Associations of Cortical and Subcortical White Matter Morphometric Abnormalities With Clinical and Genetic Findings in STXBP1 Encephalopathy
Background and Objectives Disease-causing variants in the syntaxin-binding protein 1 (STXBP1) gene are among the most common genetic causes of developmental and epileptic encephalopathies and are associated with a wide phenotypic spectrum. Qualitative neuroimaging studies are usually unrevealing or uncover variable MRI findings, including cortical atrophy, thin/dysmorphic corpus callosum (CC), hypo/delayed myelination, and focal cortical dysplasia (FCD). Methods We used quantitative MRI methods to estimate abnormal brain properties of the cortical mantle and volume of subcortical structures in patients with STXBP1 encephalopathy and age- and sex-matched controls. We performed a region-of-interest group statistical analysis between patients with STXBP1 encephalopathy and controls by multivariable linear regression models to identify morphometric patterns and to evaluate the effect of the group (patients/controls) on morphometric features. We conducted a longitudinal analysis to estimate the volumetric changes in 4 patients with serial MRI scans at different ages. We calculated the association between the structural alterations and the known STXBP1 expression levels and explored associations between morphometric and volumetric features and clinical findings (age at seizure onset, intellectual disability [ID]) and genetic variants. Results Our analysis included 24 patients and 48 controls and revealed widespread cortical thickening, reduced frontal and occipital surface area, and reduced white matter (left/right hemisphere pvalue = 0.005/0.022) and CC (pvalue < 0.050) volumes. The longitudinal analysis highlighted that brain growth trends were lower than the average trend in the control cohort. In patients with more severe ID, we observed a significantly increased volume of the lateral ventricles (left/right pvalue = 0.049/0.030) and CSF (pvalue = 0.019). Patients with missense variants exhibited more altered morphometric values and more severe reductions of white-matter volumes, possibly because of a dominant negative effect of variants. Two patients were operated for intractable focal seizures, and the histopathologic substrate was FCD-I. Discussion The altered cortical patterns and WM reductions we observed in STXBP1 encephalopathy might be the structural counterpart of the widespread impaired neurotransmitter release caused by a dysfunctional syntaxin-binding protein. The 2 histopathologic observations we describe, bring to 4 the number of reported patients with STXBP1 encephalopathy and FCD-I, suggesting cortical dyslamination as the architectural substrate for the abnormal morphometric parameters and reduced surface areas.