Nature+Medicine
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Mutations Occurring Only in Brain Responsible for Intractable Epilepsy Identified
KAIST researchers have discovered that brain somatic mutations in MTOR gene induce intractable epilepsy and suggest 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% 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. Therefore, 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% of the patients who undergo surgery are rendered free of seizures.
A Korean research team led by Professor Jeong Ho Lee of the Graduate School of Medical Science and Engineering at the Korea Advanced Institute of Science and Technology (KAIST) and Professor Dong-Seok Kim 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. They propose a targeted therapy to lessen epileptic seizures by suppressing the activation of mTOR kinase, a signaling protein in the brain. Their research results were published online in Nature Medicine on March 23, 2015.
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. The researchers used various deep sequencing technologies to conduct comparative DNA analysis of the samples obtained from the patients’ brain and blood, or saliva. They reported that about 16% of the studied patients had somatic mutations in their brain. Such mutations, however, did not take place in their blood or saliva DNA.
Professor Jeong Ho Lee of KAIST said, “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.”
The research team recapitulated the pathogenesis of intractable epilepsy by inducing the focal cortical expression of mutated mTOR in the mouse brain via electroporation method and observed as the mouse develop epileptic symptoms. They then treated these mice with the drug called “rapamycin” to inhibit the activity of mTOR protein and observed that it suppressed the development of epileptic seizures with cytomegalic neurons.
“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 co-author Dr. Dong-Seok Kim, a neurosurgeon at Yonsei Medical Center with the country’s largest surgical experiences in treating patients with this condition.
The research paper is titled “Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy.” (Digital Object Identifier #: 10.1038/nm.3824)
Picture 1: A schematic image to show how to detect brain specific mutation using next-generation sequencing technology with blood-brain paired sample. Simple comparison of non-overlapping mutations between affected and unaffected tissues is able to detect brain specific mutations.
Picture 2: A schematic image to show how to generate focal cortical dysplasia mouse model. This mouse model open the new window of drug screening for seizure patients.
Picture 3: Targeted medicine can rescue the focal cortical dysplasia symptoms including cytomegalic neuron & intractable epilepsy.
2015.03.25 View 13288 -
Genetic Cause of ADHD (Attention Deficit Hyperactivity Disorder) Found
The cooperative research team consisting research teams under Professor Kim Eun Joon and Professor Kang Chang Won of the department of Biological Sciences discovered that ADHD arises from the deficiency of GIT1 protein in the brain’s neural synapses.
ADHD (Attention Deficit Hyperactivity Disorder) is found in around 5% of children around the world and is a disorder where the child becomes unable to concentrate, show over the top responses, and display impulsive behavior.
The research team found that the difference between children with ADHD and those without it is one base in the GIT1 gene. The difference of a single base causes the underproduction of this protein, and those children with low levels of the protein had a higher probability to develop ADHD.
In addition, further evidence was provided when the research team conducted mice experiments. Those mice with low levels of GIT1 exhibited impulsive and exaggerated reactions like humans with ADHD, had learning disabilities, and produced abnormal brain waves. And upon injecting these mice with cure for ADHD, the symptoms of ADHD disappeared.
The impulsive behavior of ADHD children disappears as the child enters adulthood and a similar pattern was found in mice. A mice with low levels of GIT1 showed impulsive behaviors when 2 months old, but these behaviors disappeared as it got older to around 7 months old (equivalent to 20~30 years old for humans).
Professor Kim Eun Joon commented that there has to be equilibrium between mechanisms that excite the neurons and mechanisms that calm the neurons, but the lack of GIT1 leads to the decrease in the mechanisms that calm the neurons which causes the impulsive behavior of ADHD patients.
In addition, Professor Kang Chang Won commented that the results of the experiment has been receiving rave reviews and is being seen as the new method in the production of the cure for ADHD.
The result of the experiment was published in the online edition of Nature Medicine magazine.
2011.04.30 View 10005 -
The Irish Times: Gene link identified in ADHD, April 18, 2011
The Irish Times wrote an article on the recent research breakthrough made by a KAIST research team to identify a gene that triggers the syndrome of Attention Deficit Hyperactivity Disorder (ADHD) among children. Given the heightened attention to the syndrome across the world, the research result has received a great deal of attention not only from the academia but also from the media and public.
For the article, please visit http://www.irishtimes.com/newspaper/ireland/2011/0418/1224294910305.html. The research paper was appeared online April 17, 2011 in Nature Medicine, which will be printed in its May 2011 issue. For the paper, please click the link of http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2330.html.
2011.04.18 View 9147