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PCDH19 Conference live-blog

Welcome to the 2018 PCDH19 Epilepsy Professional & Family Symposium. We know that not every family facing PCDH19 Epilepsy is able to join us in Sonoma this weekend so we'll be sharing all the happenings here.

My name is Le Shepard and my daughter, Alyssa, has PCDH19. 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.

Key terms and notes

We often say our kids have PCDH19. Actually, they have mutations in the PCDH19 gene. Some of the researchers will be studying the gene in general to help us better understand how it works and what it does. Others will be explaining the mutations. You can learn more about PCDH19 here.

Mosaic males: PCDH19 can be carried by males or females but usually only girls have symptoms. Mosaic males have symptoms because of a difference in how their genes are expressed.


Dr Sullivan is starting us off and sharing the thank you video that many of the families contributed to. We absolutely cannot express our appreciation enough for the hard work our doctors and researchers do to find a cure.


My favorite thing about this conference is the mix of doctors, researchers and families. There are so many people here who have been impacted by PCDH19. Lacy is one of those researchers. She has lead our registry and drastically impacted the future direction of PCDH19 research. We're proud to award her the Spirit of Progress Award.

8:43 Dr. Isabel Martinez-Garay​

Further Characterization of The PCDH19-KO Mouse Model And Initial Data On The Proteolytic Processing of The Protein

PCDH19 is atypical in that it is an x-linked disorder but usually only impacts girls and women. It's difficult to understand and research the proteins that this effects because of where they are located in the cerebral cortex and how they are expressed. However, the neurons are exhibited in mice in a similar way so Dr. Martinez-Garay has looked at how PCDH19 can be studied in mice. She looks at the nucleac acid that calls for PCDH19 and is interested in where the neurons are, how many there are and what they do. Her research shows that there doesn't seem to be an issue with the number of cells or with them going where they need to go.

"neurons that express protocardehedrin 19 are not a homogeneous population so it's important to better understand them."

Dr. Martinez-Garay has also looked at the behavior of the mice with PCDH19. She found that the male mice didn't have any changes in their behavior over time but the female mice did. The animals were placed in a box two days in a row at 10 days old and at 60 days old. The first day they tend to move around a lot and the next day they move less because they are used to the box. With the female mice with PCDH19 though, they don't tend to move less in the box the next day. She tested to see if they were anxious but the results didn't seem to show that. She said that the mice show hypersenstitivity to new environments and sensory information instead of getting used to them. She said she is interested to know if the same thing is true in our kids.

She has also looked at mouse embryonic stem cells and found that the PCDH19 cells. Her current work is looking at seeing if PCDH19 is necessary for the synapses in the cerebral cortex. She is also trying to see what happens when you mix affected neurons with healthy ones. She wants to see if they are able to mix cells and what happens when you do.

9:30 Professor Paul Thomas

How do PCDH19 Mutations Affect Brain Development? Insights from Mouse Models

Prof. Thomas also does research on mice who he has caused to have PCDH19. He argues that we need to look not just at PCDH19 but at how it works within other genes and cells. Since not every cell expresses every gene, he looks at cells that express PCDH19 and those express other genes to see if they connect and work together.

He says that early in development, because of a process called x inactivation, the cells seem to split into those that have the mutation and those that don't. He looks at mosaic males, the men and boys who have PCDH19 and show symptoms. His research shows that that cells tend to only connect with others who have the exact same genetic spelling. In other words, the mutated cells may make their own networks that are disconnected from healthy ones or tend to stand alone instead of linking to others.

Professor Thomas found a way to see the protein that the PCDH19 gene creates in the brain. He showed that this protein is expressed very early in development. There are other PCDH genes and he looks at how they are related to PCDH10 and PCDH17. He also wants to know if there is a difference in how mouse brains develop when they have a PCDH19 mutation. He shows how the cells are not creating networks like they should be. There seem to be patches of mutated cells throughout the cortex and this separation from healthy cells happens almost immediately in brain development. This is important because the cells should be talking to each other instead of being completely separated.

All of the brains that he looks at with a PCDH19 mutation are different, which is interesting because in the mice they can purposely do the same thing to each mouse. That is probably related to x-inactivation. He looked to see if they could completely removed the mutated version of PCDH19 so that females only have one copy of the gene, like men, and found that the results were like those with a healthy PCDH19 genes.

The mice that the researchers give PCDH19 do not have seizures but researchers look at their brain activity. In the effected females though, there are very big differences in brain activity. However, when they completely removed the mutated gene, brain waves went back to normal.

