Aug. 11, 2013 Researchers have identified two new genes and implicated 25 distinct mutations in serious forms of epilepsy, suggesting a new direction for developing tailored treatments of the neurological disorders.

The findings by an international research collaboration, which includes investigators from Duke Medicine, appear Aug. 11 in the journal Nature.

Epileptic encephalopathies are a devastating group of severe brain disorders characterized by the onset of seizures at an early age. The seizures are often accompanied by cognitive and behavioral issues, which can hinder the quality of life of affected children and their families.

The cause of epileptic encephalopathies is largely unknown; while genes are believed to play an important role, specific genes have only been identified in a small number of cases.

"One important aspect of the study is that we identified an unusually large number of distinct disease-causing mutations -- 25 in total, all of which were de novo mutations. These mutations will be an invaluable resource to scientists working to elucidate the underlying causes of the epilepsies," said study author David Goldstein, PhD, director of the Duke Center for Human Genome Variation.

A de novo mutation is a new alteration in a gene that appears for the first time in a family, and results from a genetic mutation in a parent's germ cell (egg or sperm).

Learning more about the disorders' origin will guide development of effective therapies, which is the goal of Epi4K, an international research consortium funded by the National Institute of Neurological Diseases and Stroke (NINDS).

"This research focusing on epileptic encephalopathies is the first large-scale project of Epi4K," said study author Erin Heinzen, PhD, assistant professor of medicine in the Division of Medical Genetics at Duke. "The study was designed to identify de novo mutations and search for ones that contribute to risk."

The Epi4K researchers partnered with the Epilepsy Phenome/Genome Project, another NINDS-funded group working to unlock the mysteries of epilepsy. Led by Daniel Lowenstein, M.D., professor of neurology at the University of California, San Francisco, the researchers in the Epilepsy Phenome/Genome Project gathered genetic information on 264 children with epileptic encephalopathies and their parents.

The Epi4K researchers then focused on identifying all new mutations in the children using next-generation sequenced data, which looks at the part of genome that encodes protein. The Center for Human Genome Variation at Duke conducted this analysis, and confirmed 329 de novo mutations. Most of these mutations had no connection to the risk of disease, but the researchers showed that a fraction of them strongly influence risk.

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Newly identified genetic factors drive severe childhood epilepsies

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