脆弱Ｘ症候群関連疾患

BACKGROUND: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by FMR1 premutation CGG repeat expansions (55-200 repeats). The epigenetic landscape of the FXTAS brain remains uncharacterized. We performed genome-wide DNA methylation profiling of postmortem prefrontal cortex tissue to identify differentially methylated positions (DMPs) and candidate genes, and sought protein-level support for a neuroinflammatory signal. METHODS: DNA methylation was profiled in postmortem prefrontal cortex (Brodmann area 9) from 27 male FXTAS cases and 29 male controls using the Illumina MethylationEPIC array (EPICv1 and EPICv2 platforms), merging 721,802 common probes. Surrogate variable analysis (SVA) controlled for confounders. DMPs were defined by |Δβ| > 0.10 and FDR < 0.05; exploratory Reactome 2024 pathway analysis was performed on the DMP-associated gene list. Targeted proteomic profiling was performed in the same brain region using the Olink (proximity extension assay) Inflammation panel in 9 FXTAS cases and 12 controls, with SVA-adjusted differential abundance analysis, and concordance assessment against a prior mass spectrometry dataset. RESULTS: We identified 108 significant cg-type DMPs mapping to 80 genes (50 hypermethylated, 58 hypomethylated in FXTAS). The strongest signal was CYP2E1 (7 concordant hypomethylated DMPs, mean Δβ = -0.143), an oxidative stress gene also implicated in Parkinson's disease. FTCD , a one-carbon cycle enzyme, carried 5 hypermethylated DMPs (mean Δβ = +0.210). A cluster of DMP-associated genes with established roles in innate immune and NF-κB signaling, TRAF3 (the single most significant DMP among the inflammation genes, hypermethylated), BATF, RCOR1 , and MSI2 ; they pointed toward neuroinflammatory dysregulation. Additional genes included LINGO1 (myelination inhibitor), SYT3 (synaptic vesicle), and SLC39A4 (zinc transporter). Exploratory Reactome enrichment using the DMP-associated gene set nominated themes including neuroinflammation resolution, axonal growth inhibition, zinc homeostasis, and CYP2E1 metabolism at nominal significance (p<0.05); however, the gene-to-pathway mapping rate was low and no pathway survived correction for multiple testing. Olink proteomic analysis independently identified 60 significantly altered inflammation proteins (59 downregulated), including CXCL8, CXCL10, IL6, IL15, IL18, TLR3, IRAK1/4, and complement C1QA, which were directionally concordant with prior mass spectrometry data. CONCLUSIONS: This integrated study reveals a genome-wide epigenetic signature in the FXTAS prefrontal cortex implicating oxidative stress, myelination failure, zinc dysregulation, one-carbon cycle disruption, and most notably a coordinated set of epigenetically altered genes governing innate immune and NF-κB signaling. Convergence of TRAF3 hypermethylation with independent downregulation of TLR3 and NF-κB-pathway proteins at the protein level supports a coherent, cross-platform model of dysregulated neuroinflammatory signaling in FXTAS, identified here through individual gene- and protein-level convergence rather than formal pathway enrichment. FTCD hypermethylation proposes a self-reinforcing epigenetic loop via SAM depletion. These multi-omic findings establish FXTAS as a disorder of pervasive epigenetic reprogramming and nominate candidate genes for future mechanistic and therapeutic investigation.

