Abstracts

Rationale:
Individuals with mutations in the STXBP1 gene present with a spectrum of epilepsy, intellectual disability & movement disorder. This prospective natural history study aims to clarify the most clinically important characteristics of this disorder over time.
Method:
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, & 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) & Sleep Disorders Inventory for Students (SDIS). Instruments will be repeated annually.
Results:
In the first 9 months, 10 participants (8 females; median age 7.5 years, range: 4-21 years) have been enrolled. Most (8) have epilepsy with a median age of onset of 2 months with focal impaired awareness (6) & generalized motor (3) seizures. They tried a median of 3 anti-seizure medications. Levetiracetam was used in 7 with good efficacy (2 seizure-free, 4 50-99% seizure-reduction). Two were on CBD oil with partial & no seizure-reduction. All participants had early developmental encephalopathy. 7 were non-verbal. Features of hypotonia (7), ataxia (6) & tremor (5) were observed. 2 adolescents have scoliosis. 2 remained non-ambulatory at 4 years old. Molecular diagnoses found by whole exome sequencing (8), epilepsy gene panel (1) & chromosomal microarray (1) were 9 missense variants & 1 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 8. 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, & 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 behaviour & 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, & self-injurious or unsafe behaviour. Overall, parent ratings showed that participants have impairments in adaptive functioning & commonly show clinically significant symptoms consistent with an ASD. Furthermore, challenges with behaviour, social relations, communication, & anxiety are elevated, even when compared to a population of peers with an ID. The median sleep disturbance index was normal in both adolescents & children (SDIS median T-scores 81 & 51, respectively) though there was a higher risk of sleep-related breathing disorders in adolescents.
Conclusion:
Early-onset epilepsy is common & may be well-controlled with Levetiracetam. Neuropsychiatric development includes ID, hypotonia, movement disorder & features of ASD, behavioural & socio-emotional disturbance. Sleep breathing disorders & scoliosis may appear in adolescence. As the study progresses, further results will continue to characterize STXBP1 disorders.
Funding:
:Rare Diseases Foundation