By David N. Leff
Epilepsy — more correctly, the epilepsies — come in a broad assortment of types and severities.
At the low-risk end is a seizure disorder of newborn infants called benign familial neonatal convulsions (BFNC). At the highest-risk end is gran mal status epilepticus, in which motor, sensory or psychic seizures follow each other nonstop, for hours or days, and can terminate in death.
In between come gran mal and petit mal. The former describes the common intermittent convulsions that afflict nearly 2 percent of the world's population. The latter, petit mal, is also called "absence," because it brings on a brief but frequent loss of orientation in time and space, lasting only seconds.
Nowadays, most epilepsies are controlled (though rarely cured) by anticonvulsive drug therapy. But a standard medical textbook published in 1784 prescribed for "the falling sickness," among other remedies, blood-letting, "the Peruvian bark," snake-root, mistletoe and musk.
Its 18th-century physician-author noted — presciently — that "when the disease is hereditary, a cure is not to be expected," and "sometimes the epilepsy has been cured by electricity."
Today, epileptic disorders affect from 20 million to 40 million people worldwide. An estimated 1.7 percent of the general population experience its convulsive seizures up to the age of 40.
The fact that epilepsy is a largely inherited disease is starkly borne out by the statistic that of some 9,000 relatively rare genetic disorders described in the standard reference, Mendelian Inheritance in Man, 140 include epileptic seizures in their familial symptomology.
Research geneticists, in their effort to get a handle on the score or so of "pure" epilepsies, have focused on trying to find the gene or genes responsible for BFNC.
This rare form of the disorder makes itself known about as soon as the family brings its newborn baby home from the hospital. Its first seizure may occur on the first day or two of postnatal life, and completely disappear by six months of age.
The infantile spasms of BNFC usually involve jerky twitching of all four limbs. "A tonic-clonic convulsion, if you like," research geneticist Markus Stoffel, of the Rockefeller University, in New York, told BioWorld Today. "You can have blinking or blank staring eyes, obliviousness to loud noises, but the convulsions are really the centerpiece of the syndrome. As a rule, it doesn't last very long," he added, "but disappears after a few minutes, and the children are completely normal between seizures. It usually remits well when you treat it with standard antiepileptic medication, and in most cases completely disappears for life."
However, approximately 13 percent of BNFC infants have subsequent epileptic seizures during later childhood or adulthood, which makes them practical candidates for gene-hunting. Thus, eight years ago, molecular geneticist Mark Leppert, at the University of Utah, in Salt Lake City, reported in Nature (Vol. 337: pp. 647-648): "Benign familial neonatal convulsions linked to genetic markers on chromosome 20."
Found: Both Genes, Their Mutations
Now, in the January 1998 issue of Nature Genetics, out today, he follows up with two back-to-back articles announcing discovery of that first gene on human chromosome 20, plus its mutation, as well as a separate BFNC gene and its mutation on chromosome 8.
That second paper bears the title: "A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family." Its first author is molecular geneticist Carole Charlier, a postdoctoral student in Leppert's lab.
"To find that chromosome-8 gene," she told BioWorld Today, "we looked for gene sequences that could be close to those of the first gene, which we found on chromosome 20. When we had that gene sequence," she recounted, "we designed PCR primers, and amplified different portions of it in an affected individual from a BNFC family. In this way, we found a mutation in the pore, or channel, of the neuron where the potassium ion comes through."
Charlier and her co-authors don't yet know exactly how that mutation brings on the disorder, because they haven't yet expressed the gene. "We will know what this missense mutation does," she pointed out, "only when we will be able to express the gene, to see how it affects the potassium electrical current."
Subsequent Research Focused On Genes' Functions
She went on: "We're working on it, and hope to have it expressed this coming year. But we are sure now that the mutation causes the BNFC phenotype." So far, the co-authors know that the gene expresses a protein about 825 amino acids long.
The team's New Year's resolutions for 1998 include seeking answers to such questions as these, Charlier said:
* How do the different mutations affect the functioning of the potassium channel?
* Why does BNFC produce symptoms only in the first days of life, and afterwards completely remit?
* Is there compensation for the mutant gene's function by some other gene later in life?
* The normal gene is still expressed in normal adults. Why?
"In normal human brains," she observed, "when we look at various tissues in fetuses, newborns and adults, we find the same gene expressed, but we don't know its functions."
And as for adults who suffer from gran mal, full-blown epilepsy, Charlier observed, "We know nothing about that, but we are very interested in finding other genes — maybe from the same potassium channel gene family — that could also be involved in other kinds of epilepsy."
She concluded: "It's a lot more difficult in seizures like gran mal because you cannot have very nice pedigrees of affected families, with neat segregation of the disease."
Rockefeller's Stoffel, who wrote an editorial accompanying Leppert's two papers in Nature Genetics, told BioWorld Today: "Theirs are really the first epilepsy genes that have been identified, and certainly the first epilepsy-associated potassium channels in humans. And now that the genes and their mutations have been found," he continued, "it will be relatively straightforward to determine the likely epileptogenic mechanism in the brain."
Stoffel sees two potential clinical applications of the Utah group's discoveries: "First, a diagnostic test; where you know that epilepsy runs in the family, you might even perform prenatal diagnosis. However," he concluded, "in my eyes, the most exciting aspect to this is its potential for new drug targets." *