AUTHOR=Neul Jeffrey L. , Skinner Steven A. , Annese Fran , Lane Jane , Heydemann Peter , Jones Mary , Kaufmann Walter E. , Glaze Daniel G. , Percy Alan K. TITLE=Metabolic Signatures Differentiate Rett Syndrome From Unaffected Siblings JOURNAL=Frontiers in Integrative Neuroscience VOLUME=14 YEAR=2020 URL=https://www.frontiersin.org/journals/integrative-neuroscience/articles/10.3389/fnint.2020.00007 DOI=10.3389/fnint.2020.00007 ISSN=1662-5145 ABSTRACT=

Rett syndrome (RTT, OMIM 312750), a severe neurodevelopmental disorder characterized by regression with loss of spoken language and hand skills, development of characteristic hand stereotypies, and gait dysfunction, is primarily caused by de novo mutations in the X-linked gene Methyl-CpG-binding protein 2 (MECP2). Currently, treatment options are limited to symptomatic management, however, reversal of disease phenotype is possible in mouse models by restoration of normal MECP2 gene expression. A significant challenge is the lack of biomarkers of disease state, disease severity, or treatment response. Using a non-targeted metabolomic approach we evaluated metabolite profiles in plasma from thirty-four people with RTT compared to thirty-seven unaffected age- and gender-matched siblings. We identified sixty-six significantly altered metabolites that cluster broadly into amino acid, nitrogen handling, and exogenous substance pathways. RTT disease metabolite and metabolic pathways abnormalities point to evidence of oxidative stress, mitochondrial dysfunction, and alterations in gut microflora. These observed changes provide insight into underlying pathological mechanisms and the foundation for biomarker discovery of disease severity biomarkers.