The Harvard Mahoney Neuroscience
Institute Letter: On the Brain - Winter 1997
Epilepsy: Genes May Build the Road to Treatment
By Christopher A. Walsh, M.D., Ph.D.
Epilepsy affects almost one percent of the population of the United States.
It is a brain disorder causing unpredictable, uncontrolled seizures that can
occur at any time or place. Seizures result when the normal, tightly
controlled electrical activity of the brain becomes excessive and
disordered, interrupting normal awareness and normal activities. In the most
dramatic and severe seizures (called "grand mal"), the patient loses
consciousness and has wild movements of the limbs, followed by temporary
suppression of conscious brain activity. The brain slowly regains its normal
activity as the patient wakes up, unaware of what happened. Epilepsy is the
most common neurological disorder among young people. And because it
produces problems with school, driving, and keeping a job, it has a huge
economic cost (estimated by the government at $3.5 billion). It takes a
social toll impossible to measure in disrupted lives for both epileptics and
their families. That cost is all the more frustrating because it seems as if
it should be greatly reduced if only we had the right drugs to control the
seizures. Many useful drugs exist for epilepsy, and several new ones have
become available recently. But, for about one third of patients, seizures
cannot be controlled by presently available medical therapy. Some epileptics
can be helped by brain surgery, but thousands remain whose epilepsy cannot
be controlled by any present-day treaments. So, the hunt continues for
improved antiepileptic medications - a search now leading onto genetic
The genetic picture
Epilepsy can be caused by many factors that have nothing to do with
genetics; head trauma, stroke, infections, tumors, and drug or alcohol abuse
can all induce epilepsy. However, up to one half of all epilepsy has no
other obvious causes, and there is increasing consensus that most of these
cases have some relationship to inherited genes.
Recent rapid advances in the understanding of the human genome have begun to
allow the identification of genes that predispose to epilepsy. Each of these
new genes seems to cause epilepsy by interrupting key processes in the
normal function of the brain's neurons.
Some rare types of epilepsy seem to be almost completely caused by the
action of epilepsy genes. In families where these genes are found, anyone
who inherits the epilepsy gene (which usually means half of the children of
an affected parent) will eventually develop epilepsy no matter what.
However, we are coming to understand that epilepsy may be genetically more
"complex," like diabetes or cancer. In these complex genetic diseases,
anyone theoretically can develop the disorder, as it can be caused by the
interactions of many different genes. Depending upon which combination of
genes people inherit, some people will be more susceptible to epilepsy than
others, but the genes do not make epilepsy inevitable.
Inherited epilepsies usually require at least four complicated,
unpronounceable medical words to capture their characteristic features (see
table). For example, some families have a remarkable epilepsy: seizures
occur in their newborn babies just during the first week of life, and then
magically go away and usually never come back. The disorder is called benign
(because they go away) familial neonatal (because they occur in newborns)
convulsions - BFNC for short - and two different genes (BFNC1, BFNC2) can
cause it. Other families have a disorder called autosomal dominant
(transmitted directly from parent to child) nocturnal frontal lobe epilepsy,
ADNFLE. This epilepsy causes bizarre types of movements because the seizures
involve the frontal lobe; the seizures occurs mostly or only just after the
onset of sleep.
Researchers usually find epilepsy genes by studying families in which it is
very clear that epilepsy is a genetic trait passed on from parent to child.
Often such families have very rare and distinctive types of epilepsy. This
makes it easier for researchers to be sure that different family members
have the same kind of epilepsy and that it is caused by the action of a
gene, rather than some other cause (such as drug abuse or head trauma).
For individuals who think epilepsy may run in their family, the Eiplepsy
Foundation of America has set up a website (www.efa.org/index/htm) that
describes genetic studies in epilepsy and allows interested individuals to
contact epilepsy researchers.
Another way that epilepsy genes can be found is by finding families with
epilepsy in which slight abnormalities occur in the way the brain develops,
since abnormalities in brain development have long been associated with
seizures. The human brain can be imaged very precisely using Magnetic
Resonance Imaging (MRI), and the inheritance of certain subtle malformations
of the brain can the be analyzed by taking MRI pictures of everyone in the
Our group has used this method to localize two epilepsy genes, each one
associated with subtle abnormalities of brain development that would never
have been suspected before the advent of MRI imaging (see images). The genes
for the developmental epileptic disorders appear to be involved in
communication between cells in the developing brain as well as in the adult
brain; therefore, they may be especially central to normal brain function
and thus among the most desirable targets for drug design.
Sorting through DNA
The 50,000 to 100,000 total genes present in our DNA are like individual
entries in a vast encyclopedia: large DNA molecules each binding together
hundreds to thousands of genes. Once a large family with inherited epilepsy
is found, the tools of the international Human Genome Project can usually
allow the "mapping" or localization of that gene to a place within one of
the 46 chromosomes. Therefore, mapping an epilepsy gene basically means
narrowing the search for the epilepsy gene down to about 500 to 1000 genes
in a smaller area of one individual chromosome.
Often, however, taking the last step to find that one disease-causing gene
in a thousand takes longer than the initial mapping: it often requires
painstaking sifting through the DNA sequence of many genes to find the one
that contains an error, or mutation. Finding a mutation can be like trying
to find a single typographical error among a thousand encyclopedia entries,
all of them written in a language that we do not yet understand! That often
requires years of work and/or a stroke of good fortune.
The road from genes to drug design
Most epilepsy drugs currently on the market were discovered to have activity
against seizures first, and only later did we come to understand a little
bit about how or why they were effective. However, the ideal way to design
epilepsy drugs would be first to understand the critical workings of the
brain and the key steps that give rise to the seizures, and then make new
drugs that specifically attack the key steps. Such drugs should be more
specific, effective, and have fewer side effects.
The road that will lead to such drug development is beginning to be build,
thanks to the rapid advances in identifying epilepsy genes. The power of
genetics in opening up new avenues of investigation is unique. For example,
some recently identified genes turn out to be involved in aspects of
neuronal function that were previously not thought to be abnormal in
epilepsy. Drug design can now be aimed at the neuronal functions medicated
by these genes, without upsetting other systems. Therefore, each new
epilepsy gene provides a potential new target for developing new drug
therapies that may be more effective and have fewer side effects.
It is likely to take several more years to go from genes to successful
epilepsy drugs: only in 1994 were the first drugs released onto the market
that were designed "rationally" - that is, by exploiting our knowledge of
neuronal function to target aspects of it critical to epilepsy. However,
newly released drugs (protease inhibitors) that treat AIDS interfere with
processes that were not even understood a few years ago, illustrating how
far and how fast "rational" drug design has come and showing its potential
for new treatments given adequate understanding of epileptic mechanisms. The
further study of inherited human epilepsies should provide critical
information for future drug design.