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.

The prognostic value of sleep spindles in long-term outcome of West Syndrome.

OBJECTIVE: There is a high risk for a profound developmental disorder in West Syndrome. However, a prognostic biomarker for neurodevelopmental outcome does not exist. Hypsarrhythmia disturbs normal EEG sleep patterns and hence sleep spindles, which are thought to be important for memory consolidation and learning. We postulated that the early recurrence of sleep spindles as well as an early resolution of hypsarrhythmic patterns after onset of West Syndrome lead to a favourable long-term outcome. METHOD: 448 sleep EEGs recorded during the first two years of life in 44 patients with newly diagnosed West Syndrome between 1980 and 1989 were reviewed retrospectively. Long-term outcome was assessed in 2015-2016 by the Functional Independence Measurement Score as an indicator for coping with everyday situations. EEG-data were correlated with long-term outcome by Fisher's Exact Probability Test or Kruskal-Wallis H test. RESULTS: There were no statistically noticeable differences between time to cessation of hypsarrhythmia and long-term outcome. In a subgroup analysis of patients with cryptogenic etiology only (n = 13) recurrence of sleep spindles correlated with better long-term outcome (p = 0.038). In this subgroup 11/13 showed recurrence of sleep spindles in childhood, 10 of which had a good or intermediate outcome. Considering the whole patient cohort, recurrence of sleep spindles showed a statistically non-significant better long-term outcome. CONCLUSION: Recurrence of sleep spindles and cessation of hypsarrhythmia cannot be used as a valid prognostic biomarker of neurodevelopmental outcome in non-cryptogenic West Syndrome.

Morphometry and diffusion MR imaging years after childhood traumatic brain injury.

OBJECTIVE: Our goal was to detect possible unrecognized injury in cerebral white matter (WM) in adult survivors of traumatic brain injury (TBI) during childhood, who showed no detectable axonal injury or chronic contusion on late conventional MRI. MATERIAL AND METHODS: We used voxel-based morphometry (VBM) to detect subtle structural changes in brain morphology and diffusion-tensor imaging (DTI) to non-invasively probe WM integrity. By means of VBM and DTI we examined a group of 12 adult patients who suffered from childhood closed head injury without axonal injury on late conventional MRI. RESULTS: Patients sustained complicated mild or moderate-to-severe TBI with a mean of 7 points based on the Glasgow Coma Scale. The mean time after trauma was 19 years (range 7-31 years). For VBM, group comparisons of segmented T1-weighted grey matter and WM images were performed, while for DTI we compared the fractional anisotropy and mean diffusivity (MD) between the groups. Patients presented with higher MD in the right cerebral white matter, bilaterally in the forceps major and in the body and splenium of the corpus callosum. These findings were supported by VBM, which showed reduced WM volume bilaterally, mainly along the callosal splenium. CONCLUSION: Our results indicate that persistent focal long-term volume reduction and underlying WM structural changes may occur after TBI during childhood and that their effects extend into adulthood. Normal late conventional MR findings after childhood TBI do not rule out non-apparent axonal injury.