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. 2025 Mar;46(3):1339-1347.
doi: 10.1007/s10072-024-07783-3. Epub 2024 Oct 11.

Early mortality in STXBP1-related disorders

Francesca Furia  1   2 , Charlene Son Rigby  3 , Ingrid E Scheffer  4   5 , Nicholas Allen  6 , Kate Baker  7 , Christian Hengsbach  8 , Josua Kegele  8 , James Goss  3 , Kathleen Gorman  9   10 , Misra-Isrie Mala  11   12 , Francesco Nicita  13 , Talia Allan  4   5 , Alberto Spalice  14 , Yvonne Weber  15 ; European STXBP1 consortium (ESCO); STXBP1 foundation; Guido Rubboli  1   16   17 , Rikke S Møller  1   2 , Elena Gardella  18   19   20
Collaborators, Affiliations

Early mortality in STXBP1-related disorders

Francesca Furia et al. Neurol Sci. 2025 Mar.

Abstract

Introduction: Pathogenic variants in STXBP1 cause a spectrum of disorders mainly consisting of developmental and epileptic encephalopathy (DEE), often featuring drug-resistant epilepsy. An increased mortality risk occurs in individuals with drug-resistant epilepsy and DEE, with sudden unexpected death in epilepsy (SUDEP) often the major cause of death. This study aimed to identify the rate and causes of mortality in STXBP1-related disorders.

Methods: Through an international call, we analyzed data on individuals with STXBP1 pathogenic variants, who passed away from causes related to their disease.

Results: We estimated a mortality rate of 3.2% (31/966), based on the STXBP1 Foundation and the STXBP1 Global Connect registry. In total, we analyzed data on 40 individuals (23 males) harboring pathogenic STXBP1 variants, collected from different centers worldwide. They died at a median age of 13 years (range: 11 months-46 years). The most common cause of death was SUDEP (36%), followed by pulmonary infections and respiratory complications (33%). The incidence of SUDEP peaked in mid-childhood, while non-SUDEP causes were more frequent in early childhood or adulthood (p = 0.006). In the most severe phenotypes, death was related to non-SUDEP causes (p = 0.018).

Conclusion: We found a mortality rate in STXBP1-related disorders similar to other DEEs, with an early age at death and SUDEP as well as pulmonary infections as the main cause of death. These findings assist in prognostic evaluation and genetic counseling for the families. They help to define the mortality risk of STXBP1-related disorders and implement preventative strategies.

Keywords: STXBP1; Developmental and Epileptic Encephalopathy (DEE); Early mortality; Sudden unexpected death in epilepsy (SUDEP).

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Conflict of interest statement

Declarations. Ethical approval: All procedures were performed in compliance with relevant laws and institutional guidelines and have been approved by the appropriate institutional committee (09/03/2023, reference number: EMN-2024–03734). Informed consent was obtained. The privacy rights of individuals was observed. Ethical publication: We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. The work described has not been published previously, it is not under consideration for publication elsewhere, its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder. Conflict of interest: None of the authors has any conflict of interest related to this study to disclose. Informed consent: Written informed consent has been obtained from the involved patients’ parents or guardians; and, they have given approval for this information to be published.

Figures

Fig. 1
Fig. 1
Survival curve and clinical features at death of 40 individuals deceased with STXBP1-related disorders. A The survival curve shows the number of individuals alive at different ages from the international STXBP1 Foundation registry. B The main cause of death in our cohort is represented by SUDEP, followed by infections mainly pulmonary and respiratory complications, series of seizures / status epilepticus, global neurological deterioration, surgical complications. C In our cohort SUDEP occurs more often in mid-childhood and adolescence and non-SUDEP causes of death in early childhood and adulthood. D SUDEP is reported more often in severe phenotypes, and other causes of death in profound phenotypes
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