2022 Junior Investigators
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 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 (FXTAS) is caused by the expansion of a CGG trinucleotide repeat to a pre-mutation range of between 55-200 repeats in the 5’UTR of the FMR1 gene. Multiple lines of evidence suggest that 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 which accurately inhibit 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 (FXS), 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 (FXS), 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 questions 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 disease and essential tremor
Affiliation: Rush University
Project Summary: Fragile X-associated tremor/ataxia syndrome (FXTAS) may be misdiagnosed as Parkinson disease (PD) or essential tremor (ET) due to overlapping motor symptoms. Therefore, we sought to compare FXTAS, PD, ET and controls using quantitative measures of gait under fast speed and dual-task conditions to reveal subtle gait impairments. Distinct gait profiles in FXTAS, PD, and ET 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 (FXS). 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 FXS. 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.