Metabolomic alterations in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) premutation carriers Open Access

Hardin, Savannah (Spring 2021)

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Carriers of the Fragile X mental retardation 1 (FMR1) gene premutation are at risk of developing Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). 38 early onset FXTAS cases, 41 premutation (PM) control males, as well as 20 noncarrier controls were selected for sphingolipid profiling and identification of any further metabolomic differences for this study. Previous studies found that there were a wide variety of pathways affected such as carbohydrate, amino acid, and fatty acid pathways. Our research supports these findings and demonstrates that premutation men with FXTAS are metabolically dissimilar to noncarriers, but metabolically similar to premutation carriers without FXTAS symptoms. In the comparison between FXTAS men and noncarrier men we found significant pathways to include multiple amino acid metabolism pathways (alanine and aspartate (p=0.01); glycine, serine, alanine, and threonine (p=0.01); tyrosine (p=0.04); methionine and cysteine (p=0.04); and tryptophan (p=0.049)), some vitamin metabolism pathways (vitamin B1 (0.01), B2 (p=0.02), and H (p=0.02)), several oxidation pathways (phytanic acid and peroxisomal oxidation (p=0.009) and mono-unsaturated fatty acid beta-oxidation (p=0.04)), as well as a few other biosynthesis and metabolic pathways (alkaloid biosynthesis II (p=0.01), ubiquinone biosynthesis (p=0.01), carnitine shuttle (p=0.03), phosphatidylinositol phosphate metabolism (p=0.04), selenoamino acid metabolism (p=0.04), and dynorphin metabolism (p=0.047)). In the comparison between FXTAS men and premutation men without FXTAS symptoms we found selenoamino acid metabolism (p=0.047), Vitamin A (retinol) metabolism (p=0.03), and arachidonic acid metabolism (p=0.04) to be statistically different. Lastly, in the comparison between all premutation men and noncarrier men we identified mono-unsaturated fatty acid beta-oxidation (p=0.01), vitamin B1 (thiamin) metabolism (p=0.03), tyrosine metabolism (p=0.03), vitamin B5 – CoA biosynthesis from pantothenate (p=0.003), di-unsaturated fatty acid beta-oxidation (p=0.006), vitamin B3 (nicotinate and nicotinamide) metabolism (p=0.02), and glutathione metabolism (p=0.04) to be significant pathways. There is much research that still needs to be done, but through the use of metabolomics, we will identify pathways for potential treatments of FXTAS.

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Full Thesis----------------------pages 6-16

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