IDEAS Research Roundtable Explores Link Between idic(15) and Seizures

Nicole Cleary, IDEAS Executive Director

On June 22, 2005 IDEAS convened its third research roundtable meeting. This meeting represented the first time parents and scientists came together to explore the link between duplications of chromosome 15q and seizures.

The roundtable meeting had three objectives:

1. To review current research on idic(15) syndrome, with special emphasis on what is
   known about the relationship of this syndrome to seizures. 
2. To identify priorities for future research to further characterize seizures in idic(15)
   syndrome.
3. To determine how the meeting attendees might collaborate on research priorities
   identified at this meeting.

Our meeting started with five parents sharing their children’s experience with seizures. The scientists in attendance heard about seizures that started in infancy, in childhood and in adolescence. Families described how children started with one seizure type and other seizure types emerged as the child aged. Some seizures were easily controlled with the first medication, other seizures were controlled for awhile and then became more complex, and a few families described seizures that have never been controlled with medication. It was helpful for everyone to begin this meeting with the realization that over half of all individuals with idic(15) will experience seizures, but seizures are not uniform in their onset, their presentation or in their response to treatment.

IDEAS Professional Advisors Brenda Finucane and Dr. Carolyn Schanen provided an overview of the current understanding of the relationship of idic(15) to seizures, drawing from the IDEAS seizure survey and Carolyn’s NIH funded study on the Molecular Investigations of Duplications of Chromosome 15 in Autism.

The meeting then turned to an examination of the role of Gamma Amino Butyric Acid (GABA). GABA is a major inhibitory neurotransmitter in the brain. There are three GABA_A receptor subunit genes that are commonly duplicated in idic(15). It is hypothesized that the abnormalities in these GABA_A receptor genes may play a significant role in the seizures experienced by people with idic(15). Dr. Martin J. Gallagher from Vanderbilt University Medical Center in Nashville, Tennessee provided a very technical presentation regarding the many consequences of abnormal GABA_A receptor expression. He showed that even minor changes in the receptor structures can lead to human epilepsy syndromes. The methods that he uses to analyze the function of GABA_A receptors in the lab could be applicable to characterizing the effects of the extra copies of the GABA_A receptor genes in individuals with chromosome 15 duplications in isolated cells.

This presentation was followed by Dr. Diane Chugani from Wayne State University in Detroit Michigan. Dr. Chugani is currently engaged in a study to measure brain GABA_A receptor binding in children with chromosome 15q11-13 mutations through the use of positron emission tomography (PET). Understanding of GABA_A receptor binding abnormalities in subjects with chromosome 15q11-13 duplications may lead to clues regarding the diverse presentation of seizures among individuals with this syndrome as well as to the autism and cognitive disabilities in these children.

Dr. Art Beaudet from Baylor College of Medicine in Houston, Texas spoke about the role of the Prader-Willi/Angelman region in determining the clinical features in individuals with duplications of chromosome 15q. Dr. Beaudet’s research on genetic imprinting explores parent-specific gene activation (ie. genes coming from the maternal vs. paternal chromosomes). He suggested there is a fair amount of overlap in the phenotypes of individuals with Angelman syndrome and idic(15). Angelman syndrome is caused by an interstitial deletion/mutation in the maternal copy of chromosome 15q11 – 13 and the effects of idic(15) are more severe when caused by a maternal duplication of chromosome 15q11-13.

The final scientific presentation of the day came from Dr. Timothy DeLorey at the Molecular Research Institute, in Mountain View, California. Dr. DeLorey has been involved in research with mouse models of Angelman syndrome. He provided information about the connection between chromosome 15 abnormalities, seizures and one of the GABA_A receptor subunits. He noted that some of the issues he has heard parents of Angelman patients discuss in regards to difficulty with seizure treatment he also heard from several parents of children with idic(15) at the roundtable.  He speculated that the similarities in epilepsy treatment difficulties in both Angelman and idic(15) syndromes could have the same root cause, but more research is necessary to investigate this possibility.

In terms of future research priorities, roundtable participants agreed that Dr. Chugani’s study provides a critical opportunity to learn more about what is happening with respect to how GABA_A receptors are functioning in the brains of individuals with chromosome 15 duplications. Knowing whether the duplicated genes on 15q11-13 is resulting in over expression or under expression of the encoded proteins in the brain is will strongly impact the direction of future research in regards to both epilepsy and other symptoms of idic(15) syndrome.

In addition to studies of individuals living with idic(15) and int dup(15), roundtable participants encouraged IDEAS to educate families about the tremendous value of donating the brains of family members with chromosome 15 duplications to one of the national brain bank repositories after death. These are NIH funded brain banks that provide tissue for research into basic disease mechanisms, which have provided powerful information as to the processes that are disrupted in patients with numerous genetic disorders. Research on post mortem brains is essential to increasing our understanding of how idic(15) effects neural structures and processes.

Finally, participants debated the value of a seizure medication survey to identify seizure medications that have been effective as well as those that were ineffective or made things worse. This would be a valuable resource to both parents and researchers. However, a seizure medication survey would require the involvement of a neurologist or epilepsy researcher because the results of such a survey must be evaluated by individuals trained in interpreting this sort of data, who can also publish it in a well circulated medical journal.

As a result of this meeting, some exciting collaborative projects are in the works that may provide much greater information about the connection between idic(15) and seizures. Dr. Gallagher has interested his colleague Dr. Beth Malow, MD., Associate Professor of Neurology at Vanderbilt (Nashville, TN) in the challenges of idic(15). Dr. Malow currently leads a study looking at the causes of insomnia in children with autism spectrum disorders. She also studies the overlap of sleep and epilepsy, including the effects of treating sleep disorders on epilepsy, the relationship of epileptic seizures and interictal epileptiform discharges to sleep, and the effects of anti-epileptic drugs and vagus nerve stimulation on sleep. We will have more to report on Dr. Malow’s research in the next issue of the MIRROR, and on the IDEAS website and listserve.

The 2005 research roundtable was an exciting moment when parents and researchers came together to address the unanswered questions regarding the relationship of idic(15) to seizures and autism. IDEAS will continue working toward the day when these relationships are well characterized, and a discussion of targeted and effective treatment options becomes a reality.