The NFXF is committed to promoting scientific and treatment research advancements for Fragile X-associated conditions and disorders, including our NFXF Junior Investigator awards.
Information about applying for a Jr. Investigator award is announced before our biennial NFXF International Fragile X Conference — you can stay informed by subscribing to our newsletter. If you have any questions about the awards, please contact us.
2024 Junior Investigators
Lisa DeStefano, PhD
Visual Discrimination in FXS: Insights From Behavior and EEG
Affiliation: Cincinnati Children’s Hospital
Project Summary: Sensory abnormalities are common in Fragile X syndrome, including in the visual domain. To understand this better, participants completed a task in which they viewed a visual stimulus moving to the left or right and pressed a button corresponding to the direction of movement. In half of the trials, an auditory distractor was present. In FXS, we found that males performed worse with the distractor present, but females continued to improve. EEG analyses suggest that FXS males have an exaggerated brain response to the appearance of the visual stimulus, but less change in later brain activity associated with movement.
Brett Dufour, PhD
Evidence for Widespread Loss of Parvalbumin Expressing GABAergic Interneurons Throughout the Human Fragile X Brain
Affiliation: UC Davis
Project Summary: Parvalbumin-expressing (PV+) interneurons, critical inhibitory cells in the brain, are reduced in number in human autism and epilepsy. Here, in the largest postmortem neuroanatomical study of the human Fragile X syndrome brain to date (9 FXS and 9 control), we tested the hypothesis that PV+ INs are also reduced in the FXS brain. The number of PV+ neurons were significantly reduced in FXS subjects by 40-81% across all regions of the brain that were examined, including six cortical regions, amygdala, and hippocampus. These results implicate PV+ IN loss as a mechanism underlying E/I imbalance in FXS and can guide the development of targeted therapeutics.
Nell Maltman, PhD
Language Features Among Individuals with Symptoms of Fragile X-Associated Tremor/Ataxia Syndrome
Affiliation: University of Arizona
Project Summary: Individuals with FXTAS have known cognitive and motor difficulties, but how language may be impacted in this population is poorly understood. The primary aims of this study were to determine (a) the extent to which males and females with FXTAS symptoms differed in their language use and (b) associations between language production and FXTAS symptoms. Language did not differ between sexes, but aspects of language use predicted symptom expression. Thus, language production may be a promising candidate measure for future clinical trials.
Caroline Dias, MD, PhD
Cell-Type-Specific Effects of the Fragile X Premutation in Human Brain
Affiliation: Children’s Colorado
Project Summary: Although animal models have been critical in revealing molecular mechanisms of cellular dysfunction in Fragile X-related disorders, understanding how the human brain is directly impacted remains unresolved. We conducted a cell type-specific transcriptomic analysis of postmortem human brains from individuals with Fragile X mutations and matched controls, sequencing over 120,000 nuclei from the frontal cortex and cerebellum (areas of the brain). We found evidence for cell type-specific, disease-specific, and regional-specific patterns of transcriptional and FMR1 protein (FMRP) network perturbations, including in oligodendrocytes, the key myelinating cells of the central nervous system.
Andrew Dakopolos, PhD
Developmental Links Between Cognition, Adaptive Behavior, and Intelligence in Individuals with Fragile X Syndrome
Affiliation: UC Davis
Project Summary: Individuals with Fragile X syndrome often experience challenges related to intellectual and adaptive functioning that may interfere with learning, independence, and living skills. While these areas of relative challenge are well-established, less is known about how they interact and relate to one another in development — particularly for people with FXS. The present study sought out to examine associations of developmental changes over two years in the domains of cognition, adaptive behavior (including socialization, communication, and daily living skills), and IQ.
Our previous work has established longitudinal associations of change between cognition, adaptive behavior, and IQ in a sample of 264 individuals with intellectual disability, and the purpose of the present study is to extend and examine these patterns of associations, specifically for individuals with FXS. This investigation represents a new and innovative approach to understanding specific developmental patterns in individuals with FXS.
Sarah Nelson Potter, PhD, CCC-SLP
Correlates of Parenting Stress in Mothers and Fathers of Young Boys with Fragile X Syndrome
Affiliation: RTI International
Project Summary: Many parents of children with FXS experience elevated levels of parenting stress due to the challenges associated with raising a child with significant delays. This study examined relationships among parenting stress and measures of individual and couple well-being, as well as child characteristics, for mothers compared to fathers of young boys with FXS. Overall, we found similar relationships between mothers’ and fathers’ parenting stress and the other measures. However, we found a significant relationship between parenting stress and child autism symptoms for fathers but not mothers, suggesting that the causes of parenting stress may not be the same for mothers and fathers.
