Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder affecting subjects (premutation carriers) with a 55-200 CGG-trinucleotide expansion in the 5'UTR of the fragile X ...mental retardation 1 gene (
) typically after age 50. As both the presence of white matter hyperintensities (WMHs) and atrophied gray matter on magnetic resonance imaging (MRI) are linked to age-dependent decline in cognition, here we tested whether MRI outcomes (WMH volume (WMHV) and brain volume) were correlated with mitochondrial bioenergetics from peripheral blood monocytic cells in 87 carriers with and without FXTAS. As a parameter assessing cumulative damage, WMHV was correlated to both FXTAS stages and age, and brain volume discriminated between carriers and non-carriers. Similarly, mitochondrial mass and ATP production showed an age-dependent decline across all participants, but in contrast to WMHV, only FADH
-linked ATP production was significantly reduced in carriers vs. non-carriers. In carriers, WMHV negatively correlated with ATP production sustained by glucose-glutamine and FADH
-linked substrates, whereas brain volume was positively associated with the latter and mitochondrial mass. The observed correlations between peripheral mitochondrial bioenergetics and MRI findings-and the lack of correlations with FXTAS diagnosis/stages-may stem from early brain bioenergetic deficits even before overt FXTAS symptoms and/or imaging findings.
Previous studies in autism spectrum disorder demonstrated an increased number of excitatory pyramidal cells and a decreased number of inhibitory parvalbumin+ chandelier interneurons in the prefrontal ...cortex of postmortem brains. How these changes in cellular composition affect the overall abundance of excitatory and inhibitory synapses in the cortex is not known. Herein, we quantified the number of excitatory and inhibitory synapses in the prefrontal cortex of 10 postmortem autism spectrum disorder brains and 10 control cases. To identify excitatory synapses, we used VGlut1 as a marker of the presynaptic component and postsynaptic density protein-95 as marker of the postsynaptic component. To identify inhibitory synapses, we used the vesicular gamma-aminobutyric acid transporter as a marker of the presynaptic component and gephyrin as a marker of the postsynaptic component. We used Puncta Analyzer to quantify the number of co-localized pre- and postsynaptic synaptic components in each area of interest. We found an increase in the number of excitatory synapses in upper cortical layers and a decrease in inhibitory synapses in all cortical layers in autism spectrum disorder brains compared with control cases. The alteration in the number of excitatory and inhibitory synapses could lead to neuronal dysfunction and disturbed network connectivity in the prefrontal cortex in autism spectrum disorder.
Objective
Fragile X‐associated tremor/ataxia syndrome (FXTAS) is a late‐onset progressive genetic neurodegenerative disorder that occurs in FMR1 premutation carriers. The temporal, spatial, and ...cell‐type specific patterns of neurodegeneration in the FXTAS brain remain incompletely characterized. Intranuclear inclusion bodies are the neuropathological hallmark of FXTAS, which are largest and occur most frequently in astrocytes, glial cells that maintain brain homeostasis. Here, we characterized neuropathological alterations in astrocytes in multiple regions of the FXTAS brain.
Methods
Striatal and cerebellar sections from FXTAS cases (n = 12) and controls (n = 12) were stained for the astrocyte markers glial fibrillary acidic protein (GFAP) and aldehyde dehydrogenase 1L1 (ALDH1L1) using immunohistochemistry. Reactive astrogliosis severity, the prevalence of GFAP+ fragments, and astrocyte density were scored. Double label immunofluorescence was utilized to detect co‐localization of GFAP and cleaved caspase‐3.
Results
FXTAS cases showed widespread reactive gliosis in both grey and white matter. GFAP staining also revealed remarkably severe astrocyte pathology in FXTAS white matter – characterized by a significant and visible reduction in astrocyte density (−38.7% in striatum and − 32.2% in cerebellum) and the widespread presence of GFAP+ fragments reminiscent of apoptotic bodies. White matter specific reductions in astrocyte density were confirmed with ALDH1L1 staining. GFAP+ astrocytes and fragments in white matter were positive for cleaved caspase‐3, suggesting that apoptosis‐mediated degeneration is responsible for reduced astrocyte counts.
