In Style, but...Out of Reach

Image: Erica P. Johnson Treating people who have seizure disorders is a little like playing roulette. Place a bet on a drug from column A and hope for a hit. If that drug doesn't work, try one from column B. This process can drag on for months or years, and for many people with epilepsy--between 25% and 30%--relief from seizures never comes. With 40 to 50 million people experiencing seizures worldwide, this means that huge numbers of people receive no benefit from treatment. One might think that epilepsy would be the poster child for pharmacogenomics. Steering people to the right personal drug would save billions in medical costs, plus reduce their pain and suffering. An Epilepsy Foundation study found that this disease costs the United States $12.5 billion annually, mostly stemming from loss of productivity borne largely by those with intractable or poorly controlled epilepsy.1 But what makes epilepsy so difficult to treat is that more often than not, the seizure's cause is unknown. Familial forms exist, and certain injuries and conditions such as head trauma or a brain tumor can cause it, but these cases are the exception. Most people who have seizures don't know why, and physicians cannot predict whether another will occur, and whether patients need treatment. Ultimately it is the genes that determine whether epilepsy will develop, says Gregory Barkley, epilepsy specialist at the Henry Ford Hospital in Detroit and Epilepsy Foundation advisor. "If you do develop epilepsy, knowing your genetic composition in the future will give us clues to which drugs to pick and which not to pick," he says. READING YOUR GENES Though epilepsy genes are identified, there are no genetic tests on the horizon. For one thing, epilepsy is not a single disease but a collection of disorders, the causes of which are numerous and varied. Some epilepsies that show simple Mendelian genetics have been amenable to genetic mapping, revealing more than a dozen epilepsy genes so far.2 The majority of these familial epilepsy genes, however, code for proteins involved with neuronal transmission--ion channels, neurotransmitter receptors and the like--which are already the targets for the existing armamentarium of antiepileptic drugs. Since familial epilepsies account for less than 1% of the total cases, this approach is not likely to help those with intractable type. A different plan is required to get at the more common forms of epilepsy, which, like many human chronic diseases, are polygenic and multifactorial. Complex diseases such as diabetes, heart disease, and epilepsy involve many genes, any one of which can interact with the environment to increase slightly one's risk for developing the disease. With the recent publication of the complete human haplotype map by the SNP (single nucleotide polymorphism) Consortium,3 tools are now available for identifying genes that contribute even slightly to disease susceptibility. SNP mapping has already identified what might be the first gene for a common epilepsy. Applying a technique called quantitative trait locus (QTL) mapping, University of Pennsylvania's Tom Ferraro is ferreting out genes for common epilepsies. Ferraro started with two strains of mice well known to murine geneticists, C57 and DBA, which differ in susceptibility to seizure. Using QTL with these two strains, Ferraro has located an SNP for a potassium ion channel on chromosome 1, which associates with seizure susceptibility.4 In unpublished work, the Ferraro team has found an SNP in almost the same position in the homologous gene in humans, which, in studies of several hundred patients and controls, appears to be associated with epilepsy. While Ferraro doesn't claim to have found the epilepsy gene, he is excited by these results, as this model might work for identifying common susceptibility genes. He expects to find many more. "We might be identifying genes that provide the susceptibility substrate--genes that give the foundation for seizure susceptibility," he says. While optimistic in general about the prospects for better epileptic treatments, Jeff Noebel, epilepsy researcher at Baylor College of Medicine in Houston, is more cautious about applying genetic information to complex types. "We don't even know how single genes cause some diseases. It will be like the contents of a cereal box--10% of this gene, etc. ... Finding out the complex forms genetically is an important intellectual exercise, but it's hard to see how it will translate." PEERING INTO THE FUTURE Despite the slow progress, researchers appear excited about the prospects for genetic testing and better treatments for epilepsy stemming from the new wealth of genomic information. "It's enormously promising that there are a lot of genes known for inherited epilepsy," says Noebel. To lay the groundwork for future genetic tests, the Epilepsy Foundation's Web site allows people to plot their family trees.5 "It bespeaks the confidence we have that this will amount to something important," he says. But how long it will be before pharmacogenomics provides some answers for the millions of patients who live with seizures is anyone's guess. In a recent review, Robert Robinson and Mark Gardiner of University College London predicted that within this decade, certain epilepsies will be understood, and a revolution in their management will ensue.6 They wrote: "DNA from a buccal swab will be analyzed using a microarray (chip) designed to test for common mutations in, say, 50 ion-channel genes. A precise molecular diagnosis will be made and an anti-epilepsy drug prescribed that will be designed specifically for the particular electrophysiological dysfunction present." Laura DeFrancesco (defrancesco1@earthlink.net) is a freelance writer in Pasadena, Calif. References 1. C.E. Begley et al., "The cost of epilepsy in the United States: An estimate from population-based clinical and survey data," Epilepsia, 41:342-51, 2000. 2. M.H. Meisler et al., "Identification of epilepsy genes in human and mouse," Annual Review of Genetics, 35:567-88, 2001. 3. S.B. Gabriel et al., "The structure of haplotype blocks in the human genome," Science, 296:2225-9, June 21, 2002. 4. T.N. Ferraro et al., "Quantitative genetic study of maximal electroshock seizure threshold in mice: Evidence for a major seizure susceptibility locus on distal chromosome 1," Genomics, 75:35-42, 2001. 5. The Gene Discovery Project of the Epilepsy Foundation: www.efa.org/genetics/ 6. R. Robinson and M. Gardiner, "Genetics of childhood epilepsy," Archives of Diseases in Childhood, 82:121-5, 2000.

In Style, but...Out of Reach

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