Walker McKinney, PhD
Results from a Double-Blind, Randomized, Placebo-Control Trial of lovastatin and Minocycline in Fragile X Syndrome
Affiliation: Cincinnati Children’s Hospital
Project Summary: Single-dose drug trials in Fragile X syndrome can establish drug safety and identify small changes in behavior or brain function that help clinicians decide early on if a drug is working and for whom the drug may work best. We completed a placebo-controlled, double-blind, crossover, single-dose study of lovastatin and minocycline in 29 participants with FXS. Participants completed several measures of cognitive functioning and an EEG (a measure of brain function) before and after dosing. Both drugs were safe and well-tolerated. We discuss differences in behavior and brain function associated with the use of lovastatin or minocycline.
Kimaya Sarmukadam, PhD
Sensory Impairments Predict Anxiety Symptoms in Preschoolers with Fragile X Syndrome: A Cross-Sectional Study
Affiliation: University of South Carolina
Project Summary: Anxiety symptoms and sensory impairments are common features of Fragile X syndrome. However, the relationship between anxiety and sensory symptoms in FXS remains unknown. Therefore, the current study aimed to clarify the relationship between sensory symptoms and anxiety symptoms in 42 preschoolers with FXS and 35 typically developing preschoolers. Results suggest that children with FXS had significantly elevated sensory symptoms, and sensory symptoms predicted anxiety symptoms similarly in both groups. Further research is needed to determine how sensory symptoms impact the development of anxiety in children with FXS across childhood.
Junior Investigator Award Archives
Kate Shelley, PhD
FXPOI Alters Omega-6 Fatty Acid Metabolism and Formation of Pro-inflammatory Metabolites Compared to FMR1 PM Carriers Without FXPOI
Affiliation: Emory University
Project Summary: Metabolomic analysis of blood plasma from female FMR1 premutation carriers revealed levels of omega-6 fatty acids and arachidonic acids are increased in women with FXPOI. The identified metabolites are linked to specific ovarian functions perturbed in the FMR1 premutation mouse ovary. We used both human and mouse data to investigate how CGG repeats lead to impaired function of the ovaries.
Maria Jimena Salcedo-Arellano, MD
Metabolic Profile in the Brain With Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
Affiliation: University of California – Davis, MIND Institute
Project Summary: We analyzed changes in the concentration of primary metabolites, with emphasis in glucose and the gluconeogenesis pathway precursors, activators, and inhibitors, in the brain with FXTAS. We also investigated how these changes relate to the levels of Fragile X mental retardation protein, to the number of CGG repeats, and to the presence of the APOE ε4 allele.
Carolyn Yrigollen, PhD
Evaluation of a CRISPR Gene Editing Strategy in CGG Knock-In Mice
Affiliation: Children’s Hospital of Philadelphia
Project Summary: AAV delivery of FMR1 targeting CRISPR Cas9 and guideRNAs into the brains of CGG knock-in mice induced partial deletion of the trinucleotide repeats. These mice model FXTAS molecular and motor phenotypes. The CRISPR-treated mice showed rescued molecular and motor phenotypes compared to uninjected knock-in littermates. Next-generation Nanopore sequencing identified outcomes of in vivo editing including partial CGG repeat deletion and AAV integration events. These results inform the future development of CRISPR therapeutics for the treatment of FXTAS and other Fragile X-associated disorders.
Connor Maltby, PhD
Human Stem Cell Models for Investigating Disease Mechanisms of Fragile X-Associated Tremor/Ataxia Syndrome
Affiliation: University of Michigan
Project Summary: Fragile X-associated tremor/ataxia syndrome is caused by the expansion of a CGG trinucleotide repeat to a pre-mutation range of between 55 and 200 repeats in the 5’UTR of the FMR1 gene. Multiple lines of evidence suggest that the translation of a toxic repeat-associated polyglycine peptide, FMRPolyG, is a significant driver of toxicity in FXTAS. We have utilized genetic editing in patient-derived neurons to allow accurate detection of this product, which has allowed us to investigate how novel compounds that accurately inhibit the production of FMRPolyG lead to enhanced neuronal survival as well as restoring neuronal function.
