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 study.

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
Ascenzi@email.chop.edu

SOURCE The Children's Hospital of Philadelphia

John Ascenzi of The Children's Hospital of Philadelphia, +1-267-426-6055,
Ascenzi@email.chop.edu