Integrated multi-omics profiling reveals novel molecular biomarkers and pathways associated with Fragile X-associated tremor/ataxia syndrome

Frontiers in Molecular Neuroscience · 2026-04-17

Introduction Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of premutation expansions (55–200 CGG repeats) in the fragile X messenger ribonucleoprotein 1 ( FMR1 ) gene. Despite its clinical significance, FXTAS currently lacks reliable molecular markers for disease monitoring and evaluation of therapeutic efficacy. Methods To address this critical gap, we performed an integrated multi-omics study combining plasma metabolomics (lipidomics, amine, and primary metabolites) with proteomics analyses in plasma and peripheral blood mononuclear cells (PBMCs) from FXTAS participants ( n = 5, FXTAS stages 3–5) and age-matched non-carrier healthy controls (HC, n = 15). Results Integrated analyses revealed molecular differences distinguishing FXTAS from HC, including alterations in metabolites related to energy metabolism (e.g., UDP-glucuronic acid, succinic acid, mannose), lipids (e.g., cholesterol, triglycerides, glycerophospholipids, ceramide), and selected amines (e.g., cystine, glycerophosphocholine, histidine). Proteomic analyses identified proteins associated with FXTAS clinical stage and CGG repeat size, implicating pathways related to mitochondrial function, immune-inflammatory signaling, and lipid metabolism. Comparative analysis of plasma and PBMC proteomes identified Basigin (CD147) and phospholipid transfer protein C2CD2 as overlapping candidate markers across biological matrices. Discussion Although limited by sample size and the cross-sectional design, this exploratory study demonstrates the value of integrated, cross-matrix multi-omics profiling for identifying molecular patterns associated with advanced FXTAS. These findings reinforce prior mechanistic models and provide a foundation for future validation in larger, longitudinal cohorts.

Protective role of PASH-1 in CGG repeat-driven RNA and protein toxicity in FXTAS

iScience · 2026-01-28

as a model for dissecting FXTAS mechanisms and exploring therapeutic strategies.

Novel p.Arg534del Mutation and MTHFR C667T Polymorphism in Fragile X Syndrome (FXS) With Autism Spectrum Phenotype: A Case Report

Case Reports in Genetics · 2025-01-01

Fragile X syndrome (FXS) presents with autism spectrum disorder (ASD), intellectual disability, developmental delay, seizures, hypotonia during infancy, joint laxity, behavioral issues, and characteristic facial features. The predominant mechanism is due to CGG trinucleotide repeat expansion of more than 200 repeats in the 5′UTR (untranslated region) of FMR1 (Fragile X Messenger Ribonucleoprotein 1) causing promoter methylation and transcriptional silencing. However, not all patients presenting with the characteristic phenotype and point/frameshift mutations with deletions in FMR1 have been described in the literature. It is believed that < 1% of cases are caused by point mutations. Genetic and functional testing of point mutations in FXS has yielded insights on KH domain RNA‐binding properties of FMRP (Fragile X Messenger Ribonucleoprotein Protein) and nuclear export of the protein. Here, we report a c.1599_1601del p.Arg534del novel mutation in FMR1 with homozygous C677T MTHFR polymorphism in a 12‐year‐old boy. He presents with unique phenotype of FXS with ASD, developmental delay, nonverbal learning disorder (NVLD), overall IQ in the 5 th percentile with above average verbal IQ (66 th percentile), difficulties with quantitative reasoning, dyspraxia, below average visual‐spatial skills (2 nd percentile), difficulty with social pragmatics and social understanding, and executive dysfunction. He has a strong aptitude for music and exceptional aural skills. Identification of novel variants has helped in understanding functional aspects of FMRP. In addition, it aids families in genetic counseling and in administering therapies for children with FXS who present with atypical features.

Electroretinographic Findings in Fragile X, Premutation, and Controls: A Study of Biomarker Correlations

International Journal of Molecular Sciences · 2025-07-16 · 1 citations

The study’s aim was to evaluate electroretinographic (ERG) alterations in Fragile X syndrome (FXS), FMR1 premutation carriers, and controls, and to explore correlations with peripheral blood FMRP expression levels and behavioral outcomes. ERG recordings were obtained using a handheld device across three stimulus protocols in 43 premutation carriers, 39 individuals with FXS, and 23 controls. Peripheral blood FMRP expression levels were quantified using TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer). Correlations were assessed with cognitive and behavioral measures including IQ (Intelligence Quotient), ABCFX (Aberrant Behavior Checklist for Fragile X Syndrome), SNAP-IV (Swanson, Nolan, and Pelham Teacher and Parent Rating Scale), SEQ (Sensory Experiences Questionnaire), ADAMS (Anxiety, Depression, and Mood Scale), and the Vineland III Adaptive Behavior Scale standard score. Significant group differences were observed in multiple ERG parameters, particularly in 2 Hz b-wave amplitude (p = 0.0081), 2 Hz b-wave time to peak (p = 0.0164), 28.3 Hz flash combined amplitude (p = 0.0139), 3.4 Hz red/blue flash b-wave amplitude (p = 0.0026), and PhNR amplitude (p = 0.0026), indicating both outer and inner retinal dysfunction in FXS and premutation groups. Despite high test–retest reliability for ERG (ICC range = 0.71–0.92) and FMRP (ICC = 0.70), no correlation was found between ERG metrics and FMRP or behavioral measures. However, FMRP levels strongly correlated with IQ (ρ = 0.69, p < 0.0001) and inversely with behavioral impairment [ABCFX (ρ = −0.47, p = 0.0041), SNAP-IV (ρ = −0.48, p = 0.0039), SEQ (ρ = −0.43, p = 0.0146), and the Vineland III standard score (ρ = 0.56, p = 0.0019)]. ERG reveals distinct retinal functional abnormalities in FMR1-related conditions but does not correlate with peripheral FMRP expression levels, highlighting the need for multimodal biomarkers integrating radiological, physiological, behavioral, and molecular measures.