Anubhuti Goel, PhD
Of Mice and Humans: Hypersensitivity to Distractors in Fragile X Syndrome
Affiliation: University of California – Riverside
Project Summary: Sensory hypersensitivity is one of the most prominent and disabling features of Fragile X syndrome, often limiting social interactions, delaying learning, and impeding daily functioning. Using a novel analogous task in humans with FXS and in FMR1-/- mice, we find that auditory distractors impair task performance to a greater extent in FXS than controls. Using two photon calcium imaging and EEG we also uncover the neural deficits that contribute to sensory hypersensitivity and distractibility, thus paving the way for targeted therapeutic strategies.
Sungeun Kang, PhD
Developing Improved Outcome Measures in FXS: Key Stakeholder Feedback
Affiliation: Cincinnati Children’s Hospital Medical Center
Project Summary: Since there are limited behavioral outcome measures of behavior inflexibility available for Fragile X syndrome, the Cincinnati Fragile X Treatment and Research Center (Dr. Schmitt) is in the process of developing a novel scale of inflexible behavior for FXS. For the instrument development, we invited individuals with FXS, families, and professionals to participate in focus groups to enhance validity by generating items significant and relevant to the population. In particular, we sought to incorporate caregivers’ experiences in reporting preexisting measures. Participants provided suggestions on question formats and contents, inclusion of certain items, and shared their challenges completing common measures.
Erin Robertson, PhD, AuD
Gait Impairments Distinguish Fragile X-Associated Tremor/Ataxia Syndrome From Parkinson’s Disease and Essential Tremor
Affiliation: Rush University
Project Summary: Fragile X-associated tremor/ataxia syndrome may be misdiagnosed as Parkinson’s disease or essential tremor due to overlapping motor symptoms. Therefore, we sought to compare FXTAS, Parkinson’s disease, essential tremor, and controls using quantitative measures of gait under fast speed and dual-task conditions to reveal subtle gait impairments. Distinct gait profiles in FXTAS, Parkinson’s disease, and essential tremor were found, which if confirmed may assist in more accurate and timely diagnosis and could be used to choose the most appropriate outcome measures for future clinical trials.
Tracy Jordan, PhD
Brain Anatomy in Child and Adolescent Girls With and Without Fragile X Syndrome
Affiliation: Stanford University
Project Summary: This study utilized MRI data to examine neuroanatomy in child and adolescent girls with and without Fragile X syndrome. Participants included 43 girls with FXS and 31 age- and verbal IQ-matched girls without FXS. Regional analyses revealed significantly different between-group volumes for bilateral caudate, pallidum, and accumbens such that the FXS group, on average, displayed increased brain area volumes. Exploratory analyses examining potential associations between brain region volume and key domains of social, affective, and cognitive development revealed differential patterns of associations between groups. Findings fill a critical gap in the literature by describing neuroanatomy among girls with FXS.
Michelle Tosin, PhD
Development of Fragile X-Associated Tremor Ataxia Syndrome Rating Scale (FXTAS-RS)
Affiliation: Rush University
Project Summary: We describe the stepwise methodology used for the development of a revised and improved version of the Fragile X-Associated Tremor/Ataxia Syndrome Rating Scale (FXTAS-RS) for motor signs assessment. We conduct a multimethod approach using Delphi panel and cognitive pretesting techniques to establish the five domains, 13 subdomains, and 18 items of the revised FXTAS-RS. We tested the revised version of the scale determining its readability, comprehensiveness, applicability, and relevance.
Talia Thompson, PhD
Using Qualitative Methods to Enhance our Understanding of Anxiety in Individuals with Fragile X Syndrome
Affiliation: University of Colorado
Project Summary: Qualitative research methods can generate hypotheses and highlight patient voices to convey a range of subjective life experiences. This electronic survey study aimed to describe the observable behaviors caregivers and self-advocates ascribe to anxiety in Fragile X syndrome. Qualitative findings from free-text responses elaborated and expanded upon quantitative results revealing new information on how individuals with FXS experience anxiety and how caregivers recognize symptoms. As regulatory agencies require proxy-reported measures to reflect the lived experiences of patients and their families, qualitative methods offer a promising approach to developing valid and patient-centered outcome measures without the overlay of researcher bias.