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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)

journal contribution
posted on 12.01.2021, 05:35 by M Zafarullah, G Palczewski, SM Rivera, DR Hessl, Flora Tassone
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. It is currently unknown when, and if, individual premutation carriers will develop FXTAS. Thus, with the aim of identifying biomarkers for early diagnosis, development, and progression of FXTAS, we performed global metabolomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct categories: those who developed symptoms of FXTAS (converters, CON) at subsequent visits and those who did not (non-converters, NCON) and we compared to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern Blot and PCR analysis. Metabolomic profile was obtained by ultra-performance liquid chromatography, accurate mass spectrometer, and an Orbitrap mass analyzer. In this study we found 47 metabolites were significantly dysregulated between HC and the premutation groups (PM). Importantly, we identified 24 metabolites that showed significant changes in expression in the CON as compared to the NCON both at V1 and V2, and 70 metabolites in CON as compared to NCON but only at V2. These findings suggest the potential role of the identified metabolites as biomarkers for early diagnosis and for FXTAS disease progression, respectively. Interestingly, the majority of the identified metabolites were lipids, followed by amino acids. To our knowledge, this the first report of longitudinal metabolic profiling and identification of unique biomarkers of FXTAS. The lipid metabolism and specifically the sub pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered in FXTAS.

Funding

HHS | National Institutes of Health (NIH), Grant/Award Number: RO1NS110100-11 and RO1MH078041

History

Publication Date

01/12/2020

Journal

FASEB Journal

Volume

34

Issue

12

Pagination

(p. 16676-16692)

Publisher

Wiley

ISSN

0892-6638

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.