By Charlene N. Rivera-Bonet, Waisman Science Writer
It is a 22-hour drive from sunny Florida to snowy Wisconsin which the Doughertys, a family of seven, divide into two days. Their first road trip to Wisconsin happened in the middle of winter of 2022, but this time they got to experience a Wisconsin spring. Jessica Dougherty, her husband, and their five kids, Logan (16), Zack (15), Levi (11) and twins Parker and Chloe (8) drive up to Wisconsin to the Waisman Center to participate in a research study on fragile X syndrome (FXS).
The five Dougherty kids have FXS. This is a genetic condition that results from mutations in a gene on the X chromosome called FMR1. It is the most commonly inherited form of intellectual and developmental disability.
The kids love the car ride and Jessica enjoys taking them to experience other parts of the country. “I don’t know that I would have chosen Wisconsin in February last year, and the snow and all of that,” she says. “But it turned out to be one of the best trips we’ve ever had together.” It is the research that motivates them to come, the trip experience is just a bonus.
They come to the Waisman Center to participate in research studying cognitive and language development in boys with FXS. “We are always willing to help in any way that we can, even if it doesn’t necessarily directly affect our family, but families down the road. If it helps alleviate some of their burden, or propels them in the right direction of getting assistance for their fragile X kiddos, we’d love to help,” Jessica says.
Research studies at the Waisman Center cover both basic science and behavioral research on FXS, starting with the individual, up to the family unit, from childhood, and into old age.
Origins of FXS research at Waisman
Len Abbeduto, PhD, was one of the early FXS researchers at the Waisman Center. His FXS research began as a challenge from Randi Hagerman, MD, a guest speaker in 1998. Hagerman, from UC-Davis who is well known in the field, told him “you really need to do work on fragile X syndrome.” “She was so convincing and it kind of scared me a little bit,” Abbeduto says. Thinking she might be right, he began writing his first grant on FXS.
Abbeduto’s line of research focused on studying language development in individuals with intellectual and developmental disabilities. That grant was his first dive into a particular condition. “It was a really new area for me and for the Waisman Center, but they already had genetics experts on the clinical side who really helped to make it happen,” Abbeduto says. Susan Kirkpatrick, MD and Gregory Rice, MD, clinical geneticists in the Waisman Center Clinics at the time, were experts in FXS and critical in helping Abbeduto establish his new line of research.
His research in FXS kept evolving from a very narrow focus on language challenges in individuals with FXS to other broader areas. “If you only look at the language challenges, you’re really kind of missing the bigger picture of what these folks’ lives are, what the challenges are, what the strengths are,” Abbeduto says. Shortly after, Marsha Mailick, PhD, emeritus vice chancellor for research and graduate education, started venturing into FXS research as well, with a start similar to Abbeduto.
Mailick’s research had focused on the lifespan and family of individuals with intellectual and developmental disabilities. “Having a number of seminars focused on fragile X intrigued me in a very significant way,” Mailick says. After one seminar given by Don Bailey, PhD, former faculty at the University of North Carolina at Chapel-Hill, Mailick and Bailey had a conversation that would soon after turn into a collaboration. “He invited us to become a project in his center grant. And that was our first funding for fragile X,” Mailick says.
Mailick and the Waisman team would focus on fragile X syndrome in adulthood. “Our group was invited because we could bring our methodology that was developed in our autism work to fragile X and then focus on adults,” Mailick says. Mailick, Abbeduto, and Jan Greenberg, PhD, now emeritus professor of social work, collaborated on this project.
This project launched Mailick’s successful line of research in lifespan and family dynamics in individuals with FXS. Her research in FXS focuses on the life course trajectory of FXS during adolescence, adulthood and old age and how family environments affect the development of individuals with the diagnosis during these stages of life, and reciprocally, how parents and siblings are affected. “There’s no way that fragile X can be understood in its manifestation without understanding the family,” Mailick says.
Abbeduto now directs the MIND Institute at the University of California, Davis, where he continues his FXS research.
The Dougherty’s journey with FXS and Waisman research
In addition to working together on FXS research, Abbeduto and Mailick developed a postdoctoral training program for rising scientists in the fields of intellectual and developmental disabilities.
“We were able to recruit these wonderful postdocs, many of whom stayed and ended up as faculty at Wisconsin,” Abbeduto says. One of those postdocs, who studied FXS in Abbeduto’s lab was Audra Sterling, PhD, now an associate professor of communication sciences and disorders and Waisman investigator.
Sterling leads the study that the Dougherty family participated in 2022. After signing up on a list of open studies on FXS, Jessica heard back from Sterling with an invitation to participate in her study.
Jessica’s journey with fragile X started with her first son, but she didn’t realize this until her third. For her two oldest, Logan and Zack, “we knew that there were struggles, but their pediatrician at the time told me ‘oh, they’re boys, they’ll catch up’,” Jessica says. They were offered speech and occupational therapy, which they still receive. But when Levi, her third son, was diagnosed with FXS at age three, Jessica connected the dots and brought Logan and Zack in for testing as well.
Late diagnosis is a common occurrence in fragile X. “Many kids don’t get diagnosed until they’re older. Now, a lot of males with fragile X will be identified with a developmental delay because they often have language impairment,” Sterling says. “Females with fragile X are often identified even later, because there’s such a broad range of affectedness.”
When the Doughertys found out they were pregnant with Chloe and Parker, they decided to get an amniocentesis to test for FXS. “I didn’t feel like I could enjoy the pregnancy until I knew what I needed to do the moment they were born,” Jessica says. “And it worked out because the twins got their first therapy session when they were like three weeks old. And I feel like that’s made a ginormous difference in their development versus Levi, Logan, and Zack’s.”
