Summary of the Fragile X Messenger Ribonucleoprotein (FMRP) Series at the 18th NFXF International Conference

18th International Fragile X Conference session presenters: Anna Boggs; Kelly Dominick, MD, PhD; Lauren Schmitt, PhD; Jay Gibson, PhD; and Craig Erickson, MD

Summarized by Dr. Talia Thompson, a 2022 NFXF Jr. Investigator

Fragile X messenger ribonucleoprotein (FMRP) is a protein that impacts brain development and brain functioning. Individuals with Fragile X have reduced FMRP due to methylation of the FMR1 (fragile X ribonucleoprotein 1) gene. Historically, our understanding of the role of FMRP in Fragile X has been limited by measurement challenges. An improved method for detecting FMRP from dried blood spots (the Luminex-based immunoassay) has recently allowed Cincinnati Children’s Hospital Medical Center investigators to accurately and reliably measure a wide range of FMRP levels. Investigators presented results from several current FMRP studies in a series of research summaries at the 18th NFXF international conference. The key findings are summarized here:

•  Reliable Detection of FMRP: People with Fragile X syndrome (FXS) produce significantly less FMRP than those with mosaic Fragile X and indivdiuals who are typically developing (sometimes called “controls” in research). However, there is a subset of males with the full mutation of FXS and who have a fully methylated FMR1 gene, but who still produce consistent, trace amounts of FMRP. Further, these levels of FMRP appear to be stable over time in adults. Levels of FMRP are also strongly related to the FMR1 mRNA expression for individuals with Fragile X.
• The Role of FMRP in Early Development: Very little is known about FMRP levels in young children with FXS. A new study is linking FMRP to behavior and brain functioning in infants, toddlers, and preschool-aged children with FXS. Preliminary results show some male infants with full mutation FXS produce trace amounts of FMRP. As seen in adults, infant females and infants with mosaic FXS have higher levels of FMRP. Future analyses will determine how FMRP impacts the slope of development in FXS.
• Clinical Utility of FMRP Assay: A newly developed ability to measure trace amounts of FMRP allowed investigators to examine the relationship between FMRP and multiple psychological features. Higher levels of FMRP are associated with higher IQ in both men and women with FXS. Men with higher levels of FMRP are less likely to have psychiatric problems such as hyperactivity and impulsivity. However, the opposite is true for women with FXS, where higher levels of FMRP are associated with increased depression symptoms and reduced social skills. Brain wave testing showed FMRP was also related to EEG markers of hyperexcitability.
• FMRP and Brainwave Responses in Mouse Models: Investigators wanted to understand the minimal amount of FMRP needed to normalize development and physical functioning in FXS. They measured brainwave activity during the presentation of a brief chirping sound to mouse models. In general, the FXS mouse shows a stronger response to the sounds, reflecting the hypersensitivity found in FXS. However, the partial FXS mouse with 15% of normal FMRP levels was able to process some frequencies of sounds, but not all, at the same rate as typical mice. This indicates small amounts of FMRP may be adequate to promote some aspects of normal development in FXS.
• FMRP and Clinical Trial Research: There is a wide range of FMRP expression across individuals with FXS. Clinical trial researchers have started looking at the role of FMRP levels on response to drug treatment. Major differences have been found between males with low levels of FMRP and those who do not produce any protein. For example, a single dose of the drug Baclofen impacted gamma brainwaves and improved some social attention skills in those with low levels of FMRP but had no effect on males with zero FMRP. In contrast, low doses of the drug Baer-101 improved social engagement and memory in males with FXS producing no FMRP but had a negative social impact on males with small amounts of FMRP. Results indicate FMRP levels are an important consideration when investigating and prescribing drugs to patients with FXS.

Why This Matters

The combined findings from these FMRP studies highlight the importance of FMRP on physical and behavioral development and brainwave activity for individuals with FXS. With new methods for measuring FMRP, scientists are beginning to understand how protein levels are related to daily functioning, how levels change over time, and how FMRP can impact response to medications. Prior studies that failed to show significant results in treatment response might be partially explained by FMRP differences.

Next Steps

More research needs to be done to better understand the progression of FMRP expression across the lifespan and how FMRP is related to all aspects of functioning. Adding FMRP measurement to future research might inform the development of personalized medicine in FXS. Providers could target drug treatment protocols to specific subgroups in order to promote healthy development and ultimately improve quality of life across the diverse population of people living with FXS.

Thanks to presenters, Anna Boggs, Kelly Dominick, Lauren Schmitt, Jay Gibson and Craig Erickson, for the fabulous presentation!