Abstracts

Rationale: STXBP1-related disorders present in a spectrum of neurodevelopmental abnormalities, developmental and epileptic encephalopathies, and movement disorders. Of the hundreds described in the literature, virtually every individual had severe to profound developmental delay and intellectual disability. However, most epilepsy genes have an established milder spectrum, which has not been identified for STXBP1 so far. As diagnostic testing becomes more available, there is expanding variability in clinical presentations of individuals with STXBP1-related disorders. We aimed to delineate the milder spectrum of STXBP1-related disorders.

Methods: We recruited individuals through continuous enrollment of a clinical cohort and through referrals. Chart review and phenotyping was performed on all individuals, including review of EEG and neuroimaging data, as well as occupational therapy, physical therapy, and neuropsychological evaluations for individuals when available.

Results: We identified 5 individuals with confirmed, novel de novo variants in STXBP1 with mild neurodevelopmental disorders or learning disabilities (n=5), in some cases with focal epilepsies (n=4) and movement disorders (n=1). All individuals had variants absent from population databases and affected individuals. A mildly affected 8-year-old female (p.Arg227Ser) presented with mild learning differences and parasomnias, and was identified only when genetic testing was performed to rule out a familial nocturnal epilepsy. Another individual (p.Arg477Pro) presented with focal epilepsy at 18 months. His seizures were well-controlled on levetiracetam until 11 years of age, at which time his epilepsy became refractory. He had distinct impairment in fine motor skills, but he participated in a typical classroom setting with some IEP modifications. His neuropsychological profile and motor impairments were procured in detail, allowing us to present the first thorough outcomes assessment of an individual with mild STXBP1-related disorder. Finally, we describe one case of a 14 year old individual with mild intellectual disability, mild ataxia, and no seizures. We propose that her presentation might be explained by her variant (p.Thr570Ile) occurring in an alternative exon of STXBP1, which is the only time this has been observed in STXBP1-related disorders.

Conclusions: STXBP1-related disorders can have mild presentations, as is observed in other genetic epilepsies that were first diagnosed exclusively in individuals with developmental and epileptic encephalopathy. The unifying clinical features of this spectrum include learning impairments to mild developmental delay only, and this clinical subset appears to be linked to a unique variant spectrum, where individuals with novel missense variants in STXBP1 can present with mild neurodevelopmental differences. These findings hint at previously undescribed functional consequences of novel variants on the STXBP1 protein and informs prognostic counseling of those with STXBP1-related disorder.

Funding: STXBP1-Disorders Foundation, The Hartwell Foundation; National Institute of Neurological Disorders and Stroke, Children’s Hospital of Philadelphia