Researchers at Children’s Hospital of Philadelphia (CHOP), in collaboration with the University of Texas Southwestern Medical Center (UT Southwestern), have performed a retrospective natural history study to characterize the complex clinical features associated with a rare form of genetic epilepsy driven by the TBC1D24 gene. This study represents the first effort to characterize the clinical landscape of TBC1D24-related disorders, helping to clarify the natural progression of the disorder over the lifespan and emphasizing the urgent need for precision medicine approaches to treat these disorders. These findings were recently published in the journal Epilepsia.
Changes in the TBC1D24 gene can result in a wide spectrum of neurodevelopmental disorders ranging from isolated deafness in an otherwise healthy individual to severe drug-resistant epilepsy classified as Early Infantile Epileptic Encephalopathy (EIEE). Children affected with the severe form of this disorder have a high mortality rate in early life. To better understand the clinical trajectory of patients over time, researchers from the Epilepsy Neurogenetics Initiative (ENGIN) at CHOP performed an analysis of electronic medical record (EMR) data of 15 individuals, including 5 of Mexican descent with a novel founder variant, across 197 patient-years of information. The researchers recorded their neurological histories and response to medications to better characterize TBC1D24-related disorders.
This study revealed that early-onset focal seizures and movement disorders are hallmark features of TBC1D24-related disorders that persist throughout life. By jointly analyzing medication prescription and seizure frequency data, the researchers demonstrated the highly refractory nature of seizures in TBC1D24-related disorders. However, they also established that the most effective medications prescribed in the management of TBC1D24-related epilepsy include topiramate, phenobarbital, and oxcarbazepine, though patients in the study did not always respond to therapeutic interventions, and many live with very frequent daily seizures.
Two patients in the study cohort — one the child of JoeyLynn Nolan, a CHOP research team member and President of the TBC1D24 Foundation — were highlighted in the publication because their refractory epilepsy led to death in infancy.
“This work represents a critical turning point for the TBC1D24 community,” Nolan said. “Delineating the natural history of this disease is essential — it will inform trial design, identify meaningful clinical endpoints, and ensure that future studies accurately reflect the needs of patients and families as we pursue disease‑modifying therapies."
“These patients experience a rapid onset of seizures as infants, and our findings show a wide variety of prominent neurodevelopmental delays, and while some patients benefit from medications, many have drug-refractory epilepsy, which makes for an incredibly complex group of disorders,” said senior study author Jillian McKee, MD, PhD, an ENGIN epileptologist who specializes in neurogenetic disorders at CHOP. “This small but critical natural history study will inform the development of meaningful outcome measures that could be utilized to study the effectiveness of precision medicine approaches to treat these patients in the future.”
This study was supported by a University of Pennsylvania Orphan Disease Center Grant, in partnership with the TBC1D24 Foundation, and the National Institute of Neurological Disorders and Stroke grant K23 NS140491. This study was also supported by the National Institute of Neurological Disorders and Stroke grants R01 NS127830, R01 NS131512, and K02 NS112600. This work was also supported by intramural funds of Children’s Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative (ENGIN).
Mondragon et al, “Clinical trajectories and medication response in TBC1D24-related epilepsies.” Epilepsia. Online November 10, 2025. DOI: 10.1111/epi.70013.
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Researchers at Children’s Hospital of Philadelphia (CHOP), in collaboration with the University of Texas Southwestern Medical Center (UT Southwestern), have performed a retrospective natural history study to characterize the complex clinical features associated with a rare form of genetic epilepsy driven by the TBC1D24 gene. This study represents the first effort to characterize the clinical landscape of TBC1D24-related disorders, helping to clarify the natural progression of the disorder over the lifespan and emphasizing the urgent need for precision medicine approaches to treat these disorders. These findings were recently published in the journal Epilepsia.
Changes in the TBC1D24 gene can result in a wide spectrum of neurodevelopmental disorders ranging from isolated deafness in an otherwise healthy individual to severe drug-resistant epilepsy classified as Early Infantile Epileptic Encephalopathy (EIEE). Children affected with the severe form of this disorder have a high mortality rate in early life. To better understand the clinical trajectory of patients over time, researchers from the Epilepsy Neurogenetics Initiative (ENGIN) at CHOP performed an analysis of electronic medical record (EMR) data of 15 individuals, including 5 of Mexican descent with a novel founder variant, across 197 patient-years of information. The researchers recorded their neurological histories and response to medications to better characterize TBC1D24-related disorders.
This study revealed that early-onset focal seizures and movement disorders are hallmark features of TBC1D24-related disorders that persist throughout life. By jointly analyzing medication prescription and seizure frequency data, the researchers demonstrated the highly refractory nature of seizures in TBC1D24-related disorders. However, they also established that the most effective medications prescribed in the management of TBC1D24-related epilepsy include topiramate, phenobarbital, and oxcarbazepine, though patients in the study did not always respond to therapeutic interventions, and many live with very frequent daily seizures.
Two patients in the study cohort — one the child of JoeyLynn Nolan, a CHOP research team member and President of the TBC1D24 Foundation — were highlighted in the publication because their refractory epilepsy led to death in infancy.
“This work represents a critical turning point for the TBC1D24 community,” Nolan said. “Delineating the natural history of this disease is essential — it will inform trial design, identify meaningful clinical endpoints, and ensure that future studies accurately reflect the needs of patients and families as we pursue disease‑modifying therapies."
“These patients experience a rapid onset of seizures as infants, and our findings show a wide variety of prominent neurodevelopmental delays, and while some patients benefit from medications, many have drug-refractory epilepsy, which makes for an incredibly complex group of disorders,” said senior study author Jillian McKee, MD, PhD, an ENGIN epileptologist who specializes in neurogenetic disorders at CHOP. “This small but critical natural history study will inform the development of meaningful outcome measures that could be utilized to study the effectiveness of precision medicine approaches to treat these patients in the future.”
This study was supported by a University of Pennsylvania Orphan Disease Center Grant, in partnership with the TBC1D24 Foundation, and the National Institute of Neurological Disorders and Stroke grant K23 NS140491. This study was also supported by the National Institute of Neurological Disorders and Stroke grants R01 NS127830, R01 NS131512, and K02 NS112600. This work was also supported by intramural funds of Children’s Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative (ENGIN).
Mondragon et al, “Clinical trajectories and medication response in TBC1D24-related epilepsies.” Epilepsia. Online November 10, 2025. DOI: 10.1111/epi.70013.
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Epilepsy Neurogenetics Initiative (ENGIN)