Medical Student BC Children's Hospial Vancouver, Canada
Rationale: Individuals with mutations in the STXBP1 gene present with a spectrum of epilepsy, intellectual disability and movement disorder. This prospective natural history study aims to clarify the most clinically important characteristics of this disorder over time. Methods: Participants of any age with a mutation in STXBP1 have been recruited from clinics across Canada. An electronic REDCap survey of their medical history is completed, and confirmatory clinical reports are obtained. Participants complete standardized neuropsychiatric questionnaires: Developmental Behaviour Checklist-2 (DBC-2), Social Responsiveness Scale-2 (SRS-2), Vineland Adaptive Behavior Scales-3 (VABS-3) and Sleep Disorders Inventory for Students (SDIS). Instruments will be repeated annually. Results: In the first nine months, ten participants (eight females; median age 7.5 years, range: 4-21 years) have been enrolled. Most (eight) have epilepsy with a median age of onset of two months with focal impaired awareness (six), and generalized motor (three) seizures. They tried a median of three antiseizure medications. Levetiracetam was used in seven with good efficacy (two seizure-free, four 50-99% seizure-reduction). Two were on CBD oil with partial and no seizure-reduction. All participants had early developmental encephalopathy. Seven were non-verbal. Features of hypotonia (seven), ataxia (six) and tremor (five) were observed. Two adolescents have scoliosis. Two remained non-ambulatory at four years old. Molecular diagnoses found by whole exome sequencing (8), epilepsy gene panel (one) & chromosomal microarray (1) were nine missense variants and one deletion involving STXBP1, all of which were de novo but one (unaffected maternal carrier). MRI demonstrated only occasional non-specific white matter changes. Neuropsychiatric questionnaires were available in eight. Mean overall adaptive functioning skills were approximately 3.5 standard deviations (sd) below the general population mean (VABS-3 mean = 47.1, sd = 17.4). For individual children, overall adaptive functioning ranged from the mild to the profound range of disability (range: 23-68).When compared to the general population, symptoms of autism spectrum disorder (ASD) were overall moderately elevated (SRS-2 mean = 68, sd = 6.7). Three sub-scales of the SRS-2 were moderately elevated (Social Communication, Social Cognition, and Social Awareness). Two sub-scales were mildly elevated (Social Motivation & Restricted Interests/Repetitive Behavior).In comparison to other individuals with an intellectual disability (ID), overall behavior and socio-emotional difficulties were moderately elevated (DBC-2 mean = 47.1, sd = 9.8). All sub-scale means on the DBC-2 were moderately to seriously elevated. This includes disruptive behavior, communication difficulties, anxiety, social relations, and self-injurious or unsafe behavior.Overall, parent ratings showed that participants have impairments in adaptive functioning and commonly show clinically significant symptoms consistent with an ASD. Furthermore, challenges with behavior, social relations, communication, and anxiety are elevated, even when compared to a population of peers with an ID. The median sleep disturbance index was normal in both adolescents and children (SDIS median T-scores 81 and 51, respectively) though there was a higher risk of sleep-related breathing disorders in adolescents. Conclusions: Early-onset epilepsy is common and may be well-controlled with Levetiracetam. Neuropsychiatric development includes ID, hypotonia, movement disorder and features of ASD, behavioral and socio-emotional disturbance. Sleep breathing disorders and scoliosis may appear in adolescence. As the study progresses, further results will continue to characterize STXBP1 disorders. Funding: Please list any funding that was received in support of this abstract.: Rare Diseases Foundation