Intron 1 of the <i>C9orf72</i> gene: The RNA that RAN

Proceedings of the National Academy of Sciences · 2025-09-15

The Spectrum of Fragile X Disorders

New England Journal of Medicine · 2025-07-16 · 7 citations

Oligodendrocyte Inclusion Pathology in Fragile X‐Associated Tremor/Ataxia Syndrome

Movement Disorders · 2025-12-06

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder marked by white matter degeneration and intranuclear inclusions. While astrocytic and neuronal inclusions are well-documented, oligodendrocytes were previously thought to lack such pathology. OBJECTIVE: To demonstrate that oligodendrocytes in the prefrontal cortex of FXTAS patients do harbor intranuclear inclusions, with significantly higher burden in white matter than gray matter. METHODS: Ubiquitin and p62 immunofluorescence and enzymatic staining were employed to confirm the presence of intranuclear inclusions in oligodendrocytes across multiple brain regions. RESULTS: Oligodendrocytes contain inclusions and inclusion burden is correlated with FMR1 CGG repeat length (ρ = 0.97, P < 0.001) in white matter. CONCLUSIONS: These findings implicate oligodendrocyte dysfunction in FXTAS pathogenesis which may contribute to demyelination and white matter degeneration. Our data emphasize the need to consider cell type-specific mechanisms in FXTAS and support future therapeutic efforts aimed at restoring glial proteostasis. © 2025 International Parkinson and Movement Disorder Society.

Variation of FMRP Expression in Peripheral Blood Mononuclear Cells from Individuals with Fragile X Syndrome

Genes · 2024-03-13 · 4 citations

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and autism spectrum disorder. The syndrome is often caused by greatly reduced or absent protein expression from the fragile X messenger ribonucleoprotein 1 (FMR1) gene due to expansion of a 5′-non-coding trinucleotide (CGG) element beyond 200 repeats (full mutation). To better understand the complex relationships among FMR1 allelotype, methylation status, mRNA expression, and FMR1 protein (FMRP) levels, FMRP was quantified in peripheral blood mononuclear cells for a large cohort of FXS (n = 154) and control (n = 139) individuals using time-resolved fluorescence resonance energy transfer. Considerable size and methylation mosaicism were observed among individuals with FXS, with FMRP detected only in the presence of such mosaicism. No sample with a minimum allele size greater than 273 CGG repeats had significant levels of FMRP. Additionally, an association was observed between FMR1 mRNA and FMRP levels in FXS samples, predominantly driven by those with the lowest FMRP values. This study underscores the complexity of FMR1 allelotypes and FMRP expression and prompts a reevaluation of FXS therapies aimed at reactivating large full mutation alleles that are likely not capable of producing sufficient FMRP to improve cognitive function.

Unmethylated Mosaic Full Mutation Males without Fragile X Syndrome

Genes · 2024-03-03 · 5 citations

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability (ID) and single gene cause of autism. Although most patients with FXS and the full mutation (FM) have complete methylation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene, some have mosaicism in methylation and/or CGG repeat size, and few have completely unmethylated FM alleles. Those with a complete lack of methylation are rare, with little literature about the cognitive and behavioral phenotypes of these individuals. A review of past literature was conducted regarding individuals with unmethylated and mosaic FMR1 FM. We report three patients with an unmethylated FM FMR1 alleles without any behavioral or cognitive deficits. This is an unusual presentation for men with FM as most patients with an unmethylated FM and no behavioral phenotypes do not receive fragile X DNA testing or a diagnosis of FXS. Our cases showed that mosaic males with unmethylated FMR1 FM alleles may lack behavioral phenotypes due to the presence of smaller alleles producing the FMR1 protein (FMRP). However, these individuals could be at a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS) due to the increased expression of mRNA, similar to those who only have a premutation.

Referee report. For: Behavioural, psychiatric, and cognitive phenotypes associated with numbers of repeats of the FRAXE allele on the FMR2 gene [version 1; peer review: 1 approved with reservations]

Faculty of 1000 Research Ltd · 2024-01-01