Scientific American - May 1996
X Marks the Spots
Researchers find a genetic marker for an uncommon form of epilepsy
By Kristin Leutwyler
Genetic mutations account for a number of neurological disorders, among them
certain forms of mental retardation. By studying such illnesses, scientists
have learned a great deal about normal brain development. Now they have new
material to work with. In a recent issue of Neuron, Boston researchers from
Beth Israel Hospital and Harvard Medical School described a genetic marker
for a rare form of epilepsy called periventricular heterotopia (PH). Some
0.5 percent of the population have epilepsy, and fewer than 1 percent of
them have PH.
"The disease seemed to be expressed exclusively in females, and these
families seemed to have a shortage of male babies," says team member
Christopher Walsh. "So there was the suggestion that it was an X-linked
defect." The group examined blood samples from four affected pedigrees and
quickly confirmed the hypothesis. They singled out a common stretch of DNA
along the X chromosome that contained many well-known genes, including one
Genes such as L1 that ordinarily help to assemble the brain are strong
suspects in the search for PH's source, Walsh adds. Damage to L1 itself
causes an array of developmental disorders often marked by some subset of
symptoms, including hydrocephalus (water on the brain), enlarged ventricles,
enlarged head, thinning of the corpus callosum, retardation, spasticity in
the lower limbs, adducted thumbs and defects in cell migration. PH also
produces certain telltale brain defects. In particular, neurons that should
travel to the cerebral cortex-the outermost region of the brain- remain deep
inside the organ instead.
"We wondered why some of all cell types [in PH] failed to migrate, as
opposed to all of one cell type," Walsh notes. "We think the answer is that
the female brain is a mosaic." One of the two X chromosomes in each cell of
a female fetus is shut off at random after the first third of gestation, he
explains. So those with PH probably express normal X chromosomes in most
cells and mutants in a few others. As a result, select representatives of
all types of cortical cells are stalled in their movement. In contrast,
affected male fetuses, which possess single, flawed X chromosomes in every
cell, develop so abnormally that they are miscarried.
Finding the precise gene should make it easier to diagnosis PH, Walsh says.
Most patients have no outward symptoms other than frequent epileptic
seizures, which are usually atypical. Also, whatever mechanism prompts PH
may play some role in other forms of epilepsy. "There may be hundreds of
gene mutations that confer risk for epilepsy," Walsh states. (Indeed,
geneticists from Stanford and the University of Helsinki reported in March
that mutations in the gene encoding for a protein called Cystatin B occurred
in another uncommon inherited epilepsy, progressive myclonus epilepsy.) "But
perhaps the gene products behind PH do something throughout the brain that
causes seizures," Walsh adds, "and perhaps that same thing underlies all
forms of epilepsy."
In fact, the products of X-chromosome genes controlling development may
stand behind even more neurological disorders than has been believed.
Researchers at the J. C. Self Research Institute of the Greenwood Genetic
Center in South Carolina are currently screening for L1 defects among the 40
to 50 percent of mentally retarded individuals in the state for whom no
diagnosis has been found. To narrow the search, the group limited the survey
to men having enlarged heads and spasticity in their gait. Already they have
found a greater incidence of L1 mutations than expected. "L1-related
retardation is not as prevalent as fragile-X [another form of retardation],"
says Charles Schwartz, director of the Molecular Studies unit, "but it's
probably still more common than previously thought."
Knowledge of the actual molecular mechanisms behind L1-related disorders has
recently given workers insight into fetal alcohol syndrome as well. Several
years ago Michael E. Charness of Harvard University noted several
similarities between certain aspects of fetal alcohol syndrome, his area of
expertise, and L1 disorders. Therefore, he tested the effects of alcohol on
the L1 molecule, known to guide axon growth over long distances and connect
neurons during development.
Last month, Charness released results showing that alcohol completely
abolishes L1's adhesive properties in low doses-namely, amounts that would
be present in a pregnant woman's bloodstream after she consumed one or two
drinks. "Epidemiologists have suggested that there may be measurable effects
of low amounts of alcohol on a fetus," Charness states. "This finding
provides us with one potential molecular mechanism behind that observation."
The hope is that the unraveling of more such mechanisms will lead to
prevention or to better treatment for a wide range of neurological birth