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Subject: NIH-FUNDED STUDY DISCOVERS NEW GENES FOR CHILDHOOD EPILEPSIES

U.S. Department of Health and Human Services NATIONAL INSTITUTES OF HEALTH
NIH News National Institute of Neurological Disorders and Stroke
(NINDS)<http://www.ninds.nih.gov/>
Embargoed for Release: Sunday, August 11, 2013, 1 p.m. EDT

CONTACT: Christopher Thomas, 301-496-5751,
<e-mail:[log in to unmask]>

NIH-FUNDED STUDY DISCOVERS NEW GENES FOR CHILDHOOD EPILEPSIES New strategy
may find more genes and provide a better understanding of these and other
complex neurological disorders

A genetic study of childhood epilepsies has linked two new genes to severe
forms of disease and provides a novel strategy for identifying therapy
targets.  This study used a cutting-edge genetic technique, called exome
sequencing, to search for new mutations that are not inherited.  The results
suggest this may be a highly effective way to find and confirm many
disease-causing gene mutations.

"It appears that the time for using this approach to understand complex
neurological disorders has arrived," said David Goldstein, Ph.D., director
of the Center for Human Genome Variation at Duke University Medical Center,
Durham, N.C., and a leader of the study.  "This moderately-sized study
identified an unusually large number of disease-causing mutations and
provides a wealth of new information for the epilepsy research community to
explore." 

The study is part of a worldwide, $25 million project, largely funded by the
National Institutes of Health, called Epilepsy 4000
(Epi4K)<http://www.epgp.org/epi4k/>.  Epi4K's mission is to use the latest
genetic techniques to sequence and analyze DNA from 4000 epilepsy patients
and their relatives.  To do this, the researchers and NIH staff involved
organized a team of international research institutions devoted to the
mission, called the Epilepsy Centers without Walls.  This approach
facilitates the sharing and analysis of DNA sequences and patient
information among the dozens of institutions participating in the project.
The study, published in Nature by the Epi4K and Epilepsy Phenome/Genome
Project (EPGP) Investigators, found as many as 25 epilepsy-causing mutations
in new and previously identified genes.

"These promising results highlight the strength of supporting large
international research teams devoted to studying the genetics behind highly
complex neurological disorders," said Story Landis, Ph.D., director of NIH's
National Institute of Neurological Disorders and Stroke (NINDS).  The
project is also led by Daniel Lowenstein, M.D., a vice chair of the
Department of Neurology at the University of California, San Francisco
(UCSF) and Sam Berkovic, M.D., director of the Epilepsy Research Center at
the University of Melbourne, Australia on behalf of an international team of
investigators.

Epilepsy is a group of neurological disorders caused by abnormal firing of
nerve cells in the brain which often produces debilitating seizures and a
range of other symptoms.  More than 2 million people in the United States
suffer from epilepsies, and infants and children have a greater chance of
having the disorders than adults.  Although some studies have found genes
associated with rare inherited forms of epilepsy, finding genes associated
with the majority of epilepsies has been difficult.  

"Unlike some diseases many of the genetic mutations associated with severe
childhood epilepsies appear to be new mutations that are not inherited,"
said Randall Stewart, Ph.D., a program director at NINDS.  "This Epi4K-EPGP
project was established to find such mutations."

In this study, the researchers used exome sequencing to find mutations that
might cause two devastating forms of childhood epilepsy, called infantile
spasms and Lennox-Gastaut Syndrome. DNA and clinical data were originally
collected through the NIH-funded Epilepsy Phenome/Genome Project which was
led by Dr. Lowenstein and Elliot Sherr, M.D., Ph.D., director of the
Comprehensive Center for Brain Development at UCSF and Dr. Ruben Kuzneicky,
M.D., professor at the New York University Comprehensive Epilepsy Center.

"The Epilepsy Phenome/Genome Project, with its massive data set, laid the
groundwork for this study, and the key to this success has been the
extraordinary level of collaboration among more than 115 investigators,
study coordinators and administrative personnel involved in both EPGP and
Epi4K," said Dr. Lowenstein.

