"Epilepsy is one of the most common neurological disorders affecting over 40 million people worldwide," said Dr. Berge Minassian, one of the study's senior authors, an HSC neurologist and scientist, and an assistant professor in the Department of Paediatrics at U of T. "Lafora disease is one form of epilepsy that occurs during early adolescence and is characterized by seizures and progressive neurological degeneration. Death usually occurs within a decade of the first symptoms."
Fifty years of investigation led doctors to suspect that Lafora disease was caused by problems with carbohydrate metabolism in the brain. Beyond this, however, the fundamental defect triggering the malfunction was unknown. In 1998, the HSC team identified the first gene implicated in Lafora disease, called EPM2A.
"While the discovery of the EPM2A gene has led to the development of diagnostics and a better understanding of the fundamental defect causing seizures, it explained the underlying problem for only 50 per cent of LD families," said Dr. Stephen Scherer, the other senior author of the study, an HSC senior scientist, and an associate professor in the Department of Molecular and Medical Genetics at U of T.
"The newly discovered LD gene, named NHLRC1, produces a protein thought to be involved in marking other proteins for destruction in the cell. Our early data suggests that the EPM2A and NHLRC1 genes work together to safeguard neurons against accumulating too many carbohydrates. If either of the genes is missing, the result is epilepsy," added Dr. Scherer. "Importantly, we can now explain Lafora disease in 90 per cent of families, and for the remaining 10 per cent, we think there is a third yet-to-be-identified disease gene."
Technology in the DNA sequencing facility in The Centre for Applied Genomics at HSC allowed the research team to complete the necessary sequencing of patient and family samples more quickly than with earlier studies.
"Our discovery opens a new area of research into not only epilepsy, but also normal brain function. Ultimately, we hope that understanding the basic genetic defect will allow us to discover the basic mechanisms that underlie the severe epilepsy in this disorder, but also to possibly correct the disease by therapeutic treatment," said Elayne Chan, the study's lead author and a University of Toronto graduate student. Chan is a recipient of an Epilepsy Canada/Canadian Institutes of Health Research doctoral research award.
This research was supported by the Canadian Institutes of Health Research, the Canadian Genetic Diseases Network, Genome Canada through the Ontario Genomics Institute, the Canada Foundation for Innovation, the Ontario Innovation Trust, The Centre for Applied Genomics at The Hospital for Sick Children, and The Hospital for Sick Children Foundation. Dr. Scherer is an Investigator of the Canadian Institutes of Health Research and International Scholar of the Howard Hughes Medical Institute.
The Hospital for Sick Children, affiliated with the University of Toronto, is Canada's most research-intensive hospital and the largest centre dedicated to improving children's health in the country. Its mission is to provide the best in family-centred, compassionate care, to lead in scientific and clinical advancement, and to prepare the next generation of leaders in child health. For more information, please visit www.sickkids.ca.