When she was first given Levi’s diagnosis, Jessica was told that he would live with her forever, and given a list of things he wouldn’t get to do. But that hasn’t been the case, she says. “My hope is that they’re successful participants in the community and that they’re well accepted. And that they kind of put forth the effort on their end as well,” Jessica says. And she has been doing everything in her control to help the medical field better understand the condition, to make sure that her kids, and those who follow can get the best care and outcomes possible. Part of that, is research participation.
Sterling’s work looks at language and cognition in kids with FXS. Her long-term goal is to understand the contributions of both biology – like genetics – and environment to the development of language and cognition in children with developmental disabilities. She also seeks to understand best methods for assessment of language in FXS, and how some co-occurring impairments such as intellectual disability, autism, or social anxiety impact language use.
The focus on premutation carriers of the FXS gene
One of the big shifts in FXS research since its cause was first discovered in the 1990s has been studying premutation carriers. Premutation carriers are individuals who have a less severe mutation of the FMR1 gene, and do not present with FXS, but can pass it down to their kids, who may develop the condition. Much of what is known about premutation carriers is in males, as their symptoms are more significant than females’. “When fragile X was first discovered, we thought about the premutation carriers but only in that the gene was unstable and could mutate to the full mutation form or fragile X. Over time, we’ve found that individuals who are premutation carriers are at risk for a number of clinical problems,” says Sterling, who studies language in premutation carriers. Mailick and Leann DaWalt, PhD, director of the University Center for Excellence in Developmental Disabilities (UCEDD), have also been studying women with the premutation since 2008, and their work has been recognized by the National Fragile X Foundation.
Females with the premutation are at risk for multiple health issues. They have a heightened risk for anxiety and depression, early menopause, a Parkinson’s-like syndrome called Fragile X-associated tremor/ataxia syndrome (FXTAS), and declines on executive and cognitive function.
Arezoo Movaghar, PhD, postdoctoral fellow working with Mailick, and DaWalt, collaborated with Sterling and created an artificial intelligence (AI) assistant technique to find people with the premutation based on their speech.
Using A.I. to find patterns in FXS
Working with Mailick and DaWalt, Movaghar uses AI and big biomedical data to answer important questions about FXS. “We are using AI because it can find patterns in the data that we can’t find in any other way,” Movaghar says.
The goal is to understand all of the areas of a person’s life that are affected by FXS in order to provide better services and care. One step is creating better diagnostic tools, since FXS still remains vastly underdiagnosed. “Part of our work is to try to use AI (on population-based data like electronic health records) and create pre-screening approaches that can find potential cases based on the current state of their health,” Movaghar says. AI enables us to identify these patients much earlier than they are currently being diagnosed in clinics.
Another part of her work is identifying what the factors are that contribute to differences in the health of individuals with FXS. “For example, some people have a co-occurring autism diagnosis, but some people don’t. Or some people have intellectual disability, but some people don’t have that. So, we want to understand what is causing these differences across patients so we can have better care for them and make the intervention and services more personalized to the patient’s needs,” Movaghar says.
Basic science of FXS, finding patient-specific care
One of the benefits of a place like Waisman is the integration of multiple disciplines to tackle a question from different angles. Anita Bhattacharyya, PhD, associate professor of cell and regenerative biology, developed a stem cell model of FXS that can be used to better understand differences in brain development in FXS. She was able to develop these research tools by collaborating with Abbeduto to recruit individuals in his study for skin biopsy donation to create induced pluripotent stem cells (iPSC).
Now, Bhattacharyya collaborates with Xinyu Zhao, PhD professor of neuroscience and Jenni and Kyle Professor of Neurodevelopmental Diseases at Waisman, to use molecular approaches to study FXS. In the cells derived from individuals with FXS, they are able to observe characteristics that are relevant to the individuals with the condition.
“We’ve made stem cell models for both fragile X and Down syndrome and validated the tools. Our success is illustrated by the fact that many of the cell lines that we generated here at the Waisman Center are used by researchers all over the world,” Bhattacharyya says.
Zhao has been using mouse models of FXS to study the mechanisms underlying physiological and behavioral differences and identifying potential drug targets for FXS for nearly 20 years. More recently, Zhao started using nonhuman primate models to investigate the impact of FXS on primate neuron development.
A new grant obtained by Zhao and Bhattacharyya may also help tailor drugs to certain subpopulations of individuals with FXS. Craig Erickson, MD, a clinician at Cincinnati Children’s Medical Center who collaborates with Zhao and Bhattacharyya, found that you can stratify individuals with FXS based on their resting electroencephalogram (EEG) patterns. The two categories of individuals have different responses to medication, and also behave differently.
With pilot funding from the John Merck Fund, they have derived stem cell models from the blood cells of the individuals with FXS that show different EEG patterns. Scientists in the Zhao lab are differentiating these cells into brain neurons and organoids and are digging deeper into the molecular and physiological differences. “If we can establish a cellular model for this differential EEG phenotypes of FXS, maybe we can also identify the molecular mechanism underlying these differences, then use the information to design the kind of drug, combination, or dosage to treat the two different populations of FXS,” Zhao explains.
Evolution of the field
“When fragile X was first discovered in the 1990s,” Sterling says, “there was such an interest in the genetic side of things, and then it moved more into behavioral work. And now I think there’s been more of an integration of understanding the genetics alongside behavior.” A place like the Waisman Center, which houses experts from many disciplines and fosters collaborations between them, allows for this integration of behavior and genetics and is exemplified in the many collaborations around FXS research.
As the field has continued to evolve, Waisman investigators have kept up with, and in several cases led the trends. Although individuals with FXS are still the main focus of the research, studies now include families, and especially mothers that carry the premutation, ensuring that everyone gets the support they need in whichever stage of the journey they are on.
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