Assessing the Landscape of STXBP1-Related Disorders
Abstract number :
1.345
Submission category :
12. Genetics / 12A. Human Studies
Year :
2021
Submission ID :
1826198
Source :
www.aesnet.org
Presentation date :
12/4/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:52 AM
Authors :
Julie Xian, - Children's Hospital of Philadelphia; Shridhar Parthasarathy – Children’s Hospital of Philadelphia; Sarah McKeown – Children’s Hospital of Philadelphia; Ganna Balagura – University of Genoa; Eryn Fitch – Children's Hospital of Philadelphia; Katherine Helbig – Children's Hospital of Philadelphia; Jing Gan – West China Second University Hospital; Peter Galer – Children's Hospital of Philadelphia; Colin Ellis – University of Pennsylvania Perelman School of Medicine; David Lewis-Smith – Translational and Clinical Research Institute, Newcastle University; Kristin Cunningham – Children's Hospital of Philadelphia; O’Brien Margaret – Children’s Hospital of Philadelphia; Kate Baker – MRC Cognition and Brain Sciences Unit, University of Cambridge; Alejandra Darling – Hospital Sant Joan de Déu, University of Barcelona; Fernanda Veiga De Goes – Instituto Fernandes Figueira; Christelle M El Achkar – Boston Children's Hospital; Jan Henje Doering – University Hospital Heidelberg; Francesca Furia – University Hospital Heidelberg; Ángeles García-Cazorla – Hospital Sant Joan de Déu, University of Barcelona; Elena Gardella – Danish Epilepsy Center Filadelfia; Lisa Geertjens – Amsterdam UMC; Courtney Klein – Children's Hospital Colorado; Anna Kolesnik-Taylor – MRC Cognition and Brain Sciences Unit, University of Cambridge; Hanna Lammertse – Amsterdam UMC; Jeehun Lee – Samsung Medical Center; Alexandra Mackie – Children's Hospital Colorado; Mala Misra-Isrie – Amsterdam UMC; Heather Olson – Boston Children's Hospital; Emma Sexton – Boston Children's Hospital; Beth Sheidley – Boston Children's Hospital; Lacey Smith – Boston Children's Hospital; Luiza Sotero – Instituto Fernandes Figueira; Hannah Stamberger – University Hospital Antwerp; Steffen Syrbe – University Hospital Heidelberg; Kim Marie Thalwitzer – University Hospital Heidelberg; Annemiek Van Berkel – VU University Amsterdam; Mieke Van Haelst – Amsterdam UMC; Christopher Yuskaitis – Boston Children's Hospital; Sarah Weckhuysen – University Hospital Antwerp; Ben Prosser – University of Pennsylvania Perelman School of Medicine; Charlene Rigby – STXBP1 Foundation; Scott Demarest – Children's Hospital Colorado; Samuel Pierce – Children’s Hospital of Philadelphia; Yuehua Zhang – Beijing University First Hospital; Rikke Møller – Danish Epilepsy Center Filadelfia; Hilgo Bruining – Amsterdam UMC; Annapurna Poduri – Boston Children's Hospital; Federico Zara – University of Genoa; Matthijs Verhage – Amsterdam UMC; Pasquale Striano – University of Genoa; Ingo Helbig – Children’s Hospital of Philadelphia
Rationale: Pathogenic variants in STXBP1 are amongst the most common genetic causes of epilepsy, but the phenotypic spectrum and outcomes are wide, and clear genotype-phenotype relationships have not yet been observed.
Methods: We assessed clinical data across 534 individuals with STXBP1-related disorders and analyzed 19,973 derived phenotypic terms, including phenotypes of 281 individuals reported in the scientific literature and 253 individuals recruited through an international network of collaborators. We reconstructed the epilepsy histories of 62 individuals with STXBP1-related disorders across 4,433 patient months and retrieved 251 anti-seizure medication (ASM) prescriptions from the electronic medical records. We developed a limited comparative effectiveness framework to assess seizure patterns and ASM response in individuals with STXBP1-related disorders.
Results: The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals. More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life. Individuals with p.Arg406Cys/His (n=40) variants had a three-fold increased risk of spasticity and suppression-burst EEGs, while individuals with p.Arg551Cys/Gly/His/Leu (n=24) variants had a three-fold increased risk of developmental regression, a two-fold increased risk of generalized-onset seizures, and a three-fold decreased risk of infantile spasms. Individuals with protein-truncating variants and deletions in STXBP1 were twice as likely to present with infantile spasms and hypsarrhythmia. Adrenocorticotropic hormone, phenobarbital, and prednisolone were more likely to reduce seizure frequency, while the ketogenic diet was effective in reducing or maintaining seizure freedom.
Conclusions: We highlighted phenotypic patterns in individuals with STXBP1-related disorders, identified clinically important genotype-phenotype correlations, and demonstrated a dynamic pattern of seizures and drug response. Mapping the landscape in STXBP1-related disorders will be critically important for developing disease-specific outcome measures and guiding future precision medicine efforts.
Funding: Please list any funding that was received in support of this abstract.: Children's Hospital of Philadelphia; National Institute of Neurological Disorders and Stroke.
Genetics