Exomes essentially represent all of a person's genes.  Their DNA sequences
provide the instructions for constructing all the proteins made by the body.
The researchers compared exome sequences of 264 children with the sequences
of their parents who do not have epilepsy.  Differences in the sequences of
these subject trios were analyzed using a number of statistical tools to
identify potential disease causing mutations.  Compared with some genetic
studies, this research sequenced DNA from relatively few patients.
Nonetheless, the researchers were able to find disease-causing mutations in
six genes: four had been described before using other genetic techniques and
two genes are implicated for the first time.

Using novel genetic analysis techniques, the researchers also demonstrated
that epilepsy-causing mutations are concentrated in genes that are highly
sensitive, or intolerant, to changes in their DNA sequence in human
populations.  These genes are so sensitive that even the slightest change
can cause the gene not to work, leading to death or severe forms of
diseases.

"This study used a very sophisticated bioinformatics approach to analyze DNA
sequences and find disease-causing mutations," said Katrina Gwinn, M.D., a
program director at NINDS.

To find more genes that are likely to have epilepsy-causing mutations, the
researchers searched thousands of exome sequences from healthy volunteers
who participated in the National Heart Lung and Blood Institute Exome
Sequencing Project.  They looked for gene sequences that had only slight
differences among subjects because previous studies showed that these
sequences are highly sensitive to mutations.  The researchers estimated that
up to 90 genes could carry epilepsy-causing mutations and that many of the
mutations implicated in the risk of epilepsy have been previously associated
with other neurodevelopmental diseases, including autism.

"One of the most encouraging aspects of this study is that we're beginning
to see how best to interpret and make effective use of exome sequence data,"
said Dr. Goldstein. "We anticipate that further studies will identify many
new disease-causing genes and we intend to develop a watch list of the genes
which summarizes their clinical characteristics in way that will be helpful
for doctors, patients, and researchers."  

For instance, the researchers analyzed how the genes that could carry
epilepsy-causing mutations work and interact.  Their analysis showed that
the genes can be grouped into a few networks.  Each network appears to play
an important role in the growth and development of a child's nervous system.

"It appears that a few pathways may be responsible for many severe pediatric
epilepsies," said Dr. Goldstein, "If true, then understanding epilepsies
will be more manageable and we can find common pathways to target with drugs
and other therapies."

In addition to grants from NINDS (NS053998, NS077364, NS077274, NS077303,
NS077276), this study was funded by Finding a Cure for Epilepsy and Seizures
and the Richard Thalheimer Philanthropic Fund.

For more information about Epilepsy, Infantile Spasms, and Lennox-Gastaut
Syndrome, please visit: 
 -- <http://www.ninds.nih.gov/disorders/epilepsy/epilepsy.htm>

 -- <http://www.ninds.nih.gov/disorders/infantilespasms/infantilespasms.htm>

 --
<http://www.ninds.nih.gov/disorders/lennoxgastautsyndrome/lennoxgastautsyndr
ome.htm>

NINDS <http://www.ninds.nih.gov> is the nation's leading funder of research
on the brain and nervous system. The NINDS mission is to reduce the burden
of neurological disease - a burden borne by every age group, by every
segment of society, by people all over the world.

About the National Institutes of Health (NIH): NIH, the nation's medical
research agency, includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. NIH is the primary federal
agency conducting and supporting basic, clinical, and translational medical
research, and is investigating the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and its programs,
visit <www.nih.gov>.

NIH...Turning Discovery into Health -- Registered, U.S. Patent and Trademark
Office
-----------

The htm  version of this release contains an image of a graph of the study
results at <http://www.nih.gov/news/health/aug2013/images/ninds-11_l.jpg>

CAPTION: 
Severe Childhood Epilepsy Gene Mutations - Researchers from the Epi4K
project used advanced genetic techniques to search for mutations that are
likely to be involved with severe childhood epilespies.  This "heat map"
helps describe some of their results.  See paper for a detailed explanation.
Courtesy of Epi4K-EPGP Investigators.

REFERENCE:
EPi4K and EPGP Investigators "De novo mutation in the classic epileptic
encephalopathies."  Nature, August 11, 2013. DOI: 10.1038/nature12439.
###

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