Summary: Mechanisms underlying the EEG biomarker in Dup15q syndrome

July 3, 2019
Mechanisms underlying the EEG biomarker in Dup15q syndrome
(summary by JoAnne Mosel, Joe Elassal, edited Joel Frohlich)

We know our kids have differences and similarities from one another, be they young or old. Are there things that can be studied and helpful in better understanding dup15q across all of our children? It seems like there are.

Researchers are attempting to identify biomarkers to help us “see” the effects of certain genes that are duplicated in dup15q and to design effective drugs. A biomarker is something associated with a disease that can be observed and that can be measured. Biomarkers can be substances that are found in the blood, specific genes, findings on x-ray or CT scans, or measures of electrical brain activity like electroencephalograms (EEGs).

Small studies in recent years have described unique EEG characteristics in dup15q. These characteristics appear as an increased amount of a certain type of wave in the EEG, called beta waves. These beta waves are often seen in other types of patients being treated with medications that target the GABA receptor, which are not commonly used in dup15q.

Many genes are duplicated in dup15q and researchers aren’t sure which specific gene causes these increased beta waves. Is it the UBE3A gene that is also a gene of interest in Angelman syndrome and is important for brain development? Or is it one of the other several genes in that duplicated area that carry instructions for a molecule that receives the neurotransmitter GABA? 

Answering this question will help researchers developing drug treatments for dup15q know if their treatment has “hit the target,” so to speak, by fixing the effects of a duplicated gene. Seeing the beta waves get smaller or disappear after a drug treatment means that the effects of one of these genes have likely been corrected. 

So, which gene causes the beta waves? 

To answer this question, the researchers first looked at two children who inherited the 15q duplication from their dad. Because the body “silences” (turns off) dad’s copy of UBE3A, duplicating this silent copy should have no effect on the brain. In fact, both of these two children still showed beta waves in their EEGs. This demonstrates that the beta waves are probably not caused by UBE3A!  

So, if the beta waves are not caused by UBE3A, which gene is causing them? Genes related to GABA are the next likely suspects. GABA is a molecule that inhibits neurons which are the cells that are primarily responsible for brain activity. The genes that tell the body how to build GABA receptors (molecules on neurons that receive the GABA signal) are essential for healthy brain function. To assess whether these are the genes causing beta waves, the researchers compared the EEGs of children with dup15q to those of healthy adults who had been given a drug that enhances the effects of GABA. The EEGs from these healthy adult volunteers strongly resembled the EEGs from children with dup15q: both showed beta waves! 

Because the beta waves in the EEGs from the healthy adult volunteers were caused by a drug that increases the GABA signal, it’s reasonable to assume that GABA genes could be causing the beta waves in the EEGs from children with dup15q. If this is the case, clinical trials of drugs that target GABA can examine beta waves in EEGs to see if they are diminished by the drug. This would be a promising sign that the drug is working even before the drug has time to improve children’s symptoms! 

Here is a summary of the study findings: 

  1. Much like what has been seen in other studies, the researchers confirmed the presence of beta waves seen on the EEGs of children with dup15q. 
  2. Genes that tell the body how to build GABA receptors may be what leads to the beta waves found in our children.
  3. It’s not likely that UBE3A causes the EEG beta waves.
  4. Since these EEG findings are unique to dup15q, researchers are confident they can use EEG measurements in studies of drugs for treating seizures or other symptoms in our children.
  5. Furthermore, these results can help researchers develop animal models to better understand other causes of the symptoms that our kids live with every day.

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