Angelman syndrome and the Gut

Q: What motivated you to investigate the presence of UBE3A in the gastrointestinal tract and its potential role in gastrointestinal issues in individuals with Angelman syndrome?

A: As a mother, pediatric gastroenterologist and physician-scientist, my chief mission in life has been to make life better for kids and their families in the ways I know how. In line with these goals, I have had a long-standing personal and professional interest in working with kids with neurodevelopmental differences because this group of individuals needs special attention and care due to the unique issues they have and as such I have always strived to make a difference here. Because of this, my clinical interest and focus has largely been on caring for children with autism and other NDDs and their relationship to GI issues. I also conduct both clinical studies and preclinical studies looking at the links between neurodevelopment and gut and brain function so I have been working in this area as both a physician and a scientist for almost a decade.

In terms of my links with AS, It took a highly meaningful interaction with a family who was advocating for their child with AS and reaching out to me to gauge my focus in AS specifically.

This family has an individual who suffered from major GI problems throughout most of his life and this was a real limiting factor to his quality of life. The family, who has been extremely active with the ASF, reached out to multiple people in the gastroenterology field to see who could study why people with AS had such significant GI problems and through our mutual connections, we were introduced.

I really connected with this family and, as a mother, with their plight in making life better for their child and other people with AS.

When I started looking into what data was out there, I saw that GI problems were extremely common in AS and the few studies out there showed that they occurred in the majority of individuals. Despite how common the GI issues are, there was virtually no research done in why that might be the case.

Once we find the reasons why GI issues are so common, we can begin looking for novel treatments. This study gave me the opportunity to look for a connection based on my clinical and research expertise that could have a potentially huge impact in helping this population of children and adults and their families.

Q:  Could you explain how the presence of the UBE3A gene in the gut might be related to the GI problems commonly observed in people with AS?

A: The UBE3A gene has been shown in the brain to impact brain signaling and function and the imprinting seen in AS has been shown to affect these processes.

But there is also a nervous system in the gut, called the enteric nervous system. It can work independently from the brain to alter gut function (causing things like constipation and diarrhea) but it can also communicate with the brain to influence behavior and potentially other brain functions that are disrupted in some individuals with AS.

I have conducted aligning work, looking at other genetic disorders linked to neurodevelopment and found that when a gene impacts brain function, it often also impacts gut nervous system function. It is thus highly likely that the imprinting seen in the brain nerve cells in AS also impacts the gut nerve cells and may thus impact all the different functions that gut nerves affect, including gut to brain communication.

Q:  Can you describe the significance of understanding the impact of UBE3A in the gut on the central issues such as cognition, mood, and neurobehavior in individuals with AS?

A: A lot of research done by my group and also others has shown more and more how the role of the gut may actually impact cognition, mood and neurobehavior.

Some research has pointed towards the bacteria in our gut, termed the gut microbiome, in modulating these effects and a recent paper came out showing that the gut microbiome was distinct in 3 different animal models with AS and that there were similarities across all groups, demonstrating that specific gut microbiota may play a role in the gut or brain manifestations associated with AS. Whether the gut microbiome differences however are a cause of the gut and brain differences, or the result, still needs to be determined.

In addition to the gut microbiota, other aspects of the gut, including communication through different nerves, like the vagus nerve, or through hormones given off, the gut has also been shown to contribute to cognition and mood. These have never, however, been evaluated in AS.

So studying the gut and the mechanisms modulated by UBE3A may help us to determine not only underlying mechanisms of AS but whether we might be able to target those mechanisms to develop novel therapies.

Aside from the potentially important roles that the gut plays in brain function, another key reason it’s so important to study the gut is because it is a strong target for medications-it is much harder to access specific parts of the brain that it is to take a medicine by mouth to access the GI tract.

Q: What are the similarities in behavioral and brain phenotypes between the mouse models with UBE3A mutations and individuals with AS that make them suitable for this research?

A: There are many phenotypes mimicked in the mouse model including motor performance, repetitive behaviors, anxiety, sleep disturbances and seizure susceptibility. Part of what we ultimately plan to do is to determine which of these features may be modulated by gut function.

Q: What specific techniques or methods will you use to examine the gastrointestinal tract of the UBE3A mutant mice and locate UBE3A in the intestine?

A:  Individuals with AS has a variety of different GI problems-constipation is most common, but vomiting and feeding difficulties are also common and there are a large number of other GI issues that have been associated in general. In response to this, we will be looking at how the gut moves all the way from the mouth to the rectum and analyze each part of the gut to determine where different GI issues may originate from. For example, we will study how and why the colon may be moving abnormally to cause constipation and whether the nerves governing this process in the gut are abnormal. Abdominal-pain related conditions also tend to be higher in kids with neurodevelopmental differences so we are also looking at susceptibility to pain. In relation to all of these we are currently actively examining the gut nervous system to see if imprinting exists in the gut like it does in the brain and how that is impacting gut development and all of these long-term functions.

Q: Are there any preliminary findings or hypotheses about the role of UBE3A in the gut that you can share with us?

A: Given my prior studies, and studies from some other groups, it is common that genetic differences that present in the brain are also present in the gut nervous system. So my hypothesis is that imprinting exists in the enteric nervous system and it leads to differences in enteric nervous system development and function that go on to cause the many GI issues seen in individuals with AS. We do see a very large presence of the gene in the ENS and are currently analyzing all these different facets as we speak! More to come!

Q:  What potential therapeutic implications do you foresee based on the results of this research for individuals with Angelman syndrome?

A: As I said before, the gut is a relatively easy targetable region in the body for intervention compared to different parts of the brain. It is not only more easily accessible in terms of study but also in terms of drug delivery so if we can determine novel mechanisms underlying gut dysfunction in AS, we may be able to target those regulators to not only improve the gut but potentially also the brain manifestations, through improvement of gut to brain communication.

Q:  Are there any challenges or limitations you anticipate in this study, particularly when studying the gastrointestinal tract of mice in relation to human AS symptoms?

A:  Animal models are a great way to start because it is impossible to investigate many of the mechanisms we are looking at in humans. Our first step will be to figure out exactly which of the GI abnormalities the mice show. It is likely that not all GI manifestations will be present and that may limit some of our findings. Discovery of novel underlying mechanisms related to UBE3a imprinting, however, may enable us to expand therapies not only to the GI issues we find but to others as well as the central nervous system differences.