A big step forward. Disease natural history and clinical trial readiness are constantly discussed topics in the rare genetic epilepsy space. Additionally, these concepts have driven our work in the Helbig lab since the very beginning. So why then did last week’s launch of our group’s first prospective natural history study of STXBP1 and SYNGAP1 feel like such a monumental step forward? Last week, we evaluated our first participants in the prospective natural history study that is part of the newly established Center for Epilepsy and Neurodevelopmental Disorders (ENDD), and here are some reflections from our team.
Figure 1. I hope Ingo doesn’t mind me borrowing his figure from his prior post, but I think this is the best illustration of the different levels of data complexity needed to form a picture of rare disease. With our prospective natural history studies, we are fully in the territory of “ice,” obtaining very granular and standardized data on a smaller number of individuals. Natural history studies are one component of how we fully understand a disease presentation, and prospective studies have perhaps the highest data complexity out of all of our methods to understand phenotypic presentations.
Natural history studies. The term “natural history study” (NHS) is used to describe many different study types. This can include extracting data from medical records, or from surveys and measures completed by families. Or, investigators could be reporting data that we collect in typical clinical care of children with rare diseases. So, I’m going to separate out our new effort in ENDD by emphasizing that this is a prospective natural history study, one where we are collecting consistent and repeated measures every six months from the individuals and families enrolled. What this means in practice is that we ask families for very long days, where we can evaluate their children systematically so that we can get very standardized and discrete outcomes that reflect children’s gross motor function, fine motor function, seizure burden, cognitive differences, social and behavioral differences, visual-motor differences… And the list goes on. In a future clinical trial, these are the types of days that would be asked of kids and families, and we need to know which standardized assessments are the best at capturing the complexity of our STXers and SYNGAPians ahead of time. Our goal is to better understand the complexity of these disorders in order to provide better counseling for families, better outcomes to target via therapies, and better clinical trial design, once we get there.
Our team. Sarah Ruggiero and JoeyLynn Nolan are writing this post collaboratively, but this paragraph is just from Sarah’s perspective. After ENDD was announced in February, our team had to take an “all hands on deck” approach to building the study and getting it ready to launch in July. While this of course was a stressful process, I am certain that what made it work was our unique team. The group working on our NHS has been working together in our regular neurogenetics clinic for years, and this experience paid off in being able to get a huge study up and running so quickly. Additionally, collaboration with the STXBP1 disorders foundation and the SYNGAP1 Research Fund was essential to creating our design of the study and supporting its existence. However, our true asset as a team is the fact that we have rare disease parents built into every level of the study – into leadership, but also through JoeyLynn, our clinical research coordinator who works to keep the day running. I didn’t know quite what this would look like until the first day, but what this truly meant was a day of watching JoeyLynn run around with a giant container of bubbles and a sparkle wand, offering snacks and coffee, watching kids while parents took breaks, having heart-to-hearts. JoeyLynn is the mother of a child with genetic epilepsy, and her input into every level of the study design has been indispensable. She’ll resent this, but I really needed to highlight her amazing efforts here.
Our patients. While we are very proud of our team’s efforts, what I’m most in awe of is our patients and their families. Even as phenotype scientists, our team is new to an effort like this, where we ask families to give many hours of their time to answer question after question, and we ask children for even more time and effort than we usually ask as healthcare providers, all so we can try to help. I was so impressed with the endurance of our kids and parents throughout a long day. We know that we ask many tough questions, some of which are difficult to answer, because parents are tired of answering yet again, “no, my child can’t do that.” But our kids powered through the day even better than expected, and parents’ attitudes were patient and hopeful. I finish near every day impressed by the tenacity of rare disease parents, but this day stood out even more than most.
What you need to know. This section is coming from JoeyLynn, who is very flattered by that kind commentary from Sarah, but truly the honor is mine. Like Sarah has previously mentioned, I am the Mom of a baby with a very rare genetic epilepsy (much different than STXBP1 and SYNGAP1) that we unfortunately lost at 7 months old. What prepared me to take care of my son, and your kids seen in ENDD clinic, is my 20 years of experience as an ICU Respiratory Therapist here at CHOP. The reason this feels important to share, is so you know how much our team personally cares about your children. I hope it also gives families a sense of relief, knowing that you can leave your child safely with me while you run to grab a coffee or lunch during these long visits. What safer babysitting service is there, really? In summary, the excitement that is coming from the ENDD team and families, is palpable. These families have always known that we were in their corner, but now that a formal plan is in place, I’m feeling a real sense of relief coming from them. I feel this relief on our end too. Working together to delineate the Natural History of STXBP1 and SYNGAP1 will no doubt lead to transformational change hopefully in the near future, and the ENDD team is truly honored to be working with such an intelligent, loving, fiercely advocating group of families. Again, the honor is ours.
Sarah Ruggiero is a Genetic Counselor at the Epilepsy Neurogenetics Initiative and Helbig Lab, Children’s Hospital of Philadelphia.
