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
2 years

Individuals with a deletion of chromosome 15q11-q13 suffer from Angelman syndrome (AS), a neurogenetic developmental disorder characterized by intellectual disability, motor ataxia, absent speech, and seizures. The specific gene that is responsible for AS encodes the ubiquitin protein ligase UBE3A, although other genes in the region are also deleted.

AS can also result from loss of function mutations of UBE3A, which spares the other genes located in the region. UBE3A mutation AS patients typically have a less severe phenotype, especially with regard to cognitive and motor dysfunction and the incidence of epilepsy. This suggests that the loss of other genes in the region, in addition to UBE3A, likely contribute to the more severe phenotype in deletion AS patients. In particular, the HERC2 gene, which also encodes an E3 ubiquitin ligase, is located within the region typically deleted in AS.

Loss-of function mutation of HERC2 itself causes a severe neurodevelopmental phenotype with Angelman syndrome-like features. We hypothesize that the hemizygous loss of HERC2 contributes to the more severe behavioral phenotype in deletion AS individuals, and in conjunction with loss of UBE3A, will result in increased severity of cellular phenotypes in human AS stem cell-derived neurons.

We will test this hypothesis by comparing electrophysiological and morphological phenotypes of AS neurons derived from mutation and deletion AS patients. We will use antisense oligonucleotide and CRISPR-editing approaches to determine if reducing HERC2 expression in UBE3A-deficient neurons will confer the increased excitability, altered synaptic transmission, and other cellular phenotypes seen in neurons derived from AS deletion individuals. These studies will shed light on the cellular mechanisms responsible for behavioral phenotypes in AS and identify molecular targets for development of novel therapeutics.

Summary & Update

In neurotypical individuals, the UBE3A gene on chromosome 15 allows the proper breakdown of proteins in the brain. In Angelman Syndrome (AS) the breakdown of these proteins is impaired because the UBE3A gene is either deleted completely or it’s mutated to a nonfunctional form. This can mean that the mutated gene variants can cause either less of the functional UBE3A or a completely nonfunctional version of the UBE3A.

Furthermore, the cells that are affected, are usually neurons, the cells in our brains! These cells have a standard way of sending signals, using ions (sodium, potassium, calcium) that give the cell a net positive or net negative cell compared to its environment. These processes, termed depolarization and repolarization, help cells send those signals. When there is enough of a negative charge (from depolarization) the cell reaches what is called a “threshold” that acts like permission for that neuron to speak to the next neuron. The messages spread and spread. We measure this through electrophysiology and can describe it as a cell’s biochemical characterization.

Another gene of interest is HERC2. This gene is typically not affected in individuals with mutation-AS. However, because deletions occur randomly, not every deletion is at the same starting and ending point. Sometimes, this means HERC2 (among other genes) can get cut out in addition to UBE3A. Much like UBE3A,HERC2 encodes a protein that tags the neuron proteins for breakdown.

GABA-A receptors, which may be implicated in altering neuron communication in AS, typically functions by inhibiting communication between neurons.

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