Movement disorders significantly impact the daily lives of individuals with Angelman syndrome, including dystonia, tremors, stereotypies, and other poorly understood or unclassified movements. These disorders interfere with regular activities and require better characterization and classification to develop effective treatments.

To address this critical need, four of our leading clinicians—Elizabeth Berry-Kravis, MD, PhD (Rush Univ Medical Center, Chicago), Wen-Hann Tan, MD (Boston Children’s Hospital, Boston), Robert Carson, MD, PhD (Vanderbilt University Medical Center, Nashville) and Jean-Baptiste Le Pichon, MD, PhD, FAAP (Children’s Mercy Kansas City)—will be leading this groundbreaking work.

This project builds on the groundbreaking work previously supported by ASF, continuing to advance our understanding of movement disorders in Angelman syndrome. Through a multi-site study involving 120 individuals across four leading medical centers, researchers aim to establish a comprehensive understanding of these movement challenges. By creating a video library reviewed by movement disorder experts and testing wearable devices to monitor movements in real time, the study will provide essential tools for diagnosing and tracking these disorders.

The findings from this research will enhance clinical care, inform therapeutic development, and offer new ways to measure the effectiveness of emerging treatments—ultimately improving the quality of life for individuals with Angelman syndrome.

This project is jointly funded by the Angelman Syndrome Foundation and the Pritzker Family.

Around 10% of Angelman syndrome cases are caused by specific changes in the UBE3A gene, but many of these genetic variants are classified as “uncertain” or “conflicting,” making it difficult for doctors to determine their impact. Adding to the complexity, some mutations increase UBE3A activity, leading to different symptoms than the typical loss of function seen in Angelman syndrome.

Our lab has developed a new biosensor to accurately measure UBE3A activity, even at normal levels found in the body. This tool can distinguish harmful mutations that reduce or increase UBE3A activity from those that have no effect. Early tests have shown its ability to classify known mutations with high accuracy.

Why It Matters

This biosensor could revolutionize diagnosis and research by:

1. Helping classify uncertain UBE3A variants.
2. Measuring UBE3A activity in patient-derived cells.
3. Providing clearer answers for families and supporting better treatments for Angelman syndrome.

By bridging the gap between genetic testing and clinical care, this tool offers new hope for understanding and managing UBE3A-related conditions.

One of my long-term goals is to develop a disease-modifying treatment for Angelman syndrome. Treatments like ASOs and genome editors that unsilence the paternal UBE3A allele show incredible promise. With support from the ASF, our lab was the first to show that Cas9-based genome editors can be used to unsilence the dormant paternal UBE3A allele in mouse and human neurons. One of the major remaining challenges has been determining if individuals with small mutations that alter UBE3A protein are likely to develop Angelman syndrome. The biosensor that we will develop as part of this project has the sensitivity to determine if UBE3A is abnormally low or high in cells, including brain and blood cells. This biosensor could be used to identify those individuals who might benefit from ASOs and genome editors that are in development for the treatment of Angelman syndrome.

– Mark Zylka, PhD

A classic phenotype of AS has been described which includes developmental delay, intellectual disability, speech impairment, gait ataxia and a happy demeanor. However, these features are not apparent in infancy. Further, initial symptoms of developmental delay are non-specific, which often complicate a diagnosis. The underlying molecular mechanism of AS is complex, and is known to be caused by methylation defects, deletions, and pathogenic single nucleotide variants in UBE3A, currently requiring multiple clinical tests to access. Taken together, despite the prevalence of AS, many patients do not receive a timely molecular diagnosis, may receive an incorrect diagnosis, or receive no diagnosis at all.

As precision therapeutics are increasingly developed, including ASOs which have shown tremendous promise in animal models, receiving a molecular diagnosis becomes exponentially more important. This project will address the current limitations of diagnostic testing for AS by utilizing a novel long read (LR) based sequencing approach, capturing multiple disease categories and variant types in a single economical test.

Individuals with Angelman syndrome (AS) are known to have an increased likelihood of exhibiting challenging behavior, especially in situations that are anxiety provoking. These behaviors substantially affect family functioning and caregiver mental health. However, there is not a well-established and validated measurement that helps capture the frequency, nature, and severity of challenging behavior in people with intellectual disability, much less in conditions like AS, where communication challenges are a significant problem.

The FDA developed a series of four methodological patient-focused drug development (PFDD) guidance documents which highlights the importance of using patient input to identify endpoints that are important and valid. As several potential future therapies for AS are being developed, an assessment that appropriately and objectively measures behavioral symptoms is needed.

$200,000

Motor deficits are common and debilitating, but not well-understood, symptoms of Angelman syndrome. AS results from the loss of the UBE3A gene. The development and study of animal models of AS that lack the same gene has advanced our understanding of brain abnormalities associated with AS and has led to exciting progress in genetic therapies. However, relating motor deficits to specific brain abnormalities has remained a challenge. Understanding the specific brain mechanisms that lead to motor deficits is likely to provide insight into related symptoms, such as speech impairments or learning disability.

Motivated by recent advances in the ability to precisely track the movements of animals while measuring neural activity across multiple brain areas, this project is aimed at developing a detailed understanding of how motor deficits are related to brain function in AS. By studying animal models of AS that lack the UBE3A gene, we will, first, associate motor impairments with brain abnormalities and then, second, reintroduce the UBE3A gene into the brain at different developmental timepoints to establish the ability to recover motor deficits and related brain mechanisms.

This project aims to discover the neural mechanisms underlying motor deficits in AS, which has the potential to generalize and shed light on cognitive and speech symptoms. This understanding will inform ongoing therapy approaches and may motivate new approaches for individuals with AS.

Why This Study is Important

It is important to understand which brain regions cause the different challenges individuals with AS face. Different therapeutics are better at reaching certain brain regions, and so this understanding may help us think about why a therapeutic works or doesn’t work to relieve certain problems. Dr. Hantman’s study focuses on fine motor skills. These are important for self care (i.e. feeding, etc..), reaching for and moving objects, and may even impact language development.

Results

This project utilized a genetic mouse line in which Ube3a was removed from the brain. The mice are trained to perform reaching actions in which they reach and grab for food rewards and – as they perform these tasks – their movements and brain activity are precisely measured. It was determined that the mice lacking UBE3A perform reaching movements much slower than typical mice.

The study team looked at brain activity across many different regions to try and identify specific patterns of brain activity that are unique to mice lacking UBE3A that may explain this unique slow reaching strategy. Preliminary findings are that the cerebellum, a brain region critical for processing sensory information during movement, has distinct dynamics during reaching movements in mice lacking UBE3A mice. To determine if these distinct dynamics are responsible for the differences in reaching movements in mice lacking UBE3A mice, researchers then restore expression of UBE3A only in the cerebellum and observe whether reaching movements are performed faster, more similar to control mice. The researchers hope is that by identifying the neural correlate of this specific reaching phenotype in mice lacking UBE3A, they can shed light on a brain region in individuals with Angelman syndrome that may be producing distinct dynamics compared to neurotypical individuals.