脆弱Ｘ症候群関連疾患

BACKGROUND/OBJECTIVE: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder caused by a premutation (55 to 200 CGG repeats) in the FMR1 gene. This expansion leads to mRNA toxicity, resulting in the deterioration of executive and cognitive abilities alongside characteristic brain changes detected via Magnetic Resonance Imaging (MRI). While the Behavioral Dyscontrol Scale-2 (BDS-2) is commonly used to evaluate executive function, its specific relationship with neuroanatomical markers in FXTAS has not been fully examined. This study investigated the association between BDS-2 and MRI scores in FXTAS. METHODS: Correlation and linear regression analyses were conducted to evaluate how BDS-2 scores correlate with MRI total scores and other neurodegeneration variables, measured by white matter hyperintensities, relative to the MMSE and CANTAB subtests in 56 FMR1 premutation carriers with and without FXTAS. RESULTS: MRI scores were negatively correlated with BDS-2 total scores (Pearson's r = -0.66, p < 0.0001). The association between BDS-2 total scores and MRI scores was still significant after accounting for CGG repeat length, sex, and age as covariates (β = -0.36, p = 0.002). In the complete-case sample analysis (n = 30), the executive functioning subtests of the CANTAB were positively correlated with the MRI total score (ρ = 0.46-0.61, p < 0.05), while the MMSE demonstrated a negative correlation (ρ = -0.40, p = 0.03). CONCLUSION: These findings indicate that BDS-2 can be used alongside other instruments for measuring executive dysfunction in FXTAS, demonstrating the potential for clinical utility to complement traditional cognitive and automated executive measures.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by premutation alleles (55-200 CGG repeats) in the FMR1 gene, typically presenting in later adulthood with intention tremor, cerebellar ataxia and cognitive impairment. We report a male patient in his 5th decade presenting with progressive bilateral action tremor initially suggestive of essential tremor. Neurological examination revealed postural and intention tremor with mild dysdiadochokinesia. A family history of early-onset cognitive decline in a first-degree relative prompted brain MRI, which demonstrated bilateral T2 hyperintensities of the middle cerebellar peduncles, suggestive of FXTAS. Subsequent genetic testing confirmed an FMR1 premutation with 115 CGG repeats, establishing the diagnosis of FXTAS. Review of the brother's records revealed progressive cognitive impairment previously attributed to Alzheimer's disease, raising the possibility of unrecognised FXTAS. This case highlights the importance of family history and neuroimaging in distinguishing FXTAS from more common tremor disorders and dementia syndromes.

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.