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.
Figure. Longitudinal trajectories in TBC1D24-related disorders. Left: Age-dependent frequency of neurological features. Seizure types including focal seizures, myoclonic seizures, and status epilepticus are most common in early infancy and early childhood. Movement disorders such as tremor and ataxia become more prominent later, illustrating how the clinical picture evolves over time. Right: Individual seizure frequencies across the lifespan. Each row represents one person, with color indicating seizure burden from seizure-free to many seizures per day. Most individuals experience the highest seizure burden in infancy, with fluctuating but often persistent drug-resistant epilepsy over time. Figure adapted from Mondragon et al., 2025.
A synaptic supply problem. TBC1D24 encodes a protein involved in endosomal membrane trafficking that supports synaptic vesicle recycling. During ordinary activity, most synaptic vesicles are rapidly retrieved and reused. Under intense firing, however, this system becomes saturated, and vesicle membrane must take a detour through endosomal compartments before new vesicles can be rebuilt. TBC1D24 appears to be an important regulator of this sorting step. When its function is impaired, endosomal compartments enlarge, vesicles reform more slowly, and synapses cannot sustain neurotransmission during repeated firing — vesicle supply becomes unreliable. While the exact links between this dysfunction and seizures still need to be clarified, this unique disease mechanism may help explain characteristic seizure types in TBC1D24-related disorders, including frequent status epilepticus.
Seizure patterns. In our publication by Mondragon and collaborators in Epilepsia, we reconstructed nearly 200 patient-years of data in 15 individuals with TBC1D24-related disorders. For disease reconstruction, we applied a framework previously developed for STXBP1, SYNGAP1, and SCN8A. We found that seizure onset clustered in early infancy, with a median age of only a few months, and nearly all children developed epilepsy within the first half year of life. Focal seizures and myoclonic seizures were present in 80% of individuals and dominated the early course, while 90% experienced episodes of status epilepticus. Focal myoclonic seizures beginning around three months of age were seen in nearly 75% of individuals — a particularly characteristic seizure type for this condition. Overall seizure burden was greatest during the first years of life. Seizures were frequently refractory, although we observed relatively greater effectiveness of topiramate, phenobarbital, and oxcarbazepine compared to other medications. Because these observations derive from real-world longitudinal data rather than controlled trials, they should be interpreted with caution.
Oxidative stress. In addition to the TBC domain that is important for vesicle sorting, TBC1D24 also contains a TLDc domain. This domain is shared with proteins that help protect cells from oxidative stress. Neurons have high metabolic demand and generate reactive oxygen species. Impaired clearance of these species may therefore contribute to progressive neuronal dysfunction. While it remains unclear how early oxidative stress contributes to the clinical phenotype, non-seizure features may partly relate to this mechanism. For example, we observed non-epileptic myoclonus in all individuals, and tremor and ataxia in 67% and 45%, respectively. It is therefore reasonable to hypothesize that early seizures and later movement disorders in TBC1D24-related disease may reflect the dual functions of the protein — early seizures related to impaired vesicle recycling, and later ataxia and tremor to disrupted handling of oxidative stress.
Variability. The most severe outcomes clustered in infancy, including deaths in the setting of refractory status epilepticus and respiratory complications. During this period, synaptic demand is highest while neuronal stress tolerance is limited. Despite this plausible mechanism, disease severity varied considerably. When assessing lifetime seizure burden, we observed a wide range in seizure frequency across individuals. Notably, half of our cohort experienced two or more months with multiple daily seizures.
What you need to know. TBC1D24-related disease begins in early infancy with severe epilepsy and evolves over time to include movement disorders and developmental features. The gene sits at the intersection of synaptic vesicle recycling and neuronal stress resilience, potentially making early brain networks particularly vulnerable. In our study by Mondragon and collaborators, we systematically reconstructed the clinical trajectory of TBC1D24-related disorders and captured both the intensity and variability of seizures across the lifespan. This kind of longitudinal understanding is essential for making TBC1D24 trial-ready and for developing meaningful outcome measures.
