Imagine losing consciousness up to 200 times daily while you're learning in a classroom, playing baseball, taking ballet lessons or riding a bike.
This "blanking out" is a common occurrence in the life of patients with childhood absence epilepsy, or CAE. Such "absent" seizures, during which consciousness is impaired, can leave children staring blankly, unaware and unresponsive, for up to 10 seconds at a time.
UCLA–Veterans Affairs scientists have for the first time pinpointed the mutated gene responsible for the development of CAE, which may also help explain why the disease mysteriously disappears in adulthood. Published in the May 29 online edition of the American Journal of Human Genetics, the findings could help lead to the development of new treatments and cures for this and other forms of epilepsy.
"Childhood absence epilepsy strikes at a critical developmental age that can result in scholastic and learning disabilities, as well as problems in social adaptation and family interactions," said study author Dr. Antonio V. Delgado-Escueta, professor-in-residence of neurology at the David Geffen School of Medicine at UCLA and the Epilepsy Genetics/Genomics Laboratories of the Epilepsy Center at the Veterans Affairs Greater Los Angeles Healthcare System in West Los Angeles.
An inherited disorder, CAE accounts for 10 to 12 percent of epilepsy cases in children under 16.
Several medications, including valproate, ethosuximide and clonazepam, are currently effective in controlling the majority of absence seizures.
UCLA-VA research scientist and study author Dr. Miyabi Tanaka examined the DNA of 48 patients with CAE and discovered that four of them had a genetic mutation occurring in a receptor known as GABAR, which binds to a neurotransmitter in the brain called GABA. GABA inhibits the excitation of nerve cells in child and adult brains — when this regulation is lost or reduced, seizures develop.
"We identified this genetic mutation in 8 percent of study patients with CAE, which is significant," said study author Richard W. Olsen, a professor in the department of molecular and medical pharmacology at the Geffen School of Medicine.
Scientists also found that the mutated gene affected several generations of families. They noted that the variations were absent in the DNA of 630 healthy people who did not have CAE.
Genes direct the production more than 100,000 proteins that are responsible for all the body's functions, from digestion and movement to fighting infections.
Researchers located the genetic mutation in a subunit gene of the GABAR receptor called GABRB3. Surprisingly, they found that the problem didn't lie in the main body of GABRB3 but in a signal peptide, which guides genetic information, like an escort, to the factory inside the cell that manufactures the proteins ordered by genes.
This GABRB3 peptide — an alternative signal peptide known as exon 1A — is richly expressed in the fetus and developing brain, but its expression is reduced as children mature and become adults.
"This may help explain why CAE disappears during adolescence and adulthood, since exon 1A is not expressed at an adult age in the critical region responsible for absence seizures," said Tanaka, a research scientist with the UCLA Department of Molecular and Medical Pharmacology and the VA Epilepsy Center.
The research team found that the signal peptide with the mutation caused the developing protein to be excessively modified by sugars, which led to a reduced number of GABAR receptors on the surface of the nerve cell. This, in turn, caused a reduction in the total GABA currents that help regulate the nerve cells, leading to the "absent" seizures found in CAE.
The scientists note that this may lead to radical new treatment approaches for epilepsy that could involve suppressing the genetic expression of the mutated signal peptide.
According to researchers, the next step will involve studying a larger population of children with CAE who have no family history of epilepsy in order to determine how common these genetic mutations are in the patient population and the general public.
The research was funded by the National Institutes of Health and the U.S. Department of Veterans Affairs.
Three laboratories collaborated on the basic aspects of the research: the UCLA Department of Molecular and Medical Pharmacology; the Epilepsy Genetics/Genomics Laboratories of the Epilepsy Center at the Veterans Affairs Greater Los Angeles Healthcare System; and the Vanderbilt University Department of Neurology.
In addition, several collaborators in the international genetic epilepsies consortium GENESS — led by Dr. Maria Elisa Alonso, of Mexico, and Dr. Marco T. Medina, of Honduras, with Dr. Delgado-Escueta — participated in the family genetic studies. They included the National Autonomous University of Honduras; the National Institute of Neurology and Neurosurgery, Mexico; the University of Sonora, Mexico; University Hospital La Paz, Spain; and Nuestra Senora de La Paz Hospital, El Salvador.