Professor Thomas recommended this blog to better understand how PCDH19 works.

10:30 Dr Wei Niu Mechanisms and Models of PCDH19 Female Limited Epilepsy

Researchers have found many different mutations in the PCDH19 genes. Dr. Nie is also discussing how the cells separate themselves. She suggested that males are not impacted usually because they only have one type of PCDH19 cells, instead of two like females, so there is not the separation issue.

Dr. Niu's lab has been collecting skin cells and using them to grow neurons with PCDH19 so that they can create a human model. Some of their research shows that the PCDH19 mutated cells do not create networks with other cells like they would expect. She also found that the cells do not migrate like they should. (In typically developing kids, neurons are sent to specific areas for specific tasks. Dr. Niu found three important things when they looked at the cells they grew. They found the cells were structurally different, they migrated within the brain differently, and they were more excitable than unaffected cells. It will be interesting to see how this could be related to seizures and behaviors in people with PCDH19.

11:30 Gian Michele Ratto

Disruption of The Excitation/Inhibition Equilibrium in The Conditional PCDH19 Mouse: Insights From in Vivo Electrophysiology

Dr. Ratto's lab looks at the cognitive impacts of PCDH19. He is looking into how the mutated neurons are related to sleep disturbances, hyper-excitability, hyper-synchrony. His lab developed a way to mutate the PCDH19 gene and study it in living mice. They determine where the brain is impacted then put EEG leads into the brain there and on the opposite side of the brain.

Sleep disturbances are common in people with autism and may be an important symptom in PCDH19. PCDH19 seems to interfere with inhibiting neurons. That means that the brain's mechanisms designed to keep it from getting too excited and overwhelmed don't work as well. This could be why our kids don't always sleep as well and it could be related to seizures.

Sleep is an essential mechanism for memory, learning and for maintaining proper metabolic balance. Deep sleep is especially important but people with PCDH19 tend to get stuck in non-rem sleep. That could impact cognitive impairment.

Dr. Ratto said that the neurons mice with PCDH19 mutations were excitable, even when they should not have been. He also showed a video of a mouse having a seizure and said that they had several mice die, which is rare, and they attributed that to seizures. He pointed out that the mice were excitable even when they weren't seizing and said that's important because it is probably the same in humans. It could be that our kids' brains are overexcited, even when they aren't having seizures which might help explain cognitive and behavioral issues.

1:00 Jimena Andersen

Developing Human Cellular Models of Neurodevelopmental Disorders

Ms. Andersen works with stem cells (grown from skin cells) that she grows into floating, mini brains. These are bits of brain matter that they can keep alive for several months to study. Her lab is able to grow cells that are specific for different jobs and different parts of the brain. After they demonstrated that their methods of growing mini-brains was effective, they started trying to see if they could give the minibrains disorders. She started with Timothy Syndrome, which causes epilepsy, autism, and sometimes death.

Ms. Anderson said it is very early in the research but she has been able to grow cells with PCDH19. That's important because PCDH19 impacts cell migration (where they go), specification (what they do) and integration and synapse formation (how they form networks and connect with each other). She said it's important because now we know we can create 3D spheres of cells (mini brains) to better understand how the cells interact with each other, how PCDH19 works and watch how the cells act in real life.

1:45 Josef Gecz

Separating Wheat from Chaff in PCDH19

Dr. Gecz is the one who discovered PCDH19 and his lab is responsible for finding more than 50 different disease causing genes. It has been 10 years and 2 days since the first PCDH19 paper was published. He is summarizing some of the research thus far and how our knowledge base has grown in the last decade. It's amazing how many people have focused on understanding this disorder and how creative their research has been.

Dr. Gecz has been looking at how PCDH19 is passed down and and how it presents itself. He said the fact that women have two X chromosomes is a benefit. It means we are typically better able to handle x-linked genetic issues because we have a healthy gene. PCDH19 is atypical because it usually only impacts women, which we believe has to do with x-inactivation, the body's process for randomly choosing which piece of each gene on the x-chromosomes will be used.

Earlier seizures, especially those before 12 months, tend to predict more severe outcomes, especially with cognitive issues. They have also looked at the difference between missense variants compared to total gene loss and it seems like the total loss leads to more severe intellectual disability.

