top of page

2016 PCDH19 Epilepsy Symposium

Welcome to the 2016 PCDH19 Epilepsy Professional & Family Symposium. We know that not every family facing PCDH19 Epilepsy is able to join us in San Francisco this weekend. The best way to keep up with the conference from afar is to watch the sessions online. The second best way to learn about the newest breakthroughs is to follow along here. I’ll be live blogging and summarizing the points that stick out to me as a parent. I’m not a medical doctor so please don’t consider anything I write to be medical advice but I’ll do my best to keep you updated as the day progresses. Bookmark this page and check back throughout the weekend.

Welcome and Introduction by Joseph E. Sullivan, MD

I am so excited to be sitting here surrounded by families and researchers who are dedicated to getting our kids better. They started the day by showing the video that many of us families contributed to as a way to thank the researchers. We’ll have that up as soon as possible. Keep an eye out for that.

Clinical Update on PCDH19-related Epilepsy and Proposal for a New Classification by Nicola Specchio, MD, PhD

Our girls tend to have focal seizures or “apparently generalized” seizures. He explained that means that the seizure looks like it is generalized but the EEG shows it to be focal. Typically, seizure onset is “stormy”. I’m sure that many of you parents can attest to that. Usually the seizures start during fever and they often continue to be triggered by fevers. This type of epilepsy often has lulls. Girls may stop having seizures for a few years at a time before they come back. We’re not sure if this is a natural part of the disease or if it is related to seizure treatments.

Most of our girls go through 3 – 9 anti-epileptic drugs and they average two medications at a time to work towards seizure control.About half of our girls have behavioral issues. A majority have some cognitive challenges but only about 10% are severely delayed. It seems like the earlier the seizures start, the chance of having behavioral or cognitive issues is higher.

Dr. Specchio has suggested that we reclassify PCDH19 as Fever Induced Cluster Epilepsy (FICE). He explained that name would better explain this disorder. Please feel free to add your thoughts on that change to the comments.

Zebrafish Models of PCDH19: Translating from the Clinic to the Bench by Annapuma Poduri, MD, PhD

Dr. Poduri has to catch a flight to Paris so she will be presenting earlier in the day than planned. She is an MD who treats patients but also conducts research. Her goal is to change the way that we treat our kids’ epilepsy so that we are more effective. She is looking at Zebrafish who have been bread to have this genetic disorder. She said that the fish are genetically about 70% similar to humans which is good for the study but she sees a malformation in their brain. That is important to recognize because people with PCDH19 don’t usually have any brain malformations that show up on their MRI.

I was curious about seizures in fish. Dr. Poduri explained that they watch the way that the fish swim and they look for certain patterns or erratic behavior.

I’ll be honest, I didn’t understand a lot of the science that she shared but I spoke with Dr. Poduri for a moment after she finished. She explained that her research is working towards creating a model that shows how PCDH19 develops and what it looks like on a neurological level. She said that she hopes to use this work to help design treatments specific for this disorder.

How Do PCDH19 Mutations Affect Brain Development? Insights from Mouse Models by Paul Thomas, PhD

Dr. Thomas came all the way from Australia! He said that they have identified over 100 different mutations on the PCDH19 gene that all seem to change the way that the protein works. Losing part of the PCDH19 “code” can cause cells not to group and segregate the way that they should during development. Interestingly, it seems like the mice’s brains look normal but their brain activity is very different. That is similar to what we learned about human brains from Dr. Poduri earlier.

If you have the ability to watch Dr. Thomas’s presentation, I highly recommend it. He is doing an excellent job of explaining the way PCDH19 works in a brain. My understanding is that girls have two copies of their X-chromosome with hundreds of genes on them. During development they randomly silence once of the double genes. Each girl with PCDH19 is unique because it is random which genes will have PCDH19 and which will be missing it. The cells with it and the cells without repel each other instead of binding together like they should. The cells affected include excitatory and inhibitory neurons that are predominantly in the cortical layer of the brain.

Molecular Characterization of PCDH19 in Rat Hippocampal Neurons by Maria Passafaro

PCDH19 is expressed in the synapses of inhibitory and excitatory neurons. Those are the neurons that regulate how much activity there is between the cells. It looks like this gene is important for helping synapses mature in the way they need to. Dr. Passafaro’s research showed that silencing PCDH19 affects GABA transmission.

Paul Thomas, PhD

Dr. Thomas is answering some additional questions. He remarked that PCDH19 is unique even among other relationships. He said ever girl is different because of the randomness of which cells are impacted. This makes it harder to treat because we don’t see a structure that is always abnormal in a specific way, like you might see with other disorders.

Allopregnanolone Deficiency in PCDH19-related Epilepsy: A Case-control Study By Marina Trivisano, MD

Dr. Trivisano is discussing the current theories that attempt to explain the vastly different presentations we see in girls with PCDH19. The first theory is what Dr. Thomas proposed. The second theory is that symptoms may be related to allopregnanalone deficiency. That is an important GABA receptor modulator.

Neurosteroids are used in many existing anti-epileptic medications but they don’t work for everyone. She is currently researching the existence of a biomarker that would help doctors know which patients would be most likely to respond well to a steroid. Her study showed that some girls may have a deficiency in their ability to synthesize neuroactive steroids. She is recommending that girls be evaluated by an endocrinologist that could coordinate with their neurologists.

During the Q & A, they have clarified that sometimes typical steroids are used to combat seizures but neurosteroids are a completely different class of drugs.

Human Pluripotent Stem Cell and Rodent Models of PCDH19 by Jack M. Parent, MD

The research that Dr. Parent does relies on stem cells taken from patients with PCDH19. He uses iPSC which stands for induced pluripotent stem cells which are able to self-renew and can turn into any kind of cell in the organ. It’s amazing to me that he can take cells from someone’s skin or blood and create brain tissue. He learned that if you suspend the neurons they will self-organize into a 3D brain-like structure.

If the gene deletion is too bad, the impacted genes are automatically inactivated so the person does not have symptoms. In his lab, Dr. Parent looked a one person’s cells. The transcription was atypical but he was not sure why. He also saw, like presenters before him described, that the affected neurons and the healthy neurons segregated themselves. They suspect there is a problem with the way the PCDH19 neurons migrate to where they need to end up but they are not sure about that result.

Functional Assessment of PCDH19 Variation: Separating the Wheat from the Chaff by Jozef Gecz, RNDr, PhD

Dr. Gecz is from the University of Adelaide in Australia. His work has formed the basis for many of the studies we have heard about today. He suspects that PCDH19 regulates estrogen receptors. Unfortunately much of the research on the way cells interact with estrogen has been conducted on male animals and it is possible that female cells have different mechanisms.

Dr. Gecz is focusing on determining what variants in PCDH19 are problematic. Every person has quirks in their genes and usually they don’t cause any issues. It is important that we figure out what differences cause epilepsy and which ones are benign so that people can be accurately diagno