Research Results Roundup

We are excited to share with you some of the great research results that have been published thus far. We are committed to keeping the community up to date on research findings, taking time to reflect and celebrate successes in the field of Fragile X-associated disorders. Researchers: If you’ve recently published your scientific findings in a peer-reviewed journal, please share your work with us by emailing research@fragilex.org.

Cheers to the amazing scientific advancements in our field and the advancements to come. It would not be possible without your dedication, passion, and drive to make each day just a bit better. 

Our most recent research results are below, with previous results beginning on the next page.

10/22/2020 Research Results Roundup

Inhibition Deficits Are Modulated by Age and CGG Repeat Length in Carriers of the FMR1 Premutation Allele Who Are Mothers of Children with Fragile X Syndrome

Authors: Jessica Klusek, Jinkuk Hong, Audra Sterling, Elizabeth Berry-Kravis, and Marsha Mailick.

Summary

Drs. Jessica Klusek, Marsha Mailick, and colleagues investigated how a dimension of executive function, inhibition, is affected by age and FMR1 CGG repeats among mothers of children with Fragile X syndrome. Inhibition is the ability to suppress an action, such as not eating that piece of chocolate even though you really want it. Difficulties with inhibition can affect relationships and are linked to mental health problems. This study looked at relationships between inhibition, measured in two different ways, and individual factors, such as age and the FMR1 gene, among female premutation carriers.

This study included 134 premutation carriers who were mothers of children with Fragile X syndrome. Participants completed a test over the phone called the Hayling Sentence Completion Test, which directly measures verbal inhibition (i.e., how quickly and accurately a participant completes a sentence). Separately, participants answered questions about daily tasks associated with inhibition, such as waiting your turn. FMR1 CGG repeat length was also measured.

On the Hayling test, greater difficulties with inhibition were associated with older age. Additionally, individuals who had CGG repeats between 80 and 90 had greater difficulties with inhibition compared to individuals with who had 90–115 CGG repeats. On the questionnaire, participants with 90–110 CGG repeats reported the greatest difficulties with daily activities of inhibition.

Why This Matters

This study highlighted that older mothers of children with Fragile X syndrome (over 70 years) who have “mid-range” CGG repeats (~80–100) may be at increased risk for difficulties with inhibition. The mid-range has been previously associated with risks for mental health problems and FXPOI, as well as increased vulnerability to stress, suggesting important implications for these individuals’ health and well-being.

Next Steps

Researchers would like to better understand how age-related differences in inhibition may be associated with changes in the brain. Such information may provide insight into FXTAS and the role of the FMR1 gene in aging.

Funding: This work was supported by the National Institutes of Health under grant numbers R01HD082110, P30 HD003100-S1, U54 HD090256, R21DC017804, R03HD098291.

Clustering of Comorbid Conditions among Women Who Carry an FMR1 Premutation

Researchers: Emily Graves Allen, Krista Charen, Heather Hipp, Lisa Shubeck, Ashima Amin, Weiya He, Jessica Ezzell Hunter, and Stephanie Sherman.

Summary

Drs. Emily Allen, Stephanie Sherman (Emory University), and colleagues evaluated health conditions among women who carry an FMR1 premutation. Two conditions, FXPOI and FXTAS, have been well documented among individuals with a premutation. These authors sought to clarify how often other health-related conditions, such as migraines and sleep problems, occur among women with a premutation.

Participants included 355 women with a premutation ranging from 19 to 93 years of age. Of this group, 87 participants had been previously diagnosed with FXPOI. Participants completed questionnaires about whether they experienced or were diagnosed with health conditions such as anxiety/depression, headaches, FXTAS-associated symptoms, sleep problems, and hypertension, among others.

The most commonly reported conditions were anxiety and depression, as well as migraine and tension headaches. Forty-seven percent of women reported the presence of four or more conditions. Body mass index and smoking were associated with experiencing a higher number of conditions and having a child with Fragile X syndrome was associated with increased rates of anxiety and depression.

