Cerebral Microbleeds in Fragile X–Associated Tremor/Ataxia Syndrome

Salcedo-Arellano, María Jimena; Wang, Jun Yi; McLennan, Yingratana A.; Doan, Mai; Cabal-Herrera, Ana María; Jiménez, Sara; Wolf‐Ochoa, Marisol; Sanchez, Desiree; Juárez, Pablo; Tassone, Flora; Durbin‐Johnson, Blythe; Hagerman, Randi J.; Martínez‐Cerdeño, Verónica

doi:10.1002/mds.28559

Cited by 19 publications

(27 citation statements)

References 69 publications

(81 reference statements)

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“…Postmortem examinations provided supporting evidence of dysregulated iron transport in the putamen and choroid plexus in brains of individuals with FXTAS ( 17 , 18 ). Alternatively, microangiopathy, recently proposed as a feature of FXTAS ( 60 ), might lead to iron accumulation and neurodegeneration in the subcortical nuclei.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Molecular Correlates of Abnormal Changes in the Cerebellum and Globus Pallidus in Fragile X Premutation

et al. 2022

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BackgroundFragile X premutation carriers (55–200 CGG triplets) may develop a progressive neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), after the age of 50. The neuroradiologic markers of FXTAS are hyperintense T2-signals in the middle cerebellar peduncle—the MCP sign. We recently noticed abnormal T2-signals in the globus pallidus in male premutation carriers and controls but the prevalence and clinical significance were unknown.MethodsWe estimated the prevalence of the MCP sign and pallidal T2-abnormalities in 230 male premutation carriers and 144 controls (aged 8–86), and examined the associations with FXTAS symptoms, CGG repeat length, and iron content in the cerebellar dentate nucleus and globus pallidus.ResultsAmong participants aged ≥45 years (175 premutation carriers and 82 controls), MCP sign was observed only in premutation carriers (52 vs. 0%) whereas the prevalence of pallidal T2-abnormalities approached significance in premutation carriers compared with controls after age-adjustment (25.1 vs. 13.4%, p = 0.069). MCP sign was associated with impaired motor and executive functioning, and the additional presence of pallidal T2-abnormalities was associated with greater impaired executive functioning. Among premutation carriers, significant iron accumulation was observed in the dentate nucleus, and neither pallidal or MCP T2-abnormalities affected measures of the dentate nucleus. While the MCP sign was associated with CGG repeat length >75 and dentate nucleus volume correlated negatively with CGG repeat length, pallidal T2-abnormalities did not correlate with CGG repeat length. However, pallidal signal changes were associated with age-related accelerated iron depletion and variability and having both MCP and pallidal signs further increased iron variability in the globus pallidus.ConclusionsOnly the MCP sign, not pallidal abnormalities, revealed independent associations with motor and cognitive impairment; however, the occurrence of combined MCP and pallidal T2-abnormalities may present a risk for greater cognitive impairment and increased iron variability in the globus pallidus.

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Section: Discussionmentioning

confidence: 99%

Clinical and Molecular Correlates of Abnormal Changes in the Cerebellum and Globus Pallidus in Fragile X Premutation

et al. 2022

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“…The findings of changes in endothelial cell proportion are also interesting considering the recent description of microangiopathy in FXTAS neuropathology (Salcedo-Arellano et al, 2021). In fact, MRI findings in FXTAS of T2 hyperintensity have some similarities to microvascular ischemia (Leehey, 2009), also suggesting cerebrovascular dysfunction as an important facet of FXTAS.…”

Section: Cellular Proportionmentioning

confidence: 83%

Glial dysregulation in human brain in Fragile X-related disorders

Dias

Talukdar

Akula

et al. 2022

Preprint

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While large trinucleotide repeat expansions at the FMR1 locus cause Fragile X Syndrome (FXS), smaller “premutations” are associated with the late-onset condition Fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features, with no clear molecular explanation for these marked differences. One prevailing theory posits that the premutation uniquely causes neurotoxic increases in FMR1 mRNA (i.e., 4-8-fold increases), but evidence to support this hypothesis is largely derived from analysis of peripheral blood. We applied single-nucleus RNA-sequencing to post-mortem frontal cortex and cerebellum from 9 individuals with Fragile X mutations as well as age and sex matched controls (n=6) to assess cell-type specific molecular neuropathology. We found robust reduction of FMR1 mRNA in FXS as expected, with modest but significant upregulation (~1.3 fold) of FMR1 in glial clusters associated with premutation expansions. In premutation cases we identified alterations in glia number in cortex and cerebellum. Differential expression analysis demonstrated altered cortical oligodendrocyte development, while gene ontology analysis revealed alterations in neuroregulatory roles of glia, such as glial modulation of neurotransmission and synaptic structure. We identified significant enrichment of known FMR1 protein target genes in differentially expressed gene lists in FXS as well as the premutation, suggesting FMR1 protein target pathways may represent a shared source of dysfunction in both conditions despite opposite FMR1 mRNA changes. These findings challenge existing dogma regarding FXTAS and implicate glial dysregulation as a critical facet of premutation pathophysiology, representing novel therapeutic targets directly derived from the human condition.

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“…Additionally, persistent DWI hyperintensities in corpus callosum and enhancement of cortical surface were observed in some NIID cases [ 57 , 119 ]. More than half of FXTAS patients have cerebral microbleeds, and NIIs in the endothelial cells of capillaries, suggesting cerebrovascular dysfunction in FATXS [ 91 ]. Almost all OPDM patients have different white matter hyperintensities but without typical NOTCH2NLC -related high-intensity signals at the corticomedullary junction.…”

Section: The Common Spectrum Of Polyg Diseasesmentioning

confidence: 99%

The polyG diseases: a new disease entity

Liufu

Zheng

et al. 2022

acta neuropathol commun

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Recently, inspired by the similar clinical and pathological features shared with fragile X-associated tremor/ataxia syndrome (FXTAS), abnormal expansion of CGG repeats in the 5’ untranslated region has been found in neuronal intranuclear inclusion disease (NIID), oculopharyngeal myopathy with leukoencephalopathy (OPML), and oculopharyngodistal myopathy (OPDMs). Although the upstream open reading frame has not been elucidated in OPML and OPDMs, polyglycine (polyG) translated by expanded CGG repeats is reported to be as a primary pathogenesis in FXTAS and NIID. Collectively, these findings indicate a new disease entity, the polyG diseases. In this review, we state the common clinical manifestations, pathological features, mechanisms, and potential therapies in these diseases, and provide preliminary opinions about future research in polyG diseases.

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Cerebral Microbleeds in Fragile X–Associated Tremor/Ataxia Syndrome

Cited by 19 publications

References 69 publications

Clinical and Molecular Correlates of Abnormal Changes in the Cerebellum and Globus Pallidus in Fragile X Premutation

Clinical and Molecular Correlates of Abnormal Changes in the Cerebellum and Globus Pallidus in Fragile X Premutation

Glial dysregulation in human brain in Fragile X-related disorders

The polyG diseases: a new disease entity

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