STXBP1 in Philly. From August 18-20, the STXBP1 community met in the Bellevue Hotel in Philadelphia, the first in-person summit after our initial Philadelphia meeting in 2019. Much has changed since our initial meeting – an entire scientific community has woken up to study one of the most common (and enigmatic) neurodevelopmental disorders, the STXBP1 Foundation has grown significantly in activities and scope, and there are very promising developments in the main therapeutic areas, namely drug development, antisense oligonucleotides, and gene therapy. It is not an exaggeration to say that STXBP1 is on the map in 2022 and it is one of the genes with the fastest growing knowledge. Here are my personal reflections from the 2022 STXBP1 Summit – and I want to thank our entire ENGIN team for their fantastic work during our first Synapse Clinic the day before the Summit.
Shout-outs to our team. First of all, I would like to give a shout-out to Sarah, our genetic counselor who has talked to more than 100 newly diagnosed families in the last two years. Sarah, out sick during the entire meeting, took it upon herself to have video sessions with families on Saturday, literally from her sick bed. This amount of dedication is truly unprecedented and really deserves a mention on this blog. Sarah, if you’re reading this, you are officially forbidden from falling sick during the next STXBP1 Summit, this is totally verboten. Another shout-out to our entire team – I don’t really know where to start to express my thanks, I just wanted to say that I am truly impressed by everybody’s effort and enthusiasm. Rahma, Lucy, Lea, Aiyanna, Debbie, Vikram, Shridhar, Julie, Kim, Jan, Katie Rose, Amanda, Stacey, Natalie, Sam, Kristin, Danielle, and Alexis, your names are in bold in this post as you made our first-ever Synapse Clinic on 8/18 happen, a long-standing goal that I secretly had for the last five years, but I never thought that we would actually do. It could not have gone more smoothly on Thursday (with the exception of Sarah’s absence, of course).
Open Questions. On Friday, I started the Researchers’ meeting with a presentation about Open Questions in STXBP1-related disorders, which I distilled down to a list of three points. Given that many other scientists presented their research findings, including three junior researchers from our group (Julie, Kim, Katie Rose), I actually had very little content that I could share myself – I was even accused, tongue-in-cheek, at some point to have stolen my lab’s acknowledgement slide from my own team. Given that my input felt somewhat superfluous, I tried to focus on three major questions that I want to briefly address.
How many conditions are STXBP1?
When trainees first encounter individuals with STXBP1-related disorders, they invariably experience Dunning-Kruger effect. After having seen 5-10 individuals, most trainees feel very confident in their understanding of STXBP1-related disorders, but I typically like to stop them at this point to reflect on this confidence. There is a much wider variety of clinical presentations that extend the STXBP1 spectrum (Figure 1, see above). Overconfidence in clinical judgement after only being familiar with a few patient histories can almost be counterproductive. So where should we draw the line, and should we draw the line clinically or molecularly? We have seen previously that individuals with protein-truncating variants (PTV) have a 2.5-fold increased risk for infantile spasms and ataxia, while individuals with a p.R406H/C variant have a three-fold increased risk for spastic tetraplegia, burst-suppression, and regression. But these are not clear boundaries, and we see wide variation, even between individuals with the same variant. Another approach would be to attempt a molecular classification – however, large-scale variant testing to generate sufficiently robust numbers still remains out of reach. For now, I would recommend keeping our eyes open with respect to meaningful sub-groupings that may have therapeutic relevance and are related to outcomes.
How do we connect phenotypic dots?
This question is straight from our lab’s day-to-day work, where connecting dots (or “atoms”) is our main task. Disease histories in STXBP1-related disorder are complicated, but I am categorially opposed to capitulating in face of the wide range of presentation. We have seen that engaging with concepts that enable us to connect “dots” is actually a meaningful exercise and can lead to some of the technical innovations that allow us to interpret large-scale data, including data extracted from the Electronic Medical Records (EMR). For example, STXBP1-related disorders are the first conditions where clinical information provided by EMR aggregators such as Ciitizen was translated into developmental percentiles and longitudinal trajectories (Julie’s presentation). Likewise, we added a longitudinal component to our analysis of a Disease Concept Model (DCM) to meaningfully integrate the changes in lived experience over time (Katie Rose’s presentation). While this work is often less spectacular than early-stage advances in drug development or animal models, it is robust and granular, trying to answer what a 10% improvement in STXBP1-related disorders truly means and how we can accurately measure this.
What is stability versus variability in STXBP1-related disorders?
To make a long story short, we have good evidence by now that a subset of individuals with STXBP1-related disorders follow a predictable developmental path. In clinic, we are confronted with questions of if and when a child with an STXBP1-related disorder will walk and how the trajectory of communicative abilities will be. While we are still teasing out developmental trajectories in STXBP1, we tend to tell families (especially those with younger STXers): we still have time. Yes, there is wide variability, but I hope that we can eventually generate developmental percentiles similar to what has been done for Trisomy 21. This will be meaningful as making STXBP1 as predictable as possible is one of our stated goals. The terms natural history study, clinical trial readiness, and longitudinal clinical studies are variably used for this, but it basically comes down to one thing: understanding STX, which is the major prerequisite for measuring any type of true effect or known or future therapies.
The seizure trajectory in STXBP1-related disorders is one clinical aspect where increasing evidence for clinical heterogeneity has been observed recently. Infantile Spasms, for example, can easily remit, last into the second year of life, or become refractory, apparently independent of the underlying variant or initial seizure treatment. In brief, the answer to seizure trajectory may actually not be in STXBP1 itself. We are currently working on genetic modifiers and polygenic risk scores (PRS) to better understand potentially causative factors. In addition, recurrence of seizures after long period of seizure freedom may either be primarily due to the STXBP1 variant or secondary epileptogenesis amendable to surgical approaches or at least a presurgical work-up. In brief, we hope that the developmental trajectory in STXBP1-related disorders will become more predictable while we are simultaneously trying to find reasons why seizure trajectories vary.
Finally, I would like to thank Charlene, Melissa, Jackie, Heather, Jennifer, Russ, Cristina, Jared, Jim, and many other advocates for making this Summit a success. Science + Love = CURE. And thank you for the new STX socks.