Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy into Adulthood

Hannah Stamberger*, David Crosiers, Ganna Balagura, Claudia M. Bonardi, Anna Basu, Gaetano Cantalupo, Valentina Chiesa, Jakob Christensen, Bernardo Dalla Bernardina, Colin A. Ellis, Francesca Furia, Fiona Gardiner, Camille Giron, Renzo Guerrini, Karl Martin Klein, Christian Korff, Hana Krijtova, Melanie Leffner, Holger Lerche, Gaetan LescaDavid Lewis-Smith, Carla Marini, Dragan Marjanovic, Laure Mazzola, Sarah McKeown Ruggiero, Fanny Mochel, Francis Ramond, Philipp S. Reif, Aurélie Richard-Mornas, Felix Rosenow, Christian Schropp, Rhys H. Thomas, Aglaia Vignoli, Yvonne Weber, Elizabeth Palmer, Ingo Helbig, Ingrid E. Scheffer, Pasquale Striano, Rikke S. Møller, Elena Gardella, Sarah Weckhuysen


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Background and ObjectivesPathogenic 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.MethodsIn 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.ResultsThirty 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.DiscussionSTXBP1-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.

Udgave nummer3
Sider (fra-til)E221-E233
Antal sider14
StatusUdgivet - 19. jul. 2022

Bibliografisk note

Funding Information:
The Article Processing Charge was funded by the authors.

Funding Information:
H. Lerche and Y. Weber were supported by the BMBF Treat-ION grant (01GM1907). I. Helbig was supported by the Hartwell Foundation through an Individual Biomedical Research Award. I.E. Scheffer received funding from the National Health and Medical Research Council of Australia and the Australian Epilepsy Research Fund. F. Furia, E. Gardella, and R.S. Møller received funding from Grant Lundbeck Fonden (R277-2018-802), and E. Gardella and R.S. Møller are members of the ERN EpiCARE. S. Weckhuysen received funding from FWO-FKM (1861419N). This study received support through the German Research Foundation: DFG/FNR INTER Research Unit FOR2715 (We4896/4-1 to Y.W. and He5415/7-1 to I.H.). This work was further supported by the National Institute of Neurological Disorders and Stroke (K02 NS112600), including support through the Center Without Walls on ion channel function in epilepsy (Channelopathy-associated Research Center, U54 NS108874), 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 (U54 HD086984), and by intramural funds of the Children's Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative (ENGIN). Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the NIH under Award Number UL1TR001878. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This project was further 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 research was funded in whole, or in part, by the Wellcome Trust [203914/Z/16/Z].

Publisher Copyright:
© American Academy of Neurology.


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