STXBP1 and SYNGAP1 Natural History – Reflections after Day 1 of ENDD Clinic

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.

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CLTC: The neurological backpacker of intracellular transport

Shouldering the Load. The CLTC gene encodes the protein clathrin, which plays a crucial role in the formation of clathrin-coated vesicles, responsible for transporting proteins and other molecules within neurons. Clathrin-mediated endocytosis is also a crucial process for the recycling of synaptic vesicles in neurons, enabling efficient neurotransmitter release and synaptic transmission. The discovery of CLTC-related disorders has revealed a diverse spectrum of neurological conditions, ranging from intellectual disability to epilepsy. Here is a blog post on CLTC-related disorders as the forgotten disease of synaptic vesicle recycling, highlighting the crucial role of clathrin in maintaining proper neurological function.

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The landscape of epilepsy genetics in 2023

Clinical neurogenetics. Characterization of the genetic landscape of the epilepsies continues at a rapid pace, and the effects of this vast gain of knowledge are beginning to show within routine clinical care of people with epilepsy. In our most recent review, we discuss an overview of epilepsy genetics in 2023, spanning topics of novel methods of gene identification, polygenic mechanisms, new presentations of established genes, and multifaceted efforts of phenotypic characterization. In addition, we discuss the increasingly critical roles of advocacy organizations. Here is a summary of our recent review.

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TRPM3 – a heat sensor involved in epileptic encephalopathies

A long-awaited answer. Gene discovery in the epilepsies is continuing, and some novel genetic etiologies are quite surprising given that the particular genes had previously been described in a completely different context. One of these examples is TRPM3. In our recent publication, we further define TRPM3 as a gene causative of a variety of neurodevelopmental disorders. Also notably, we find that the anti-seizure medication primidone can be a helpful treatment in individuals with TRPM3. Beyond outlining the TRPM3 spectrum, our publication helped us find a long-awaited diagnosis for one of our research participants, one that took four years to prove. Here is the TRPM3 story. Continue reading