Seizure clusters are still the defining marker of PCDH19 but there are many challenges that go along with it. 60% of the people affected have had psychiatric challenges. 65% have either autism or spectrum like symptoms. He also says that there are somewhere between 5 - 20% of the people who carry a mutated gene don't have any challenges. It is still difficult to get testing for people with seizures and more so to get seemingly healthy people tested so that impacts our understanding. He suggested that PCDH19 may have a bigger impact than we have previously thought. So, it may interact with other genes to cause only intellectual disabilities or different epilepsy types and some variants (specific types of mutations) are not disease causing at all. If you are interested in enrolling in the survey, please email

Dr. Gecz estimated about 500 - 600 people have been diagnosed with PCDH19 at this point. He said he believes it is probably the most prevalent disorder among girls with epilepsy.

2:45 Nicola Pietrafusa

The Electro‐clinical Phenotype and Outcome of PCDH19‐Related Epilepsy

Dr Pietrafusa completed a study on 61 people (59 girls) with PCDH19. They found that 93.4% had fever sensitivity and 85.4% had seizure clusters. In their sample 31% had gone into status epilepticus which is a medical emergency. When they looked at EEGs, only 49% had typical readings while they were sleeping. That seems to align with several other presentations that we've heard today. They only had 6 patients who were photosensitive (seizures triggled by light) and in those people that tended to be temporary. More than half of the patients developed intellectual disabilities or behavioral problems, often both. About half were diagnosed with autism. He noted that if they were able to have seizure control as the girls got older, the cognitive and behavior problems became more of a concern for their families.

Dr Pietrafusa shared several videos of children having seizures, along with the associated EEGs. He said 80% of the kids showed fear as the seizure began. They found that in their sample most of the seizures started in the temporal region.

When discussing the progression of the disorder, Dr Pietrafusa pointed out that we don't have medications for PCDH19, only the symptoms. So we can treat seizures and behavioral issues but not the disorder itself.

3:50 Discussions

The floor has been opened for general questions. I won't be able to credit each speaker but I'm going to share some of the takeaways.

Is an animal model still necessary?

Creating a better animal model is important because we need to see which pathways are being altered and if we can possibly make changes in brains to find a cure. We know that mouse models are simplified versions of what is going on in our kids but they are still very helpful in understanding.

Dr. Gecz shared his frustration that treatments in mice often don't translate to treatments for people. He thinks they are necessary but not always reliable.

When Dr. Gecz looked at families, sometimes women who have gained seizure control and have been seizure free for many years start to have them again at menopause. It is possible that hormonal differences play a role in how seizures change over time.

One family member at the conference shared that she had brain surgery as an adult and has been seizure free since. Typically, surgery is not considered an option for people with PCDH19. It seems like most of the times when surgery has been performed, it did not impact seizured.

Are there natural treatments that may be helpful for PCDH19?

There have been 3 trials on CBD in lennox-gasteux and one in dravet syndrome. Dr Pietrafusa thinks that when it has been effective, it has been because it makes the anti-seizure drugs more effective by causing them to stay in the patient's system longer. The doctors don't want to completely endorse any specific drug or treatment but they noted that they think CBD oil could also be effective on it's own.

There is a discussion on serotonin and the role it may be playing. One parent asked if her use of an SSRI could have caused her daughter's denovo mutation but Dr. Gecz has assured us it did not. However, the link between serotonin and PCDH19 might be interesting and that could be part of why steroids can be an effective treatment for seizures.

It's possible that mosaic males, it may be that they have the patches of disconnected cells in more places around the brain.

Do kids with PCDH19 have weakened immune systems?

The PCDH19 gene doesn't have any link to immunity. It could be that the kids bodies do have an increased stress response so they have seizures for diseases that do not cause alarm in neurotypical kids.

4:30 Sara Sullivan

Urban Zen Integrative Therapy: An Introduction and Demonstration for Parents

The unfortunate truth is that a cure, or even a targeted treatment, for PCDH19 is realistically at least several years off. That means that we have to support families as they cope in the meantime.

Ms. Sullivan is a part of the Urban Zen Integrative Therapy that aims to move the focus from treating diseases to treating patients. Her program uses reiki, yogo therapy, essential oils*, contemplative care (focuses on mindfulness), and nutrition. They have adapted all of the movements so that they can be done while in a hospital bed. Ms. Sullivan led the group through a series of relaxation exercises.

*remember that some essential oils can trigger seizures. Please be careful and consult your physician before trying any of this at home.

5:00 - We're adjourning for the night and heading to a reception. I'll be back on tomorrow and I'm looking forward to learning more.

June 10, 2018

Good morning!

