Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in STXBP1.

BACKGROUND AND OBJECTIVES: Pathogenic variants in STXBP1 are among the major genetic causes of neurodevelopmental disorders. Despite the increasing number of individuals diagnosed without a history of epilepsy, little is known about the natural history and developmental trajectories in this subgroup and endpoints for future therapeutic studies are limited to seizure control. METHODS: We performed a cross-sectional retrospective study using standardized questionnaires for clinicians and caregivers of individuals with STXBP1-related disorders capturing medical histories, genetic findings, and developmental outcomes. Motor and language function were assessed using Gross Motor Function Classification System (GMFCS) scores and a speech impairment score and were compared within and across clinically defined subgroups. RESULTS: We collected data of 71 individuals with STXBP1-related disorders, including 44 previously unreported individuals. Median age at inclusion was 5.3 years (interquartile range 3.5-9.3) with the oldest individual aged 43.8 years. Epilepsy was absent in 18/71 (25%) of individuals. The range of developmental outcomes was broad, including 2 individuals presenting with close to age-appropriate motor development. Twenty-nine of 61 individuals (48%) were able to walk unassisted, and 24/69 (35%) were able to speak single words. Individuals without epilepsy presented with a similar onset and spectrum of phenotypic features but had lower GMFCS scores (median 3 vs 4, p < 0.01) than individuals with epilepsy. Individuals with epileptic spasms were less likely to walk unassisted than individuals with other seizure types (6% vs 58%, p < 0.01). Individuals with early epilepsy onset had higher speech impairment scores (p = 0.02) than individuals with later epilepsy onset. DISCUSSION: We expand the spectrum of STXBP1-related disorders and provide clinical features and developmental trajectories in individuals with and without a history of epilepsy. Individuals with epilepsy, in particular epileptic spasms, and neonatal or early-onset presented with less favorable motor and language functional outcomes compared with individuals without epilepsy. These findings identify children at risk for severe disease and can serve as comparator for future interventional studies in STXBP1-related disorders.

Early seizures predict the development of epilepsy in children and adolescents with stroke.

PURPOSE: To identify risk factors for the development of epilepsy after pediatric stroke. METHODS: Retrospective analysis of hospital charts of 93 children and adolescents with post-neonatal non-traumatic stroke and a minimum follow-up of two years. Seizures during the first 48 h after onset of stroke symptoms were defined as "early seizures"; when two or more seizures occurred after this period, the patient was classified as "epileptic". RESULTS: Early seizures, young age at stroke and MRI evidence of cortical involvement were observed more frequently in the children who developed epilepsy. These factors were, however, significantly interrelated; a stepwise multiple regression analysis in 46/93 patients with complete datasets identified only the occurrence of early seizures as a significant risk factor: 15/19 (79%) children with early seizures developed epilepsy, as opposed to only 7/53 (13%) without early seizures. CONCLUSION: Children with stroke who show seizures during the first 48 h after onset of stroke symptoms have a high risk to develop post-stroke epilepsy, whereas in children without early seizures, post-stroke epilepsy is rare.