Genetics & Precision Medicine in Early Life Epilepsies

Beginning a discussion on early life epilepsies (ELE) at AES 2015, Anne Berg, PhD, professor at Northwestern University, explained that ELE needs to be thought of differently than it traditionally has been. Simple classifications of epilepsies (ie, generalized or focal and symptomatic or idiopathic) no longer work. Since human genomes of patients with epilepsy have hit gene sequencers, researchers have learned that there are at least 1000 genes associated with epilepsy. Further, these genes are involved with almost every aspect of brain development, and not primarily ion channels, as previously thought.

“One of the paradigmatic shifts that has come along into the clinic is that most malformations of the brain are genetic in origin,” says Berg.

The advantage of the genetic origin is that instead of simply suppressing seizures, “we are getting upstream of the seizure, treating the disease process.”

The promise of such testing is high; however, there are two major challenges, the first being a poor perception of genetic testing, whether from insurance companies, physicians, or even patients. The other obstacle is the lack of a “research culture” that focuses on the clinical outcomes.

Berg, along with colleagues, started the Pediatric Epilepsy Research Consortium in response to these problems. One project of the consortium provided evidence that highlights the necessity for inclusion of genetic testing as part of early-life evaluations, as well as guidelines for genetic testing.

Alex Paciorkowski, MD, of the University of Rochester, provided insight to the importance of biological pathways of epilepsy.

According to Paciorkowski, “discovery of the large genetic heterogeneity of epilepsy is going to end up being the most important development in the understanding of the biology of epilepsy in the past decade.”

Given genetic heterogeneity, pathways may be more important than individual genes.

Putting complex biological systems in a data structure and using algorithms from graph theory, data from pathways could help us identify new epilepsy genes, correlate genes, identify diagnostic tests, and possibly develop a “common target for new therapies.”

Biological pathways reveal a multiplicity of the problem and indicate that epilepsy may more closely resemble a “sinking ship,” in that there may be multiple gene mutations in one pathway.

Ghayda Mirzaa, MD, a geneticist at Seattle Children’s Hospital, highlighted the mammalian target of rapamycin (mTOR) signaling pathway and provided some new research regarding genes associated with brain malformation-related epilepsy, such as PTEN, CCND2, and PIK3CA. One group of researchers¹ found that a PIK3CA inhibitor dramatically reduced epileptic activity in mice that harbor PIK3CA mutations, despite presence of cortical dysplasia and brain overgrowth.

Mirzaa’s hope is that the “emerging correlation between molecular, genetic abnormality with pathway deregulation” will lead to clinically important new therapies.

Ann Poduri, MD, of Boston Children’s Hospital concluded the talk by urging those present to impart passion and new epilepsy knowledge on colleagues.  Further, Poduri says, “what we really need to do and we’ve begun to do in this community is to integrate the clinical, clinical research, and bench research.”

Session: Investigators’ Workshop 1: Genetics, Biology, and Treatment of the Early Life Epilepsies. Dec. 5, 2015.

References:

• Roy A, et al. Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. Elife. 2015; 10.7554/eLife.12703