We're about to get started again. Several parents met with some researchers this morning who is interested in doing a natural history study. That means that they will be looking not just into seizures but also into all the ways that PCDH19 impacts our kids and families. It was wonderful to be asked about the questions that really matter to us. One of the challenges with studying PCDH19 is that it is so variable and we tend to have really bad seasons with pauses between. I thought the meaning was really productive though and I'm excited to see how this work progresses.

9:00 Lacey Smith & Nilika Singhal

PCDH19 Registry Update: Enrollment, Findings and Future Directions

Dr. Smith is responsible for the PCDH19 registry and she is giving us an update on their current findings. The registry is a centralized database that collects information on people with PCDH19. They enrolled their first patient in November, 2014. The registry is open to any individual with a PCDH19 variant that is disease causing, or might be, and their family members that also carry the gene.

Right now we have 71 people in the registry. Of those 58 are patients, 11 are parents and 2 are other family members. Of the 58, 47 have a diagnosis of PCDH19 and have all their paperwork completed. About half have a de novo mutation which means that it was not passed down from one of their parents.

Most of the kids started having seizures by 16 months old and half were uncontrolled on three or more medications. Many kids had developmental delays and usually those developed after seizures. Almost 70% of the kids had behavioral issues ranging from ADHD or anxiety to autism. A majority also reported sleep issues for their kids.

The registry is important because it has helped us recruit researchers to study PCDH19. When researchers or labs know that we have a sample of patients, they are more interested in this disorder. It is also easier on families because they can provide medical records once and participate in multiple studies. This lowers the burden on families while helping us find a cure.

9:35 Khyati Brahmbhatt Behavior in Epilepsy, Getting a Proper Diagnosis

Dr. Brahmbhatt is a psychiatrist who specializes in treating children with epilepsy. She argues that our kids need integrated care, meaning that we go to one place and have one record that our whole medical team is able to access and work from. She uses what she calls the 4 Quadrant Model where they note how severe the challenge is in mental health and physical health.

About half of kids with epilepsy also have psychiatric disorders, more when the epilepsy is complicated or severe. In PCDH19, we tend to see more intellectual disabilities and autism than in other types of epilepsy. She agrees that treating people with PCDH19 is complex because we don't know whether behaviors are related seizures, medications, or environmental factors.

Unfortunately, almost 2/3 of the kids with mental illnesses do not get any treatment and those that do usually receive fewer than 3 sessions. Dr. Brahmbhatt said only 1 in 8 patients gets the mental health care that they need. She recommended every patient be screened each year and provided with the resources that they need according to where they are on the quadrant. So, kids with few mental or physical needs would have access to a library of resources but wouldn't need to be seen constantly. As the needs get bigger, the child is seen more frequently until the child is stabilized and can step back down. Ideally the team would include nurse practitioners, social workers, neurologists, child & adolescent psychiatrists, therapists and behaviorists. Obviously this isn't possible everywhere because those kinds of resources aren't always available.

10:40 Ashley Wood LCSW

Life Support Tips and Tools for Families

Ms. Wood is a clinical social worker and mom to a daughter with Dravet syndrome. She said she used to think she was supposed to be a perfect parent all the time but then she learned we are only supposed to be getting along perfectly about 33% of the time. She said that the rest of the time is split evenly between messing up and making repairs. She says that how we make repairs after we hurt the relationship with our kids.

Ms. Wood spoke about how parenting a child with epilepsy can cause emotional wounds in our other children. That doesn't mean that we are "bad parents." Sometimes we have no choice to focus on the child with a disability instead of more neurotypical kids but we still need to go back when it is safe and repair the relationship with the sibling.

Ms. Wood said that she initially got so overwhelmed with fighting the epilepsy that she lost track of why she had kids and forgot to enjoy them. Luckily the research shows that we only need 15 minutes every day for child-centered & child-focused time to make sure we have secure attachments with our kids.

She also recommends that we:

  • Pause to give a long hug, until the kid lets go, after waking up and longer periods apart.

  • Set aside 1-2 hours of technology free time and let each family member take a turn deciding what activity y'all will complete.

  • Speak 5 kind things for every 1 negative statement or criticism.

  • Always come back to the person you have been rude to and repair the relationship.

Future research:

We need to find an antibody for PCDH19. That will make it easier to detect it in research studies.

It seems like when the seizures start impacts long term prognosis. That means that it is important for us to look into what triggers the first seizure or the first cluster. It may be that if we can delay the first clusters, we can have better outcomes for our girls.

It would be very helpful for researchers to have access to seizure diaries so that they can understand how seizures progress across lifetime. (Note: There was an app created by a member of the group for tracking seizures and triggers. We will post that when we can.)

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