Mice reveal three epilepsy genes.

Scientists are slowly unraveling the secrets of epilepsy, the most common human neurological affliction next to stroke. This complex disorder, often characterized by repeated seizures, comes in several forms with varying degrees of severity. A Boston research team now has linked areas of three chromosomes to a specific type of epilepsy in mice.

Within these areas lie three genes, not yet isolated, that appear to play a major role in temporal lobe epilepsy, Thomas N. Seyfried of Boston College and his colleagues report in the Aug. 9 Science. This type of epilepsy, common among humans, involves seizures that originate in the temporal lobe and spread throughout the brain. After breeding normal mice back and forth with moce susceptible to these seizures, the researchers performed a statistical analysis of seizure frequencies and discovered a connection with genes on the mouse chromosomes 2, 4 and 9.

Chromosome 9 holds the "major gene" that indicates the presence of temporal lobe epilepsy, says Seyfried. The other two genes apparently modify the severity of the disorder. He notes that several other genes located near the major gene code for proteins that bind to heavy metals such as copper, zinc and iron. This observation, along with other rearch linking zinc deprivation to epilepsy, suggests a possible cause for some types of the disorder, including the temporal lobe variety. "Abnormalities in [the brain's] metal levels could contribute to epileptic seizures," Seyfried says.

With the new findings, "we can now predict on the human genome where an epilepsy gene could exist," he asserts. Despite their obvious differences, mice and humans share about 38 percent of the same genetic code, he says. In fact, many areas of the mouse chromosome 9 -- including the place where the Boston team discovered the major gene -- are very similar to the human chromosome 3. Researchers should therefore include chromosome 3 in any studies of the genetic basis of human epilepsy, Seyfried says.

The researchers also point out that previous mouse studies have implicated the modifier gene on chromosome 4 in audiogenic seizures, another form of epilepsy. This raises the intriguing possibility that a single gene influences a wide range of seizures, says V. Elving Anderson, a geneticist at the University of Minnesota in Minneapolis.

Isolation of epilepsy genes and their products could lead to more specific drugs for the disorder, the Boston researchers suggest. Current anticonvulsant drugs often have severe side effects and sometimes do not even work, Seyfried says. A drug designed to correct specific gene defects should work much more efectively, he says. However, such drugs remain a long way off. The mechanisms of epilepsy in mice and humans may differ significantly, and researchrs still need to identify similar epilepsy genes in humans. Moreover, both Seyfried and Anderson note that additional epilepsy genes may still await detection.