Interpretation
We have established that FXTAS neuropathology includes robust degeneration of astrocytes, which is specific to white matter. Because astrocytes are essential for maintaining homeostasis within the central nervous system, a loss of astrocytes likely further exacerbates neuropathological progression of other cell types in the FXTAS brain. ANN NEUROL 2024;95:558–575
This case documents the co-occurrence of the fragile X-associated tremor ataxia syndrome (FXTAS) and Alzheimer-type neuropathology in a 71-year-old premutation carrier with 85 CGG repeats in the ...fragile X mental retardation 1 (
gene, in addition to an apolipoprotein E (
ε4 allele. FXTAS and Alzheimer's Disease (AD) are late-onset neurodegenerative diseases that share overlapping cognitive deficits including processing speed, working memory and executive function. The prevalence of coexistent FXTAS-AD pathology remains unknown. The clinical picture in this case was marked with rapid cognitive decline between age 67 and 71 years in addition to remarkable MRI changes. Over the 16 months between the two clinical evaluations, the brain atrophied 4.12% while the lateral ventricles increased 26.4% and white matter hyperintensities (WMH) volume increased 15.6%. Other regions atrophied substantially faster than the whole brain included the thalamus (-6.28%), globus pallidus (-10.95%), hippocampus (-6.95%), and amygdala (-7.58%). A detailed postmortem assessment included an MRI with confluent WMH and evidence of cerebral microbleeds (CMB). The histopathological study demonstrated FXTAS inclusions in neurons and astrocytes, a widespread presence of phosphorylated tau protein and, amyloid β plaques in cortical areas and the hippocampus. CMBs were noticed in the precentral gyrus, middle temporal gyrus, visual cortex, and brainstem. There were high amounts of iron deposits in the globus pallidus and the putamen consistent with MRI findings. We hypothesize that coexistent FXTAS-AD neuropathology contributed to the steep decline in cognitive abilities.
While an association between full mutation CGG-repeat expansions of the
(
) gene and connective tissue problems are clearly described, problems in fragile X premutation carriers (fXPCs) CGG-repeat ...range (55-200 repeats) of the
gene may be overlooked.
To report five
fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype.
We collected medical histories and
molecular measures from five cases who presented with joint hypermobility and loose connective tissue and met inclusion criteria for hEDS.
Five cases were female and ranged between 16 and 49 years. The range of CGG-repeat allele sizes ranged from 66 to 150 repeats. All had symptoms of hEDS since early childhood. Commonalities in molecular pathogenesis and coexisting conditions between the fXPCs and hEDS are also presented. The premutation can lead to a reduction of fragile X mental retardation protein, which is crucial in maintaining functions of the extracellular matrix-related proteins, particularly matrix metallopeptidase 9 and elastin. Moreover, elevated
messenger RNA causes sequestration of proteins, which results in RNA toxicity.
Both hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.
Individuals with the fragile X premutation report symptoms of chronic pain from multiple systems, have increased incidence of comorbid conditions where pain is a prominent feature, and ...pathophysiology that supports disrupted pain regulation, inflammation, and energy imbalance. Less is known about how pain manifests for the subpopulation of carriers that develop the motor and cognitive changes of fragile X-associated tremor and ataxia syndrome (FXTAS), and how pain may differ between men and women. We gathered data collected from 104 males and females with FXTAS related to chronic pain, comorbid conditions related to pain, and medications used for pain control to further explore the types of pain experienced and to better characterize how individuals with the fragile X premutation experience pain sensation across genders. We found that women experience significantly more pain symptoms than men, particularly allodynia (20 vs. 2.0%,
= 0.008), peripheral neuropathy pain (43.9 vs. 25.4%,
= 0.0488), migraine (43.9 vs. 14.5%,
= 0.0008), fibromyalgia (26.8 vs. 0%,
= 0.0071) and back pain (48.5 vs. 23.4%,
= 0.008). We found onset of peripheral neuropathy predicts the onset of ataxia (β = 0.63 ± 0.25,
= 0.019) and tremor (β = 0.56 ± 0.17,
= 0.004) across gender. Women also report significantly more anxiety (82.9 vs. 39.7%,
< 0.001), which has implications for ideal pain treatment. These pain symptoms need to be recognized in the medical history and treated appropriately, with consideration for overlapping comorbidities.
