Philadelphia, November 28, 2023 – Researchers from Children's Hospital of Philadelphia (CHOP) found that seizure patterns and response to treatment strategies were able to help clinical teams determine epilepsy and developmental trajectories for patients with STXBP1-related disorders, one of the most common genetic epilepsy disorders. The findings were published online by the journal Brain.
Disease-causing variants in the gene STXBP1 are implicated in one of the most common genetic epilepsies and neurodevelopmental disorders, which are sometimes accompanied by autism spectrum disorder, increased or decreased muscle tone, or movement disorders. There are often no tell-tale signs of STXBP1-related disorders, which means it cannot be diagnosed based on clinical features alone and requires genetic testing to confirm.
However, even with confirmation through genetic testing, the epilepsy and developmental trajectory of these disorders varies significantly, making it difficult to design clinical trials where the benefits of therapy cannot be uniformly measured across patients. Overcoming this important hurdle is critical in the design of clinical trials for new therapies, including gene therapies that specifically target the STXBP1 gene.
"By assessing epilepsy trajectories and developmental endpoints across the age span, this study helps establish an important baseline to help inform personalized treatment options and enable us to meaningfully interpret future therapeutic strategies," said Julie Xian, a data scientist with the Epilepsy Neurogenetics Initiative (ENGIN) and the University of Pennsylvania and CHOP Center for Epilepsy and Neurodevelopmental Disorders (ENDD) and first author of the study.
To better understand the natural history of these disorders, the researchers assessed 162 individuals with STXBP1-related disorders over 1,281 cumulative patient-years of seizure and developmental histories, breaking down seizures and medications into monthly increments. This large amount of data that has been assembled in this way for the first time in a developmental disorder required new methods and innovations that the team has established over the last few years, including novel machine learning tools.
The researchers found that the onset of epilepsy differed across seizure types, with 90% of patients who experience infantile spasms having onset by six months and focal-onset seizures by the time they are 27 months old.
However, in the first two years of life, epilepsy histories diverged between two major subgroups of individuals with STXBP1 variants. For example, 39 patients with variants that shorten the protein sequence of genes were more likely to have infantile spasms between 5 and 6 months followed by a remission of seizures. Conversely, 30 patients in the study with variants that switched nucleotides in their genetic sequence had an increased risk for focal seizures and ongoing seizures after the first year.
The study also revealed high variability for developmental outcomes in the first five years of life, with more predictable outcomes in a subset of patients. An earlier epilepsy onset was associated with lower developmental abilities, particularly motor skills and expressive communication. Additionally, individuals who experienced neonatal seizures or early infantile seizures followed by seizure remission prior to 12 months of life had more predictable seizure trajectories in early to late childhood compared with individuals with ongoing and refractory seizures in the first year.
Finally, the study demonstrated an optimal age window between 8 months and 3.5 years of life for detecting a significant treatment effect in STXBP1-related disorders. The authors developed the concept of a "virtual clinical trial" using the large amount of clinical data they had reconstructed of the entire lifespan of their patient cohort. This virtual trial framework rooted in the data-driven analysis of real world data presents novel insights into the design of future clinical trials for STXBP1-related disorders and demonstrate the potential of computational approaches in the genetic epilepsies.
"This study is another major milestone in our commitment to patients and families diagnosed with STXBP1-related disorders," said senior study author Ingo Helbig, MD, co-director of ENGIN and clinical director of ENDD. "We identified treatment windows and outcome measures that will help us interpret the success of clinical trials for these disorders. Most importantly, we were able to demystify the complex disease pattern in STXBP1 disorders to make these conditions ready for clinical trials."
This study was supported by The Hartwell Foundation through an Individual Biomedical Research Award, the National Institute for Neurological Disorders and Stroke grants R01 NS127830-01A1, R01 NS131512-01, and K02 NS112600, the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Intellectual and Developmental Disabilities Research Center (IDDRC) at Children's Hospital of Philadelphia and the University of Pennsylvania through grant U54 HD086984, and by intramural funds of Children's Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative (ENGIN). Additional support was provided by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001878. This project was also supported in part by the Institute for Translational Medicine and Therapeutics' (ITMAT) Transdisciplinary Program in Translational Medicine and Therapeutics at the Perelman School of Medicine of the University of Pennsylvania. The study also received support through the EuroEPINOMICS-Rare Epilepsy Syndrome (RES) Consortium by the German Research Foundation grant HE5415/3-1within the EuroEPINOMICS framework of the European Science Foundation, by the German Research Foundation grants HE5415/5-1 and HE5415/6-1, the DFG/FNR INTER Research Unit FOR2715 grants We4896/4-570 1 and He5415/7-1, and by the Genomics Research and Innovation Network.
Xian et al, "Delineating clinical and developmental outcomes in STXBP1-related disorders." Brain. Online November 28, 2023. DOI: 10.1093/brain/awad287.
About Children's Hospital of Philadelphia: A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the 595-bed hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as an inpatient hospital
