Arc. Among the various synaptic disorders, TBC1D24 remains one of the more mysterious conditions. Although this genetic epilepsy was first described in 2010, the trajectory of symptoms over time has been poorly understood. In a recent publication, we reconstructed longitudinal seizure histories and developmental trajectories from electronic medical record data. What emerged was a disorder that dramatically changes shape over time. Here is what we found.
USP25 and the gravity well of evidence
Evidence. I was a contributor to a recent commentary questioning whether the USP25 gene should currently be considered a validated gene for genetic generalized epilepsy. The motivation behind this commentary was not to challenge the initial data, but to ask what happens when a claim for gene validity encounters the full weight of accumulating evidence. Does USP25 remain robust as our expectations for validation rise? Or has it reached the point where additional evidence no longer supports the initial discovery?
Cure vs. treat: the Babel problem in rare disease language
Language. There are a few words in medicine that seem simple until you say them out loud in front of the wrong audience. In rare disease clinics, two of them are cure and treat. We use them constantly, sometimes interchangeably, and rarely stop to ask what they do to hope, to expectations, and to the quiet contract between clinicians and families. In rare disease, language is not a neutral medium. It is an intervention.
Ten Years of Accumulation: Snow-Day Thoughts Between Jonas and Fern
Decade. Over the past week, winter storm Fern has blanketed large parts of the United States with several feet of snow, leading to a virtual standstill in many regions. When I looked back, I realized that the last major snowstorm that paralyzed public life was a decade ago, a storm called Jonas. Snowed in exactly ten years ago, I reflected on the state of epilepsy genetics. Let’s see what has changed in the field since Jonas in 2016.
UNC13A and the gate of synaptic release
Fusion. If you have ever tried to merge soap bubbles, you know the paradox. Soap bubbles look soft and fragile, but the moment you bring them close, they push each other away. Membranes behave similarly. A synaptic vesicle and the presynaptic membrane do not naturally want to merge. They repel each other. Therefore, synaptic vesicle release requires a mechanism that overcomes this resistance, holds two membranes in close contact, and then triggers fusion on demand within milliseconds. In a recent paper, that mechanism is brought into focus through UNC13A, a gene encoding one of the central priming factors that makes synaptic fusion possible. Here is what the study shows.
The MACF1 puzzle: when a cytoskeletal giant causes multiple brain disorders
Connections. Spectraplakins sit at the interface of architecture and motion inside a cell. They do not merely hold structures together but coordinate how the cytoskeleton rearranges itself when neurons migrate, polarize, and extend processes. One of the central spectraplakins is encoded by MACF1, a microtubule–actin crosslinking factor that couples microtubules to actin filaments and helps steer growing microtubules. This job requires multiple binding domains, flexibility, and scale. Spectraplakins are therefore large proteins encoded by enormous genes. A recent study examined how variants in MACF1 translate into human brain disease, and why seemingly similar variants may lead to surprisingly different neurodevelopmental outcomes. Here is why interpreting MACF1 variants is so complex.
Signals in the noise – qEEG patterns in genetic epilepsies
qEEG. The electroencephalogram is one of the oldest tools in neurology. We use it every day to diagnose and monitor brain function, yet, even in the era of genomic medicine, most of our EEG interpretation still relies on visual inspection, a human reading of squiggled traces. In a recent publication in Neurology, we asked whether the information embedded in these signals could be measured more objectively in children with STXBP1, SCN1A, and SYNGAP1-related disorders. Here is the story on how we identified hidden signals in the EEG tracings of individuals with genetic epilepsies.
The quiet revolution – revising ACMG criteria for epilepsy genes
VUS. The story begins with a patient in clinic. A young child with severe epilepsy, carrying a variant in SCN1A, the classic gene for Dravet Syndrome. But the variant is labeled a variant of uncertain significance (VUS). Dravet Syndrome is a clinical diagnosis, and the treatments we have today do not hinge on whether the variant is clearly pathogenic or not. But then we wonder whether a novel precision therapy could be an option, and we look up inclusion criteria and hesitate. Trial frameworks often require a variant to be pathogenic or likely pathogenic, and future precision medicine approaches in routine clinical care may require the same. For this patient, a VUS is a door that does not open. Here lies the quiet revolution in epilepsy genetics that is unfolding in the background: the refinement of variant interpretation itself.
The gentle singularity that cannot draw a synapse
Singularity. A few months ago, Sam Altman, the CEO of OpenAI, published a short essay about the future of artificial intelligence. His central message was a gentle role for AI—a vision in which technology supports us quietly in the background rather than staging some dramatic takeover of human life. What caught my attention, however, was not the word “gentle” but the word “singularity.” For science fiction readers, this term carries weight. It evokes images of runaway technology, accelerated futures, and the moment when machines surpass human intelligence. Yet in the world I inhabit, working with rare diseases and clinical genetics, the reality is far more modest. AI is entering our lives in practical, incremental ways. And despite its advances, one telling detail remains: it cannot draw a synapse. This small but persistent limitation says something important about where we are—and where we are not.
Influenza and acute necrotizing encephalopathy – the genetic dimension
ANE. A rare complication with hidden genetic clues. Imagine a healthy child who goes to bed with a fever and wakes up unable to recognize their parents, slipping rapidly into coma. This is the terrifying course of acute necrotizing encephalopathy (ANE), one of the most severe neurological complications of influenza. In a recent study, children with influenza who developed ANE showed an unexpected pattern: nearly half of those tested carried genetic variants that might predispose them to this devastating complication.