BACKGROUND AND OBJECTIVES: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that affects carriers of the FMR1 premutation (55-200 CGG repeats). It is characterized by motor and cognitive impairments. However, the mechanisms underlying individual susceptibility to FXTAS among carriers remain poorly understood. Emerging evidence suggests that neuroinflammation and glymphatic dysfunction may interact and play key roles in the pathological cascade leading to neurodegeneration. This study aimed to investigate potential glymphatic and/or inflammatory dysfunction in FMR1 premutation carriers with FXTAS using the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, as well as gene expression and functional enrichment analyses in individuals with FXTAS versus controls. METHODS: We analyzed the DTI-ALPS index in 14 participants with FXTAS and 25 age- and sex-matched controls, and assessed the expression and pathway dysregulation of genes related to neuroinflammation and glymphatic function using Reactome analysis in postmortem brain tissue from 3 individuals with FXTAS and 12 controls and skin fibroblasts from 6 individuals with FXTAS and 3 controls. RESULTS: The DTI-ALPS index was significantly lower in individuals with FXTAS compared to controls in the right but not left hemisphere (p = 0.0051) and globally in both hemispheres (p = 0.0473). There was no correlation between lower DTI-ALPS index and increasing CGG repeat length but a trend was observed in males. Reactome analysis revealed downregulation of aquaporin-mediated transport in brain tissue and fibroblasts, upregulation of multiple immune-related and inflammatory pathways, predominantly in brain tissue, and increased circadian-related pathway activity in fibroblasts. DISCUSSION: Our findings point at glymphatic system dysfunction and neuroinflammation in FXTAS pathophysiology, as evidenced by in vivo DTI-ALPS metrics and gene pathway dysregulation and expression in fibroblasts and in postmortem FXTAS brains.

Repeat-associated non-AUG (RAN) translation of mutant FMR1 messenger RNA (mRNA) containing CGG repeat expansions results in the production of a toxic polyglycine protein (FMRpolyG), which contributes to fragile X premutation-associated conditions (FXPAC), including fragile X-associated tremor/ataxia syndrome (FXTAS). The 5' untranslated region of FMR1 mRNA folds into a thermodynamically stable secondary structure at the region of excessively expanded CGG repeats and constitutes a template for RAN translation initiated from near-cognate start codons located upstream of the CGGs. Cis-regulatory elements, including sequence context and stable secondary structures within mRNA, can affect translation initiation and elongation. Here, we show that different nucleotide sequence contexts close to the near-cognate start codon affect FMRpolyG synthesis. Moreover, the distance between the near-cognate start codon and downstream stable RNA structure considerably affects the efficiency of RAN translation initiation, which is positively correlated with the number of CGG repeats. In contrast, translation elongation is impaired as CGG repeats expand. We show that native FMRpolyG containing a short polyglycine tract is synthesized efficiently but rapidly degraded by the proteasome. Our results provide insight into the structural dependencies that regulate the translation of CGGs and can be used in other repeat expansion disorders. We also show that the RNA structure is a potential therapeutic target in FXPAC.

BACKGROUND: While genetic testing in Movement Disorders (MD) has expanded enormously, access to genetic testing and genetic counseling remains asymmetric at the global scale. Guidance on efficient testing strategies for clinicians, governments and stakeholders is crucial. OBJECTIVES: Establish a list of genetic movement disorders considered essential as determined by a group of MD experts. METHODS: All genes associated with MD were searched using the OMIM and MDS Gene database. We collected all additional tests available at 4 different laboratories from the EuroGentest database. The results were compiled in 6 questionnaires. A genetic test was considered essential if molecular testing had a direct impact in the management of the patient, including treatment of the disease or its comorbidities, or genetic counseling of the patient and family members. Two Delphi rounds were conducted asking MD experts which specific tests they considered essential in an adult MD clinic. RESULTS: Fifty-nine disorders were considered essential to genetically identify by the MD experts. This included 25 genes associated with ataxia, 15 with parkinsonism, 14 with dystonia, eight with chorea, five with paroxysmal disorders, four with myoclonus, four with hereditary spastic paraparesis, and one with tremor. Sixteen disorders reached 100% consensus among experts: Huntington's disease, PxMD-PPRT2, Wilson's disease, DYT-SGCE, DYT-THAP1, DYT-TOR1A, DYT/PARK-GCH1, Fragile-X Tremor-ataxia syndrome, PARK-GBA, PARK-LRRK2, PARK-PINK1, PARK-PRKN, PARK-SNCA, Cerebrotendinous Xanthomatosis, Ataxia-Telangiectasia, and Niemann-Pick disease type C. CONCLUSION: This study provides a list of genetic MD that should be molecularly tested in adult centers with a compatible phenotype according to a group of MD experts.

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.