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

Marwa Zafarullah; Blythe Durbin-Johnson; Emily S Fourie; David R Hessl; Susan M Rivera; Flora Tassone

doi:10.3389/fpsyt.2021.691717

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

Front Psychiatry. 2021 Aug 16:12:691717. doi: 10.3389/fpsyt.2021.691717. eCollection 2021.

Authors

Marwa Zafarullah¹, Blythe Durbin-Johnson², Emily S Fourie^{3

4}, David R Hessl^{5

6}, Susan M Rivera^{3

4

5}, Flora Tassone^{1

5}

Affiliations

¹ Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Sacramento, CA, United States.
² Division of Biostatistics, School of Medicine, University of California, Davis, Davis, CA, United States.
³ Center for Mind and Brain, University of California, Davis, Davis, CA, United States.
⁴ Department of Psychology, University of California, Davis, Davis, CA, United States.
⁵ MIND Institute, University of California, Davis Medical Center, Sacramento, CA, United States.
⁶ Department of Psychiatry and Behavioral Sciences, University of California, Davis Medical Center, Sacramento, CA, United States.

Abstract

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.

Keywords: area of the pons; brain measures; fragile X-associated tremor/ataxia syndrome; lipids; metabolic biomarkers; premutation carriers.

Abstract

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