Gait as a Quantitative Translational Outcome Measure in Angelman Syndrome

Abstract

Angelman Syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, and walking and balance disorders. Recently, motor ability became an interesting outcome measure in AS, as it is broad including ataxia, hypotonia, delayed and abnormal walking and postural movements and affects nearly every individual with AS. We predict that gait presents a strong opportunity for rigorous, reliable, and quantitative metrics with direct translation to evaluate pharmacological, dietary, and genetic therapies. Numerous motoric deficits have been identified clinically. In this study, we used an innovative, automated gait analysis as well as gold standard motor behavioral assays to further delineate components of motor, coordination, balance, and gait impairments in an AS mouse model across development. Our study demonstrated marked global motoric deficits in AS mice, corroborating many previous reports. Uniquely, this is the first report of nuanced and pertinent aberrations in quantitative spatial and temporal components of gait between AS and wildtype littermate controls, that are analogous in AS individuals. These metrics were followed longitudinally to observe the progression of maladaptive gait in AS, a clinical phenotype. This has not been reported previously and contributes a substantial novel metric for therapeutic development. Taken together, these findings demonstrate the robust translational value in the study of nuanced motor outcomes, i.e., gait, for AS, as well as similar genetic syndromes, in the endeavor of therapeutic screening.

Sex‐dependent influence of postweaning environmental enrichment in Angelman syndrome model mice

“…However, the finding of an uncorrected rearing deficit may not be explained by unmitigated anxiety; rather, it is possible that AS mice have muscle weakness that that is not ameliorated with 7 weeks of EE, despite restored horizontal movement in the open field and improvement on the rotarod after 9 weeks of EE. Indeed, recent studies have started to document subtle, clinically relevant motor deficits in AS rodent models (Berg et al., 2021 , 2020 ; Petkova et al., 2021 ). Nevertheless, anxiety is a key part of the clinical presentation of AS (Wheeler et al., 2019 ).…”

Neurological and Psychiatric Overlap in an Atypical Presentation of Epilepsy

“…Gait disturbances are also seen in psychogenic nonepileptic seizures [8]. Gait disturbance and seizures have been seen in genetic syndromes like Dravet syndrome [9] and Angelman syndrome [10].…”