Lafora disease can be caused by mutations in a gene that regulates the concentration of the protein laforin

Researchers at University of California, San Diego (UCSD) have found that Lafora disease, an inherited form of epilepsy that results in death by the age of 30, can be caused by mutations in a gene that regulates the concentration of the protein laforin. These findings are reported in the current issue of Proceedings of the National Academy of Sciences (PNAS).

Lafora disease is characterized by normal development for the first decade of life, followed by an initial seizure in the second decade, progressively worsening seizures, early dementia, and death within 10 years of onset. Medications can ease the severity of initial symptoms, but there is no long-term treatment or cure for the disease.

A puzzling aspect of the disease is the accumulation of starch-/glycogen-like granules in most tissues of Lafora disease patients. Thus, researchers have long thought that a defect in glycogen metabolism is intimately linked to the disease. Recessive mutations in two genes have been shown to cause Lafora disease. The genes encode the proteins laforin and malin, but the molecular mechanism defining how loss of laforin or malin causes Lafora disease has remained unclear.

Jack E. Dixon, Ph.D., UCSD dean of scientific affairs and professor of pharmacology, and colleagues at UCSD investigated the role of malin in Lafora disease and found that malin physically interacts with laforin and regulates laforin’s concentration by marking it for degradation. Their results show that approximately 40 percent of patients with Lafora disease have mutations in malin that render it unable to mark laforin for degradation. This increase in laforin may lead to Lafora disease through aberrant glycogen metabolism.

This work establishes a few testable models as to the molecular mechanism of the disease. Dixon and colleagues are currently designing experiments to test these models with the hope of gaining the necessary insights to develop potential therapies for Lafora disease.

Co-authors are Matthew S. Gentry, Ph.D., and Carolyn A. Worby, Ph.D., both of the UCSD Department of Pharmacy. This research was funded by the National Institutes of Health.