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Title: Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy Into Adulthood.
Austin Authors: Stamberger, Hannah;Crosiers, David;Balagura, Ganna;Bonardi, Claudia M;Basu, Anna;Cantalupo, Gaetano;Chiesa, Valentina;Christensen, Jakob;Dalla Bernardina, Bernardo;Ellis, Colin A;Furia, Francesca;Gardiner, Fiona;Giron, Camille;Guerrini, Renzo;Klein, Karl Martin;Korff, Christian;Krijtova, Hana;Leffner, Melanie;Lerche, Holger;Lesca, Gaetan;Lewis-Smith, David;Marini, Carla;Marjanovic, Dragan;Mazzola, Laure;McKeown Ruggiero, Sarah;Mochel, Fanny;Ramond, Francis;Reif, Philipp S;Richard-Mornas, Aurélie;Rosenow, Felix;Schropp, Christian;Thomas, Rhys H;Vignoli, Aglaia;Weber, Yvonne;Palmer, Elizabeth;Helbig, Ingo;Scheffer, Ingrid E ;Striano, Pasquale;Møller, Rikke S;Gardella, Elena;Weckhuysen, Sarah
Affiliation: Austin Health
The Florey Institute of Neuroscience and Mental Health
Murdoch Children's Research Institutes, Melbourne, Australia
Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia
Faculty of Medicine and Health Sciences, Translational Neurosciences, Institute Born-Bunge, Antwerp, Belgium
µNEURO Research Centre of Excellence, University of Antwerp, Belgium
IRCCS Istituto Giannina Gaslini, Genova
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Italy
Department of Epilepsy Genetics, Danish Epilepsy Centre Filadelfia, Dianalund, Denmark
Department of Woman's and Child's Health, Padova University Hospital, Italy
Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
Department of Paediatric Neurology, Newcastle upon Tyne Hospitals NHS Foundation Trust, United Kingdom
Child Neuropsychiatry Section, Department of Surgical Sciences, Dentistry, Gynecology and Paediatrics, University of Verona
UOC Neuropsichiatria Infantile, Dipartimento Materno-Infantile, Azienda Ospedaliero-Universitaria Integrata, Verona
Center for Research on Epilepsies in Pediatric Age (CREP), Verona
Epilepsy Center, ASST Santi Paolo Carlo, Milan, Italy
Department of Clinical Medicine, Aarhus University
Department of Neurology, Aarhus University Hospital, Denmark
Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia
Institute for Regional Health Services Research, University of Southern Denmark, Odense
l'Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière University Hospital, Department of Neurology, Paris, France
Child Neurology Unit and Laboratories, Neuroscience Department, Children's Hospital A. Meyer-University of Florence, Italy
Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute & Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Canada
Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, Johann Wolfgang Goethe University
LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt am Main, Germany
Pediatric Neurology Unit, University Hospitals, Geneva, Switzerland
Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital Prague, Czech Republic
The GOLD Service, Waratah, New South Wales, Australia
Department of Neurology and Epileptology & Hertie Institute for Clinical Brain Research, University of Tubingen, Germany
Department of Medical Genetics, Lyon University Hospital, Université de Lyon, INMG, France
Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
Department of Clinical Neurosciences, Newcastle Upon Tyne Hospitals NHS Foundation Trust, United Kingdom
Child Neurology and Psychiatric Unit, G. Salesi Pediatric Hospital, United Hospitals of Ancona, Italy
Department of Adults with Handicap, Danish Epilepsy Centre, Dianalund, Denmark
Department of Neurology, University Hospital of St-Etienne
Team "Central Integration of Pain", Lyon Neuroscience Research Center, INSERM U 1028, CNRS UMR 5292, France
The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, PA
AP-HP, Pitié-Salpêtrière University Hospital, Department of Genetics, Reference Centers for Adult Neurometabolic Diseases and Adult Leukodystrophies
INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Paris Brain Institute, ICM
Service de Génétique, Centre Hospitalier Universitaire de Saint-Etienne, France
Department of Neurology, Ortenau Klinikum Offenburg Kehl, Germany
Unit of Neurophysiology and Epileptology, Hospices Civils of Lyon, France
Kinderklinik Dritter Orden, Passau, Germany
Child Neuropsychiatry Unit, Department of Health Sciences, ASST Santi Paolo e Carlo, San Paolo Hospital, Università Degli Studi di Milano, Italy
Department of Epileptology and Neurology, University of Aachen, Germany
School of Women and Children's Health, Faculty of Medicine, UNSW
Sydney Children's Hospital Network, Randwick, Australia
Division of Neurology, Children's Hospital of Philadelphia, PA
Department of Neurology, Antwerp University Hospital
Applied and Translational Neurogenomics Group, VIB Center for Molecular Neurology, University of Antwerp
Royal Children's Hospital, Melbourne, Victoria, Australia
Issue Date: 19-Jul-2022 2022-06-03
Publication information: Neurology 2022; 99(3): e221-e233
Abstract: Pathogenic STXBP1 variants cause a severe early-onset developmental and epileptic encephalopathy (STXBP1-DEE). We aimed to investigate the natural history of STXBP1-DEE in adults focusing on seizure evolution, the presence of movement disorders, and the level of functional (in)dependence. In this observational study, patients with a minimum age of 18 years carrying a (likely) pathogenic STXBP1 variant were recruited through medical genetics departments and epilepsy centers. Treating clinicians completed clinical questionnaires and performed semistructured video examinations while performing tasks from the (modified) Unified Parkinson Disease Rating Scale when possible. Thirty adult patients were included for summary statistics, with video recordings available for 19 patients. The median age at last follow-up was 24 years (range 18-58 years). All patients had epilepsy, with a median onset age of 3.5 months. At last follow-up, 80% of adults had treatment-resistant seizures despite long periods of seizure freedom in 37%. Tonic-clonic, focal, and tonic seizures were most frequent in adults. Epileptic spasms, an unusual feature beyond infancy, were present in 3 adults. All individuals had developmental impairment. Periods of regression were present in 59% and did not always correlate with flare-ups in seizure activity. Eighty-seven percent had severe or profound intellectual disability, 42% had autistic features, and 65% had significant behavioral problems. Video examinations showed gait disorders in all 12 patients able to walk, including postural abnormalities with external rotation of the feet, broad-based gait, and asymmetric posture/dystonia. Tremor, present in 56%, was predominantly of the intention/action type. Stereotypies were seen in 63%. Functional outcome concerning mobility was variable ranging from independent walking (50%) to wheelchair dependence (39%). Seventy-one percent of adults were nonverbal, and all were dependent on caregivers for most activities of daily living. STXBP1-DEE warrants continuous monitoring for seizures in adult life. Periods of regression are more frequent than previously established and can occur into adulthood. Movement disorders are often present and involve multiple systems. Although functional mobility is variable in adulthood, STXBP1-DEE frequently leads to severe cognitive impairments and a high level of functional dependence. Understanding the natural history of STXBP1-DEE is important for prognostication and will inform future therapeutic trials.
DOI: 10.1212/WNL.0000000000200715
Journal: Neurology
PubMed URL: 35851549
PubMed URL:
Type: Journal Article
Appears in Collections:Journal articles

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