Findings in Epilepsy Gene in Animals May Guide Treatment Directions for Infants
PHILADELPHIA, June 1 /PRNewswire-USNewswire/ -- Researchers studying a
difficult-to-treat form of childhood epilepsy called infantile spasms have
developed a line of mice that experiences seizures with features closely
resembling those occurring in patients with infantile seizures. These
genetically engineered mice provide a new opportunity for scientists to
test treatments that may benefit children.
"Approximately one out of every 100 infants has a seizure. Many of them
go on to have epilepsy -- characterized by recurrent seizures. One obstacle
to developing better therapies for children has been the lack of a good
animal model," said study leader Jeffrey A. Golden, M.D.,
pathologist-in-chief at The Children's Hospital of Philadelphia.
Golden's team described a new mouse model for infantile spasms on May
12 in an online study in the journal Brain.
Infantile spasms are a type of seizure that occurs in an estimated 1 in
2000 to 1 in 6000 babies, with onset between ages three months and one
year. During the seizures, infants have jerking movements and abnormal
brain waves (seen on EEGs). "Children with infantile spasms often have a
poor developmental outcome," said Golden. "Despite current treatment, many
children with infantile spasms go on to develop lifelong epilepsy and
varying degrees of mental retardation."
Finding a treatment for infantile spasms is crucial. "If we could
better treat the infantile spasms, it is very possible some of these later
problems could be prevented," added Golden.
Neurologists previously knew that mutations in Arx, the X-linked
aristaless-related homeobox gene, were associated with abnormal brain
development, neurocognitive problems, and with childhood neurological
conditions involving seizures and spasms.
Golden's team developed genetically engineered mice in which the Arx
gene was removed from interneurons, a type of brain cell that inhibits
electrical firing in brain circuits. Removing the gene's role appears to
have resulted in overexcited brain cells and seizures in the mice. The
seizures resembled human infantile spasms. Equally exciting to the
researchers, these mice had another brain wave abnormality similar to that
found in children with infantile spasms -- an abnormal background EEG.
"This is the first genetic model of a developmental epilepsy, and even
more importantly, it was generated by mutating the same gene that can be
found mutated in humans with infantile spasms," said Golden. In an
unexpected development, the researchers found that half of the female mice
carrying the mutation also developed seizures. Because the mutation occurs
on the X chromosome, it was expected that male mice would have seizures,
which was true, and that all the females would be unaffected carriers,
which was not the case.
This discovery prompted the researchers to take a closer look at human
families with an infantile spasms patient. They found that the patients'
mothers (14 women) had experienced normal development. But of the patients'
nine other relatives -- sisters, aunts and a cousin -- six had neurological
problems, including four with epilepsy. The neurological problems included
varying degrees of mental retardation or other learning disabilities. These
findings, said Golden, will immediately change the evaluation and testing
of women with mental retardation and epilepsy, particularly in families
with other affected individuals.
This new finding will also assist genetic counselors in advising
parents who already have a child with an Arx mutation and are contemplating
having another child.
Going forward, Golden said, this new animal model provides an important
tool: an opportunity to begin testing drugs in the mice to identify
potential treatments for children. "We can screen existing drugs to see if
they are effective against this type of epilepsy," said Golden, adding that
understanding the biological mechanism by which infantile spasms develop
may also lead to more specific treatments.
Golden and first author Eric D. Marsh, M.D., Ph.D., are both from
Children's Hospital and the University of Pennsylvania. Other co-authors
were Amy Brooks-Kayal, of the Children's Hospital, Denver and the
University of Colorado; and faculty members of the University of Chicago;
Vanderbilt University; the University of Rotterdam, Netherlands; and the
University of Pennsylvania School of Medicine. The National Institutes of
Health, the American Epilepsy Society/Milken Family Foundation and The
Children's Hospital of Philadelphia provided funding support for this
Marsh et al, "Targeted loss of Arx results in a developmental epilepsy
mouse model and recapitulates the human phenotype in heterozygous females,"
Brain, published online May 12, 2009.
About The Children's Hospital of Philadelphia: The Children's Hospital
of Philadelphia was founded in 1855 as the nation's first pediatric
hospital. Through its long-standing commitment to providing exceptional
patient care, training new generations of pediatric healthcare
professionals and pioneering major research initiatives, Children's
Hospital has fostered many discoveries that have benefited children
worldwide. Its pediatric research program is among the largest in the
country, ranking second in National Institutes of Health funding. In
addition, its unique family-centered care and public service programs have
brought the 430-bed hospital recognition as a leading advocate for children
and adolescents. For more information, visit http://www.chop.edu.
Contact: John Ascenzi
Phone: (267) 426-6055
SOURCE The Children's Hospital of Philadelphia