Harvard University Gazette - April 24th,
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
"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.
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
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
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
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
"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.