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.
Highlights
Aging is a complex and evolutionarily conserved process that is found to be one of the main risk factors for a number of human neurodegenerative disorders [1]
Three groups of male participants were included in this study: 1) premutation carriers (PM) who converted at visit 2 (V2) (CON; n = 10), 2) PM who did not convert at V2 (NCON; n = 10) and 3) healthy controls (HC; n = 10)
We investigated the correlation between these potential metabolic biomarkers and brain measures among healthy control (HC), and PM including converter and non-converter (CON and NCON) at visit 1 (V1)
Summary
Aging is a complex and evolutionarily conserved process that is found to be one of the main risk factors for a number of human neurodegenerative disorders [1]. Increasing evidence suggests that metabolic alterations can strongly influence the development and the progression of various neurodegenerative disorders. Compromised energy metabolism and adverse changes, are potentially contributing to increased vulnerability of the brain to develop neurodevelopmental and neurodegenerative processes [3]. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a late-onset neurodegenerative disorder, mostly affecting carriers of the fragile X mental retardation 1 (FMR1) gene mutation after the age of 50. The high prevalence of the premutation allele among the general population (1:110–200 females and 1:430 males), leads to an estimate of approximately 1.5 million individuals in the general US population being at risk for FMR1 associated disorders, over their life spans. Among the PM population, an estimated 40–75% of male and 8–16% of female PMs are at risk of developing FXTAS [5, 6]
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