israel Deaconess Medical Center with neurologists Joseph Gleeson and Kristina Allen, Walsh is close to cloning the DC gene. He also is close to locating the PH gene as a result of his work with Jeremy Fox, Edward Lamperti, and Yaman Eksioglu.

Using these clones, they can conduct experiments to determine exactly which mutations lead to these epilepsies and how. Such information reveals specific targets for drug companies to aim for.

Walsh and his collaborators have been trying to get drug and biotechnology companies interested in designing new treatments as the location and function of different epilepsy genes become known. Many of these disorders, however, are too rare for the companies to make enough money to cover the costs of developing drugs.

Walsh's lab is also making progress toward his other goal of studying epilepsy to gain insight into how normal brains develop and function. The key to this involves understanding how cells migrate to the cortex from lower parts of the brain.

His most surprising finding is that the cortex seems to direct its own development.

"The earliest born cells appear to act as a gate that can block or regulate the movement of later-born cells," Walsh explains. In PH epilepsy, brain cells don't leave the nursery where they're born. In double cortex, cell movement is arrested just below the cortex, as if the oldest cells won't let the younger ones get past them.

Neurologists once believed that each brain cell's position was fixed by the genes of its mother cell, the cell that divides in two to produce it and a sister. But evidence is accumulating to show that both daughters do not move to the same preset location. They can go in different directions, getting information from neighboring cells about what they should become.

These neighbors, Walsh notes, "seem to be able to say, 'OK, we've got enough brain cells here; you can stop sending any more.' If we could understand and control this regulation process, we might be able to trigger growth of new brain cells to replace damaged ones."

That would mean custom-tailoring human brains to repair the tears and fraying caused, not only by epilepsy, but by many other defects that wear out a brain before its time.


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