AsianScientist (Apr. 2, 2015) – Somatic mutations in MTOR gene are responsible for intractable epilepsy, according to research published in Nature Medicine. The findings could lead to the development of a precision medicine to treat epileptic seizures.
Epilepsy is a brain disorder which afflicts more than 50 million people worldwide. Many epilepsy patients can control their symptoms through medication, but about 30 percent suffer from intractable epilepsy and are unable to manage the disease with drugs. Intractable epilepsy causes multiple seizures, permanent mental, physical, and developmental disabilities and even death.
Surgical removal of the affected area from the brain has been practiced as a treatment for patients with medically refractory seizures, but this too fails to provide a complete solution because only 60 percent of the patients who undergo surgery are rendered free of seizures.
A research team led by Professor Lee Jeong Ho of the Korea Advanced Institute of Science and Technology (KAIST) and Professor Kim Dong-Seok of Epilepsy Research Center at Yonsei University College of Medicine has recently identified brain somatic mutations in the gene of mechanistic target of rapamycin (MTOR) as the cause of focal cortical dysplasia type II (FCDII), one of the most important and common inducers to intractable epilepsy, particularly in children.
FCDII contributes to the abnormal developments of the cerebral cortex, ranging from cortical disruption to severe forms of cortical dyslamination, balloon cells and dysplastic neurons. The research team studied 77 FCDII patients with intractable epilepsy who had received a surgery to remove the affected regions from the brain.
Using various deep sequencing technologies to conduct comparative DNA analysis of the samples obtained from the patients’ brain and blood, or saliva, they found that about 16 percent of the studied patients had somatic mutations in their brain. Such mutations, however, did not take place in their blood or saliva DNA.
“This is an important finding. Unlike our previous belief that genetic mutations causing intractable epilepsy exist anywhere in the human body including blood, specific gene mutations incurred only in the brain can lead to intractable epilepsy. From our animal models, we could see how a small fraction of mutations carrying neurons in the brain could affect its entire function”, according to Lee.
When mutated mTOR was expressed in the brains of mice, the mice developed epileptic symptoms. When the mice were then treated with the mTOR inhibitor rapamycin, the epileptic seizures stopped.
“Our study offers the first evidence that brain-somatic activating mutations in MTOR cause FCDII and identifies mTOR as a treatment target for intractable epilepsy,” said Kim.
The article can be found at: Lim et al. (2015) Brain Somatic Mutations in MTOR Cause Focal Cortical Dysplasia Type II Leading to Intractable Epilepsy.
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