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How Genetic Epilepsy Research Is Offering Pediatric Patients New Options: A Q&A With Drs. Ghayda Mirzaa and Jay Hauptman

May 3, 2023

In Part 1 of our Epilepsy Q&A, Dr. Jay Hauptman discussed advances in neurosurgery and the many new options available for children with intractable epilepsy. In Part 2, we hear from Dr. Hauptman and Dr. Ghayda Mirzaa about the genetics of epilepsy and how research is leading to new nonsurgical treatment options.

Dr. Mirzaa is a Seattle Children’s clinical and molecular geneticist at the Center for Integrative Brain Research and Seattle Children’s Epilepsy Program. Dr. Hauptman is a neurosurgeon with Seattle Children’s Epilepsy Program.

Dr. Hauptman (left) and Dr. Mirzaa (right)

Q: What do we know about the role of genetics in epilepsy?

DR. HAUPTMAN: We know genetics contribute significantly to many types of epilepsy. Roughly a third of cases have an underlying genetic cause. We are still learning how and why genetic mutations cause epilepsy in kids.

Q: What is the focus of recent research?

DR. MIRZAA: We’ve made great progress in the last few years, at Seattle Children’s Center for Integrative Brain Research and elsewhere. Our Seattle Children’s team has traced focal cortical dysplasia, which is among the leading causes of intractable epilepsy, to mutations in a family of genes that control important pathways, such as the mammalian target of rapamycin (mTOR) pathway. Now we are exploring if drugs that are known to inhibit this pathway, which are already being used or tested to treat cancer, can be effective for epilepsy too.

One discovery recently made here at Seattle Children’s is that in many cases the genetic change causing a child’s early-onset epilepsy is not detectable in their blood, saliva or other peripheral tissues but is rather found exclusively in their brain tissue. This finding marks a big leap forward, as testing brain tissue samples from tissues removed during epilepsy surgery is now helping us learn about the genetic mutations associated with their epilepsy and in turn helping other families in the future.

As a result of these genetic findings, we’re looking at being able to develop targeted therapies to stop seizures. To do this, we first have to understand genotype-phenotype relationships, which means we try to link genetic changes to the clinical features for that particular child. We may also generate brain cells or neurons in a dish and study some of these genetic risk factors in the lab in that context. Our ultimate hope is to improve our medical management and overall clinical care for every child with epilepsy. We have a long way to go in our research, but our work is improving patient care already today.

Q: Do you have an example of a child who was helped by the genetic research at Seattle Children’s?

DR. MIRZAA: Yes. One of our patients, Jiana, had seizures as an infant due to hemimegalencephaly (enlargement of one hemisphere of the brain), and we found that the cause of her epilepsy syndrome was genetic. We knew this from prior genetic testing on brain tissue collected from another child who had exactly the same kind of presentation and the same kind of seizures that she had.

Jiana had a functional hemispherectomy when she was just a few months old, from which she is recovering well. Genetic testing on her brain tissue afterward revealed a genetic change in her brain cells that we believe did contribute to or cause her seizures. It was in a well-known gene (called AKT3) that we know can trigger epilepsy when malfunctioning. The genetic results allowed us to provide helpful information to her parents about her future expected recovery and development.

DR. HAUPTMAN: Young Arthur is another inspiring example. Arthur has tuberous sclerosis (TS), which is a genetic disease we understand quite a bit about. Kids with TS have epilepsy that is frequently so severe that it requires surgery in order to preserve their neurological development.

Arthur’s epilepsy originated from a tumor on his temporal lobe. We removed that tumor but he eventually began to have seizures again. At that point we began asking ourselves what else we could do for him. We enrolled him in our clinical trial that targets the mTOR enzyme, which we believe to be critical in the development of epilepsy in a variety of disease states in children. Not only did the drug work, but it worked really well. A year and a half later, Arthur continues to be seizure free.

Q: How are other patients in the RACR trial doing?

DR. HAUPTMAN: The trial is ongoing. The medicine we’re testing is a novel antiseizure medicine that is in a completely different class than antiseizure medicines that have been tried to date. It has been shown to be safe and well tolerated. Some of the children in the trial have had incredible reductions in their seizure burden. One patient in particular, who was having hundreds of seizures a week with no surgical options for cure, has been seizure free since starting the medicine over two and a half years ago.

Q: How long has Seattle Children’s been doing genetic research on epilepsy?

DR. HAUPTMAN: We started enrolling families, collecting samples, and doing genetic testing about 10 years ago. It has helped us learn a great amount about different types of epilepsy. Fast-forward to now, all of the genetic testing we did then is now part of clinically available testing panels that we offer patients at the hospital. It has also led to better drugs for certain types of epilepsy based on the individual child’s genetics.

DR. MIRZAA: One of the most important and really humbling things about doing research at the Center for Integrative Brain Research is that it’s so translational and integrated with what we do at the hospital. We have a lot of experts working very closely together from many different disciplines, trying to move things beyond genetics into the realm of targeted therapies.

Q: Are you able to give parents information about their future children’s risk for epilepsy?

DR. MIRZAA: Oftentimes, yes. In Jiana’s case we collected some of her brain tissue during surgery and performed genetic testing that led us to conclude that the genetic mutation responsible for her epilepsy was brain-specific and therefore probably arose spontaneously very early in her brain’s development. While we know that this can happen in any pregnancy, an important implication of this genetic finding is that the chance of the same genetic mutation occurring again in her family is extremely low.

For families who are really concerned and wish to make sure, we have a wide range of genetic tests available. Genetic testing options now are routinely offered during pregnancy or prior to pregnancy to help families plan for the future, and we have many more options now for genetic testing than we did a few years ago. Our genetics team is always happy to help families walk through that process and think about their options for genetic testing so they can decide what is right for them, via the Epilepsy Genetics Clinic (refer to Neurosciences).

Q: Do you recommend that providers refer epilepsy patients for genetic testing?

DR. MIRZAA: There’s a lot of data showing that early-onset epilepsy in particular is more likely to be genetic. We would like to see these kids in particular in the Epilepsy Genetics program. We do a broad evaluation to review the family history, pregnancy, their early life, treatments that have been tried, what has and hasn’t worked. We examine the child to see if there could be anything that could suggest an underlying genetic cause. Prior to their visit, families receive information to help them know what to expect (either What to expect at your Epilepsy Genetics Clinic evaluation or What to expect at your Genetic Counseling Clinic visit). A full team of genetic counselors, a neurogeneticist (myself), neurologist, and epileptologist reviews each patient’s history together prior to their visit. The wait time to be seen at the Epilepsy Genetics Clinic is six to eight months currently.

Q: Where do you hope that your research goes in the future?

DR. MIRZAA: Genetic technologies are getting much more sensitive. We used to talk about testing broadly at the tissue level. Now we’re talking about testing at the cellular level. Can we pinpoint the exact mutation at which brain cells are affected or involved? That’s one direction we really hope to work on in the near future.

Q: Parting thoughts about genetic epilepsy research?

DR. HAUPTMAN: I have a belief that maybe in my lifetime there will be no surgery needed at all for children like Jiana. We’re still a long ways away from that, but the way that we’re going to get there — and potentially save children from a lifetime of epilepsy — is by studying the genetics and creating new gene-targeting medicines.

DR. MIRZAA: I am excited about the translational work that is ongoing here at Seattle Children’s, where we go from finding the genetic mutation all the way to not just clinical trials but targeted therapies that we can offer to individual patients. It requires many people to work together — neurologists and epileptologists, geneticists, pathologists, neurosurgeons, scientists and more — to try to connect the dots. This is really a big motivator for us for the next few years.

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