Brain GABA_A receptor abnormalities in children with chromosome 15q11-13 mutations

Diane C. Chugani, PhD
Associate Professor of Pediatrics and Radiology
Wayne State University
Children's Hospital of Michigan
Detroit, Michigan
http://peds.med.wayne.edu/

Why do we think that it is important to study GABA_A receptors in children with chromosome 15q duplication syndrome?
GABA stands for Gamma- Amino Butyric Acid, and it is a neurotransmitter in the brain. When GABA communicates between nerve cells, it causes them not to respond to other stimulatory signals in brain. Thus, GABA is considered an inhibitory neurotransmitter. The overall effect of GABA and GABA_A receptors is to stabilize the activity of nerve cells. 

Children with chromosome 15q duplications can experience cognitive disabilities, autism and seizures. The region of chromosome 15q most commonly duplicated in chromosome 15q duplication syndrome includes 3 GABA receptor genes. Impaired GABA function, especially GABA_A receptor function, has been proposed to play an important role in the pathophysiology of several neurodevelopmental and genetic disorders including autism and Angelman syndrome.

GABA also plays an important role in seizures.  Because GABA inhibits neurons from firing, and seizures are caused by inappropriate or unregulated firing of nerve cells, increasing GABA activity through its receptors can cause the system to stabilize and decrease seizures. A lot of seizure medications work by increasing GABA activity or responsiveness (some have GABA in their names- ViGABAtrin, GABApentin etc). One might guess that having more GABA receptors should stabilize the system more (since in theory, they would be able to respond better to GABA), but it is likely that the balance needs to be maintained and the extra receptors from this extra chromosome 15 may confuse the cells. It is also possible that there are specific regions of brain which contain these abnormal number of GABA_A receptor, which could be responsible for the cognitive disabilities , seizures and autistic features in these children.

No one has studied the GABA_A receptors in the brains of children with chromosome 15q11-13 duplications. We think that it is important to study and learn more about the abnormalities of GABA_A receptors in these children, in order to develop new treatment strategies.

Study aim  The purpose of this study is to understand how changes in the genes of people with abnormalities of chromosome 15q11-13 may cause changes in GABA_A receptors. Another purpose of the study is to understand how changes in the GABA_A receptors are related to cognitive disabilities, autism and epilepsy.

Eligible participants  We are hoping to recruit twenty-five subjects (aged 2-18 years) with autism and chromosome 15q11-13 abnormalities for this study.  Our study is open to any family with a family member who has a chromosome 15q11-13 abnormality, regardless of where they live.  Individuals must be enrolled in Carolyn Schanen’s study so we can collaborate to learn the exact makeup of the chromosome 15q duplication.  IDEAS can help support travel costs for families who must travel to Detroit. (Contact Kadi Luchsinger for more information about travel support at kadi@twcny.rr.com)

What does the study involve?   This study involves three types of procedures: Positron Emission Tomography (PET) scan with an EEG, and MRI scan.

The PET scanner is a device which makes a picture of your child's brain. It consists of a bed on which your child rests and following the injection of a radioactive tracer, the radioactive distribution of the tracer in your child's brain is detected by the scanner's electronics. A pregnancy test will be performed in all female adolescents, to rule out the pregnancy, before performing the PET scan.   The data from the PET scanner are sent to a computer which makes a three-dimensional image of the tracer in your child's brain. This three-dimensional image is then reviewed by researchers in order to determine the abnormalities in GABA_A  receptor in your child’s brain. The PET scanning procedure involves the use of an intravenous catheter (a tube placed in the vein) to inject the radioactive tracer, as well as an arterial catheter (a tube placed in the artery) to collect blood samples during the scan. Our study physician will carefully examine your child's arm and decide on the best place to put in the needles. The catheters will be inserted without your child being sedated (given medications that cause relaxation) so that the physician can interact with your child during the placement of catheters. After the catheters are inserted, your child will be sedated if your child is not able to remain still for the one-hour scanning period. The exposure to radiation  from this radioactive tracer is considered small. The amount of radiation is less than from many radiological procedures such as X-ray or CT scan.

The MRI scan will be used to rule out any abnormalities in the brain and to measure the size of different parts of your child’s brain. Your child will be sedated if your child is not able to remain still for the one hour scanning period.  Your child will then be positioned in the MRI scanner and the MRI scan will be performed.

How can families learn more and get involved?  Families who wish to learn more about this study may contact me by email at dchugani@pet.wayne.edu or by phone at 313-993-3847.