Individuals with fragile X syndrome (FXS) typically demonstrate profound executive function (EF) deficits that interfere with learning, socialization, and emotion regulation. We completed the first ...large, non-pharmacological controlled trial for FXS, designed to evaluate the efficacy of Cogmed, a computer/tablet-based working memory (WM) training program.
The study was a randomized, blinded, parallel two-arm controlled trial in 100 children and adolescents with FXS (63 male, 37 female; 15.28 ± 3.36 yrs.). Participants were randomized equally to adaptive (difficulty level adjusted to performance) or non-adaptive (control) Cogmed training. Participants were assessed at home using objective measures of WM (primary outcome) and EF at baseline, following 20-25 caregiver-supported sessions over 5-6 weeks, and at follow-up 3 months after cessation of training. Parents and teachers provided ratings of WM, attention, and EF.
The WM composite and selective domains of EF (distractibility, cognitive flexibility), as well as parent- and teacher-reported attention and EF, significantly improved across the full study sample, with many changes maintained at follow-up. However, comparisons of improvement between adaptive and non-adaptive control conditions did not differ, showing that progressively challenging the WM system by expanding span length did not provide added benefit overall.
Further experimental comparisons are needed before Cogmed working memory training can be considered empirically validated for children with FXS, forming the basis of treatment recommendation. However, given that prior studies show no significant changes on these measures in FXS without treatment, that improvements were maintained for 3 months, and that blinded teachers reported improvements in the classroom, the modest benefits seen in both adaptive and non-adaptive groups overall are unlikely to be attributable to placebo or practice effects alone. Future analyses examining inter-individual differences (e.g., baseline capacity, training efficiency, co-morbidity, training environment, characteristics of training aide) may help to link this intervention to outcomes and potential transfer effects.
US National Institutes of Health (ClinicalTrials.gov), NCT02747394 .
The course of pathophysiological mechanisms involved in fragile X-associated tremor/ataxia syndrome (FXTAS) remains largely unknown. Previous proteomics and metabolomics studies conducted in blood ...samples collected from FMR1 premutation carriers with FXTAS reported abnormalities in energy metabolism, and precursors of gluconeogenesis showed significant changes in plasma expression levels in FMR1 premutation carriers who developed FXTAS. We conducted an analysis of postmortem human brain tissues from 44 donors, 25 brains with FXTAS, and 19 matched controls. We quantified the metabolite relative abundance in the inferior temporal gyrus and the cerebellum using untargeted mass spectrometry (MS)-based metabolomics. We investigated how the metabolite type and abundance relate to the number of cytosine-guanine-guanine (CGG) repeats, to markers of neurodegeneration, and to the symptoms of FXTAS. A metabolomic analysis identified 191 primary metabolites, the data were log-transformed and normalized prior to the analysis, and the relative abundance was compared between the groups. The changes in the relative abundance of a set of metabolites were region-specific with some overlapping results; 22 metabolites showed alterations in the inferior temporal gyrus, while 21 showed differences in the cerebellum. The relative abundance of cytidine was decreased in the inferior temporal gyrus, and a lower abundance was found in the cases with larger CGG expansions; oleamide was significantly decreased in the cerebellum. The abundance of 11 metabolites was influenced by changes in the CGG repeat number. A histological evaluation found an association between the presence of microhemorrhages in the inferior temporal gyrus and a lower abundance of 2,5-dihydroxypyrazine. Our study identified alterations in the metabolites involved in the oxidative-stress response and bioenergetics in the brains of individuals with FXTAS. Significant changes in the abundance of cytidine and oleamide suggest their potential as biomarkers and therapeutic targets for FXTAS.
Here we report five cases of male
premutation carriers who present without clinical symptoms of the fragile X-associated tremor/ataxia syndrome (FXTAS), but who on MRI demonstrate white matter ...hyperintensities in the middle cerebellar peduncles (MCP sign) and other brain regions, a rare finding. MCP sign is the major radiological feature of FXTAS; it is therefore remarkable to identify five cases in which this MRI finding is present in the absence of tremor and ataxia, the major clinical features of FXTAS. Subjects underwent a detailed neurological evaluation, neuropsychological testing, molecular testing, and MRI evaluation utilizing T2 imaging described here. Additional white matter disease was present in the corpus callosum in four of the five cases. However, all cases were asymptomatic for motor signs of FXTAS.
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