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Christopher A. Walsh Laboratory 
 

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 dubbed L1.

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 defects.

 

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