title: Plasma Biomarkers for Monitoring Brain Pathophysiology in FMR1 Premutation Carriers.
abstract: Premutation carriers have a 55-200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene. Currently, 1.5 million individuals are affected in the United States, and carriers are at risk of developing the late-onset neurodegenerative disorder Fragile X-associated tremor ataxia syndrome (FXTAS). Limited efforts have been made to develop new methods for improved early patient monitoring, treatment response, and disease progression. To this end, plasma metabolomic phenotyping was obtained for 23 premutation carriers and 16 age- and sex-matched controls. Three biomarkers, phenylethylamine normalized by either aconitate or isocitrate and oleamide normalized by isocitrate, exhibited excellent model performance. The lower phenylethylamine and oleamide plasma levels in carriers may indicate, respectively, incipient nigrostriatal degeneration and higher incidence of substance abuse, anxiety and sleep disturbances. Higher levels of citrate, isocitrate, aconitate, and lactate may reflect deficits in both bioenergetics and neurotransmitter metabolism (Glu, GABA). This study lays important groundwork by defining the potential utility of plasma metabolic profiling to monitor brain pathophysiology in carriers before and during the progression of FXTAS, treatment efficacy and evaluation of side effects.
authors: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CAUSA; Medical Investigation of Neurodevelopmental Disorders Institute, University of California, Davis, Davis, CAUSA.
authors: Cecilia
authors: C
authors: Giulivi
authors: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA USA.
authors: Eleonora
authors: E
authors: Napoli
authors: Medical Investigation of Neurodevelopmental Disorders Institute, University of California, Davis, Davis, CAUSA; Department of Biochemistry and Molecular Medicine, University of California, Davis, Davis, CAUSA.
authors: Flora
authors: F
authors: Tassone
authors: Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA USA.
authors: Julian
authors: J
authors: Halmai
authors: Medical Investigation of Neurodevelopmental Disorders Institute, University of California, Davis, Davis, CAUSA; Department of Pediatrics, University of California Davis Medical Center, Sacramento, CAUSA.
authors: Randi
authors: R
authors: Hagerman
keywords: Fragile X; metabolomics; mitochondrial dysfunction; neurodegeneration; trinucleotide repeat disease