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Published on: September 20, 2024
Epilepsy Course and Developmental Trajectories in STXBP1-DEE
Ganna Balagura1, Julie Xian1, Antonella Riva1
1Pediatric Neurology and Muscular Diseases Unit (G.B., A. Riva, E.A., C. Minetti, V.S., M.S., A.A., M.S.V., P. Striano), IRCCS "G. Gaslini" Institute, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (G.B., A. Riva, E.A., C. Minetti, V.S., M.S., A.A., M.S.V., P. Striano), University of Genoa, Italy; Department of Functional Genomics (G.B., R.T.), Center for Neurogenomics and Cognitive Research (CNCR), Vrije Universiteit (VU) Amsterdam, the Netherlands; Division of Neurology (D., I.H.), Children's Hospital of Philadelphia; The Epilepsy NeuroGenetics Initiative (ENGIN) (D., I.H.), Children's Hospital of Philadelphia; Department of Biomedical and Health Informatics (DBHi) (D., I.H.), Children's Hospital of Philadelphia, PA; Child Neuropsychiatry Unit (F. Marchese), Arnas Civico Di Cristina, Palermo, Italia; Edmomd and Lilly Safra Pediatric Hospital (B.B.Z., M. Tzadok), Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel; Clínica Integral de Epilepsia Infanto-Juvenil (L.R.), Santiago, Chile; Division of Pediatric Neurology (D.S.), Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas and Children's Medical Center of Dallas, TX; Child Neurology and Psychiatry Unit (P.A., L.G.), Spedali Civili, Brescia; Department of Developmental Neuroscience (G.A., A.F.), IRCCS Stella Maris, Calambrone, Pisa; Unit of Medical Genetics (S.B., Francesca Madia, M.I., P. Scudieri, F.Z.), IRCCS Giannina Gaslini Institute, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genova; Epilepsy Center (F.B., G. Capovilla), Department of Child Neuropsychiatry, ASST Mantova, Mantua; Pediatric Neurology Unit (A.B., T.M., A. Parmeggiani, A. Russo), IRCCS Istituto delle Scienze Neurologiche di Bologna; UO Pediatria Cava de Tirreni (M.B.), AOU "S.Giovanni di Dio e Ruggi d'Aragona" Salerno; Child Neuropsychiatry (G. Cantalupo, E.F.), Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona; Fondazione Poliambulanza Brescia Italy (G. Capovilla); Department of Child Neuropsychiatry (E.C., C. Marini), G. Salesi Children's Hospital, University of Ancona; Epilepsy Center-Child Neuropsychiatric Unit (V.C., A. Vignoli), ASST Santi Paolo e Carlo, Milan; Department of Neuroscience (A.C.), Odontostomatology and Reproductive Sciences, Federico II University of Naples; Neuropathophysiology Unit (R.D.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan; University of Ferrara (R.F.), Clinical and Experimental Medicine, Pediatrics Ferrara, IT; UOC Laboratorio di Genetica Umana (E.G.), IRCCS Istituto Giannina Gaslini; Department of Neurosciences (T.G., L.N.), Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa; Unit of Child Neuropsychiatry (T.G.), Department of Medical and Surgical Neuroscience and Rehabilitation, IRCCS Istituto Giannina Gaslini, Genova; Neurological Clinic (S.L.), Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona; Child Neuropsychiatry (M.M.M.), Epilepsy Center, Department of Medical and Surgical Neuroscience and Rehabilitation, IRCCS Istituto Giannina Gaslini, Genova; Paediatric Neurology Unit (M.M.), Department of Pediatrics, Children's Hospital Vittore Buzzi, Milan; Child Neuropsychiatry (A. Papa), Maggiore della Carità University Hospital Novara; Child Neurology and Psychiatry Unit (A. Parmeggiani), Infermi Hospital, AUSL Romagna, Rimini, Italy; Child Neurology and Psychiatry (T.P.), Neuroscience Department, Children's Hospital A. Meyer, Florence; Pediatric Clinic (S.S.), IRCCS Policlinico San Matteo Foundation, University of Pavia, Viale Golgi, Pavia; Department of Pediatric Neurology Unit (B.S.), Buzzi Children's Hospital ASST-FBF-Sacco, Milan; Child Neurology Division (A.S.), Department of Pediatrics, Sapienza University of Rome; Rare and Complex Epilepsy Unit (N.S., M. Trivisano), Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS; Child Neurology Unit (M.V., F.V.), Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome; Department of Pediatrics (A. Verrotti), University of Perugia, Italy; and Department of Neurology (I.H.), University of Pennsylvania, Perelman School of Medicine, Philadelphia.
Background And Objectives:
Clinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy.
Methods:
Retrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE.
Results:
Forty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course.
Discussion:
The disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.
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