Metabolic profiling reveals dysregulated lipid metabolism and potential biomarkers associated with the development and progression of Fragile X‐Associated Tremor/Ataxia Syndrome (FXTAS)

Zafarullah, Marwa; Palczewski, Grzegorz; Rivera, Susan M.; Hessl, David; Tassone, Flora

doi:10.1096/fj.202001880r

Cited by 12 publications

(18 citation statements)

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“…The present study results provide evidence that brain measures, specifically the area of the pons cross-sectional area, correlate with plasma levels of metabolites that are part of the fatty acid and sphingolipid metabolism. These findings expand upon our previous study of plasma metabolic profiling of participants who developed symptoms of FXTAS over time (25), potentially representing biomarkers of early diagnosis and progression of FXTAS and suggest that these factors play a role in the brain structure of individuals with FXTAS. Magnetic resonance imaging (MRI) takes advantage of a strong magnetic field for non-invasively imaging of parts of the brain parts to identify regional tissue abnormalities and to obtain volumes of brain structures.…”

Section: Discussionsupporting

confidence: 77%

“…In addition, these metabolites are part of the lipid and fatty acid metabolism (Figure 3B) and sphingolipid metabolism (Figure 3C). We previously shown that lipid metabolism was associated with the development and progression of FXTAS (changes of the FXTAS stage from V1 to V2) (25) and this association has also been reported in the premutation mouse model (24).…”

Section: Metabolite Expression Levels Correlate With Fxtas Progressionmentioning

confidence: 53%

“…Our recent study identified metabolic biomarkers of FXTAS early diagnosis and disease progression by characterizing individuals who developed symptoms of FXTAS over time. Specifically, we found that lipid metabolism and specifically the sub pathways involved in mitochondrial bioenergetics, are significantly altered in FXTAS (25).…”

Section: Introductionmentioning

confidence: 88%

“…Samples were placed briefly on a TurboVap R (Zymark) to remove the organic solvent. The sample extracts were stored overnight under nitrogen before preparation for further analysis as explained in Zafarullah et al (25).…”

Section: Sample Preparation and Metabolite Profilingmentioning

confidence: 99%

“…We have recently reported 94 potential metabolic biomarkers for early diagnosis and progression of FXTAS that showed significant changes in expression (P ≤ 0.05) in the CON as compared to the NCON both at V1 and V2 or only at V2 (25). In this study, we investigated the correlation between these potential metabolic biomarkers and brain measures (midbrain, area of the pons, and MCP width) among healthy control (HC), and PM including converter and non-converter (CON and NCON) at V1.…”

Section: Differential Metabolite Levels Linked With Area Of the Pons Area In Healthy Control And Premutation Groupsmentioning

confidence: 99%

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Metabolomic Biomarkers Are Associated With Area of the Pons in Fragile X Premutation Carriers at Risk for Developing FXTAS

et al. 2021

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Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late adult-onset neurodegenerative disorder that affects movement and cognition in male and female carriers of a premutation allele (55–200 CGG repeats; PM) in the fragile X mental retardation (FMR1) gene. It is currently unknown how the observed brain changes are associated with metabolic signatures in individuals who develop the disorder over time. The primary objective of this study was to investigate the correlation between longitudinal changes in the brain (area of the pons, midbrain, and MCP width) and the changes in the expression level of metabolic biomarkers of early diagnosis and progression of FXTAS in PM who, as part of an ongoing longitudinal study, emerged into two distinct categories. These included those who developed symptoms of FXTAS (converters, CON) at subsequent visits and those who did not meet the criteria of diagnosis (non-converters, NCON) and were compared to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern Blot and PCR analysis. Magnetic Resonance Imaging (MRIs) acquisition was obtained on a 3T Siemens Trio scanner and metabolomic profile was obtained by ultra-performance liquid chromatography, accurate mass spectrometer, and an Orbitrap mass analyzer. Our findings indicate that differential metabolite levels are linked with the area of the pons between healthy control and premutation groups. More specifically, we observed a significant association of ceramides and mannonate metabolites with a decreased area of the pons, both at visit 1 (V1) and visit 2 (V2) only in the CON as compared to the NCON group suggesting their potential role in the development of the disorder. In addition, we found a significant correlation of these metabolic signatures with the FXTAS stage at V2 indicating their contribution to the progression and pathogenesis of FXTAS. Interestingly, these metabolites, as part of lipid and sphingolipid lipids pathways, provide evidence of the role that their dysregulation plays in the development of FXTAS and inform us as potential targets for personalized therapeutic development.

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Section: Discussionsupporting

confidence: 77%

Section: Metabolite Expression Levels Correlate With Fxtas Progressionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 88%

Section: Sample Preparation and Metabolite Profilingmentioning

confidence: 99%

Section: Differential Metabolite Levels Linked With Area Of the Pons Area In Healthy Control And Premutation Groupsmentioning

confidence: 99%

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Metabolomic Biomarkers Are Associated With Area of the Pons in Fragile X Premutation Carriers at Risk for Developing FXTAS

et al. 2021

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Identification of three potential novel biomarkers for early diagnosis of acute ischemic stroke via plasma lipidomics

Xue²,

Lin³

et al. 2023

Metabolomics

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Characterization of the Cerebrospinal Fluid Proteome in Patients with Fragile X-Associated Tremor/Ataxia Syndrome

et al. 2021

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Metabolic profiling reveals dysregulated lipid metabolism and potential biomarkers associated with the development and progression of Fragile X‐Associated Tremor/Ataxia Syndrome (FXTAS)

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 12 publications

References 65 publications

Metabolomic Biomarkers Are Associated With Area of the Pons in Fragile X Premutation Carriers at Risk for Developing FXTAS

Metabolomic Biomarkers Are Associated With Area of the Pons in Fragile X Premutation Carriers at Risk for Developing FXTAS

Identification of three potential novel biomarkers for early diagnosis of acute ischemic stroke via plasma lipidomics

Characterization of the Cerebrospinal Fluid Proteome in Patients with Fragile X-Associated Tremor/Ataxia Syndrome

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