The study team also used an approach called a “cluster analysis” to determine whether particular conditions tended to occur together. They found eight sub-groups of participants based on the conditions they reported. The biggest group (123 women) had few reported health problems. Two sub-groups included women who reported headaches or mental health problems, but few other conditions. One sub-group included women with sleep problems who reported several other health conditions. Among the three sub-groups of women who had a high rate of a diagnosis of FXPOI (87 people), different patterns emerged: those with minimal health problems, those with mental health problems, and those with multiple conditions such as chronic muscle pain, fibromyalgia, and/or irritable bowel syndrome. The last sub-group (11 women) had symptoms related to FXTAS (e.g., tremor, ataxia, and neuropathy), but few other conditions.

Why This Matters

This study highlights the variability in health profiles among women with a premutation. The majority of women report few health problems, however a significant group report complex health profiles. This study takes the first step to characterize this variability and to understand the impact of an FMR1 premutation as well as environmental factors, such as body mass index and smoking, that may negatively affect health among women with a premutation.

Next Steps

Researchers would like to better understand why the health profiles are so diverse among women with a premutation — what are the genetic and environmental factors associated protection and risk? How can those be identified to help weaken the effect of a premutation and improve health? Clearly, more work is needed.

Funding: This work was supported by an award (NIH U54NS09185) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke.

Cerebellar-Cortical Function and Connectivity during Sensorimotor Behavior in Aging FMR1 Gene Premutation Carriers

Authors: Mr. Walker McKinney, Dr. James Bartolotti, Dr. Pravin Khemani, Dr. Jun Yi Wang, Dr. Randi Hagerman, and Dr. Matthew Mosconi.

The study team thanks the participants for their time and effort in participating in the study and Dr. Elizabeth Berry-Kravis and the Molecular Diagnostic Laboratory at Rush University for their assistance in molecular testing.

Summary

Doctoral student Walker McKinney, Dr. Matt Mosconi, and colleagues investigated how aging as a premutation carrier may affect sensorimotor (exactly as it sounds, both sensory and motor) brain systems. Premutation carriers of the FMR1 gene are at risk of developing Fragile X-associated tremor/ataxia syndrome (FXTAS), and although several studies have documented sensorimotor issues in aging premutation carriers before the onset of clinical symptoms of FXTAS, the brain processes associated with sensorimotor issues and their potential to serve as early indicators of FXTAS have not been determined.

This study included 16 FMR1 premutation carriers and 18 control participants. Participants’ brain activity was measured with functional magnetic resonance imaging (fMRI) while they performed a test of sensorimotor control. Participants were instructed to grip a handle that measured their force level while they received visual feedback about how hard they were pressing. Participants viewed a white force bar that moved upward with increased force and downward with decreased force and a red static target bar (A) that turned green to begin each trial. Participants were instructed to press (C) so that the white force bar stayed as steady as possible at the level of the green target bar (B). Participants completed this sensorimotor task while the fMRI machine recorded small changes in blood flow in the parts of the brain that were active during the task.

Black square with red and a white horizontal line, black square with a green and white horizontal line, and hand holding unit for pressing

Sensorimotor test stimuli and custom fiber-optic transducer (C; Neuroimaging Solutions, Gainesville, FL). Participants pressed when the red bar (A) turned green (B) in order to move the white bar up to the target green bar. They were instructed to maintain their force level at the level of the green bar as steadily as possible.

Researchers found that the functional connectivity of the cerebellum (a brain area that controls movement accuracy and timing) and the extrastriate cortex (a brain area involved in processing visual information) is reduced in aging FMR1 premutation carriers. This suggests that communication between visual processing regions in the brain and the cerebellum, a brain region critical for monitoring and adjusting movements so that they are accurate, is disrupted during aging in FMR1 premutation carriers and may be an early indicator of FXTAS.

Why This Matters

Researchers have struggled to find biomarkers to indicate who might develop FXTAS and who is showing early signs of neurodegeneration before the emergence of clear clinical concerns. These findings meant that functional connectivity between the cerebellum and extrastriate cortex could serve as a biomarker for FXTAS. This potential biomarker could help researchers and clinicians better predict which premutation carriers may develop FXTAS before they experience the tell-tale symptoms (e.g., kinetic tremor, gait issues).

Next Steps

Researchers will need to follow these participants over time to see if these functional connectivity differences are in fact a biomarker or an early indicator for FXTAS. More research using sensorimotor tasks and connectivity measurements is needed to further understand this potential biomarker.

Funding: This work was supported by the Once Upon a Time Foundation and the National Institutes of Health (U54 HD090216).

Last Updated: 11/11/2020