Quantification of neuromotor control in STXBP1-Related Disorders with wearable sensors

STXBP1-Related Disorders (STXBP1-RD) are a spectrum of neurodevelopmental conditions that often present with prominent motor impairments which affect fine and gross motor development and are in part attributed to abnormalities of neuromotor control, such as involuntary movement, dystonia, tremor, and ataxia. There is a lack of precise, scalable measurement tools to characterize motor control abnormalities, particularly in children with physical and intellectual disability who cannot complete traditional testing protocols, which has contributed to an incomplete understanding of movement disorders within the broader disease trajectory of STXBP1-RD. Emerging wearable sensor technology has the potential to meet this need. Here, we quantified the prevalence and clinical features of tremor and other motor control impairments in 31 individuals with STXBP1-RD, 64.5% with tremor, compared to 19 typically developing controls during a simple reaching task using inertial sensors on the upper arms and forearms. We then evaluated the clinical relevance of the sensor-derived metrics of motor control in the context of traditional developmental clinical assessments and additional data sources, including previously published retrospective studies, aggregated EMR data, and a prospective natural history study. Individuals with STXBP1-RD demonstrated slower reaching time, decreased arm acceleration intensity, less smooth reaching, and tremor frequency characteristics consistent with an unstable or irregular rhythmic movement pattern. Combining features from all four upper limb sensors predicted tremor with the highest accuracy (AUC = 0.87) over combinations with fewer sensors, and multiple motor control metrics were significantly related to clinical assessment scores, including those from the Bayley Scales of Infant and Toddler Development, Peabody Developmental Motor Scales and the Gross Motor Function Measure-66. We also found that more than 65% of individuals with STXBP1-RD present with tremor in the natural history study cohort. This prevalence exceeds by fivefold what has been reported in other genetic neurodevelopmental disorders, suggesting that tremor may be heavily underreported in historical, retrospective datasets. Our study provides a novel understanding of the motor control features in one of the most common genetic neurodevelopmental disorders and establishes a robust paradigm to quantify neuromotor control in individuals with developmental differences. Our observations demonstrate strong relations between motor control measures and developmental function in this population. With a range of personalized therapies currently in development for STXBP1-related disorders, assessment of neuromotor control and tremor in this cohort could serve as biomarkers for future clinical trials.