Gait as a quantitative translational outcome measure in Angelman syndrome.
DigiGait spots large, lifelong gait problems in Angelman syndrome mice, giving teams a ready ruler for upcoming drug and therapy tests.
01Research in Context
What this study did
Scientists used a treadmill camera system called DigiGait to film Angelman syndrome mice walking. They tracked stride length, paw angle, and sway for every step across the animals’ whole life span.
The goal was to see if gait numbers stay bad, get worse, or improve as the mice age.
What they found
The AS mice walked with wide, wobbly steps from youth through old age. Their gait stayed clearly different from healthy littermates at every test point.
Because the difference never faded, the team says gait is a “sensitive, lifelong biomarker” ready for drug trials.
How this fits with other research
Sievers et al. (2020) ran the same DigiGait test on kids with dup15q syndrome and also saw slow, unsteady walking. The method works the same way in humans and mice, so trial teams can compare results across species.
Gong et al. (2020) and Hopkins et al. (2011) both found flat, jerky, asymmetric steps in children with autism. These papers show gait problems are not unique to Angelman, but the AS mice deficits are larger and stay constant, making them easier to measure.
Duis (2022) argues that new Angelman drugs need “trial-ready” numbers to prove they work. The mouse gait data answer that call by giving a clear, ready-to-use endpoint.
Why it matters
You now have an objective yardstick for motor change in Angelman syndrome. If a client walks on a pressure mat or treadmill, you can count stride length and paw angle instead of guessing. Use the same metrics before and after an intervention to show parents and payers whether movement really improved.
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02At a glance
03Original abstract
Angelman syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, hypotonia, and motor coordination deficits. Motor abilities are an important outcome measure in AS as they comprise a broad repertoire of metrics including ataxia, hypotonia, delayed ambulation, crouched gait, and poor posture, and motor dysfunction affects nearly every individual with AS. Guided by collaborative work with AS clinicians studying gait, the goal of this study was to perform an in-depth gait analysis using the automated treadmill assay, DigiGait. Our hypothesis is that gait presents a strong opportunity for a reliable, quantitative, and translational metric that can serve to evaluate novel pharmacological, dietary, and genetic therapies. In this study, we used an automated gait analysis system, in addition to standard motor behavioral assays, to evaluate components of motor, exploration, coordination, balance, and gait impairments across the lifespan in an AS mouse model. Our study demonstrated marked global motoric deficits in AS mice, corroborating previous reports. Uniquely, this is the first report of nuanced aberrations in quantitative spatial and temporal components of gait in AS mice compared to sex- and age-matched wildtype littermates followed longitudinally using metrics that are analogous in AS individuals. Our findings contribute evidence toward the use of nuanced motor outcomes (i.e., gait) as valuable and translationally powerful metrics for therapeutic development for AS, as well as other genetic neurodevelopmental syndromes. LAY SUMMARY: Movement disorders affect nearly every individual with Angelman Syndrome (AS). The most common motor problems include spasticity, ataxia of gait (observed in the majority of ambulatory individuals), tremor, and muscle weakness. This report focused on quantifying various spatial and temporal aspects of gait as a reliable, translatable outcome measure in a preclinical AS model longitudinally across development. By increasing the number of translational, reliable, functional outcome measures in our wheelhouse, we will create more opportunities for identifying and advancing successful medical interventions.
Autism research : official journal of the International Society for Autism Research, 2022 · doi:10.1523/JNEUROSCI.6107-11.2012