Westminster. The Westin in Westminster, Colorado has an inbuilt alarm clock. As the hotel is a relatively isolated tall building, you get the most intense sunrise over the big Colorado sky that gently wakes you up as it intensifies – a consolation prize if your hotel room doesn’t have the majestic mountain view, as was my case this year. The Westin the venue for this year’s STXBP1 Summit+ Family Meeting. Here are three takeaways from the summit, from my perspective as a clinician researcher.
Category Archives: 2025
AP2M1 and the mystery of missing haploinsufficient genes
AP2M1. The genetic landscape of neurodevelopmental disorders is shaped as much by what we see as by what we don’t. In 2019, we discovered dominant-negative mutations in AP2M1 as a novel cause of neurodevelopmental disorders with epilepsy, but it also left a lingering question. Judging from large population databases, AP2M1 has all the features of a haploinsufficient gene rather than a dominant-negative disease mechanism. However, protein-truncating variants or deletions in AP2M1 have never been described. In a recent study, we demonstrate that a small deletion on chromosome 3 offers a compelling insight into this mystery. By narrowing down the candidate region of the 3q27.1 deletion syndrome to a 430 kb region, AP2M1 remerges as the most likely candidate. But it also reopens a broader question: Where are the missing haploinsufficient genes?
RBFOX3 and the hunt for epilepsy genes in 100,000 genomes
Large scale. Novel epilepsy genes are typically discovered through collaborative studies that combine information across various centers and research groups. However, there are also large-scale sequencing initiatives on a national level that include individuals with epilepsy. In a recent study published in Nature, a wide range of clinical phenotypes were assessed in an initial cohort of 34,000 individuals in the UK 100,000 Genomes Project. Let me dive into the associations related to epilepsy in this publication.
Five principles for teaching epilepsy genetics
Transition. When our epilepsy genetics program was formally approved in 2019, my former division chief asked me what I was most excited about. I spontaneously replied that we finally got a fellowship and training program. This year marks the fifth anniversary of our epilepsy genetics fellowship, and I am stepping down in my role as the inaugural fellowship director. I wanted to mark this transition by pointing out five principles for teaching epilepsy genetics that have become relevant in the last few years. Spoiler alert: they are not what you think they are.
Predicting genetic epilepsies through EMR fingerprints
EMR. Clinical data on rare disease is not necessarily rare; it is our ability to unlock already existing data that is rare. Over the last decade, we have tried to understand the fingerprints that rare genetic epilepsies leave in the electronic medical record (EMR). In our flagship publication last year, we tried to push the boundary. Is EMR data, with all its strength and weaknesses, able to predict genetic diagnosis? Here is our journey through the hidden signals in large EMR datasets.
Revisiting SYNGAP1 through a disease-concept model
DCM. This is my second blog post on SYNGAP1-related disorders within a month, which highlights how fast the area of clinical trial readiness is moving for one of the most common synapse disorders. Over the last few years, we have become more and more attuned to the fact that readying genetic epilepsies for clinical trials requires a systematic approach. The first step in this process is a disease concept model (DCM). In a recent publication in Pediatric Neurology, the authors comprehensively mapped the lived experience of SYNGAP1-related disorders. Here is what the authors found.
The 70-mile synapse – riding for Lulu’s Crew
MDBR 2025. Imagine a sugar cube-sized piece of our brain. Within this small segment of neuronal tissue, the total length of nerve fibers amounts to approximately 70 miles. This is exactly the distance I rode for the 2025 Million Dollar Bike Ride last Saturday as a member of Lulu’s Crew. Here is my blog post on a different kind of fundraising for rare disease research, the type of advocacy that has raised more than a million dollars for STXBP1 in the last seven years while making your legs feel like Jello.
CACNA1A-related hemiplegic migraine—the big unknown
FHM. There are few neurological phenomena that are as perplexing as CACNA1A-related hemiplegic migraines. Neither migraines, seizures, nor strokes, CACNA1A-related hemiplegic migraines are poorly characterized neurological events that often defy explanation. In a recent publication, we characterized how hemiplegic migraines in children with CACNA1A-related disorders present across time. Here is what we found.
A bittersweet goodbye – my decade on the ILAE Genetics Commission
Stepping down. You may have noticed that the ILAE logo on the blog has disappeared. After having served on the ILAE Genetics Commission for roughly a decade, I decided to step down. It is somewhat of a bittersweet feeling. Being part of the international epilepsy genetics community has always been very important to me. However, over the last two years, I realized that I could no longer devote the effort to the ILAE that I wanted to. We were incredibly busy in two new areas: clinical trial readiness studies for STXBP1 and SYNGAP1 and our data-driven analyses of natural histories in genetic epilepsies. Here is a brief personal overview of the three things that made the ILAE Genetics Commission special during this time. Continue reading
Life, Liberty, and the Pursuit of Precision Medicine
Taking the Oath. I was naturalized as a United States citizen in Philadelphia today. This was a big step for me personally that started with my move to the US more than a decade ago. As an immigrant physician-scientist, I have lived through the most dynamic decade in child neurology, which is my chosen field of work. During this time, many previously unnamed conditions have been deciphered, genetically characterized, and moved towards targeted treatments such as gene therapies. With this as a background, let me summarize why I am excited to be a US citizen.