Plasma Biomarkers for Monitoring Brain Pathophysiology in FMR1 Premutation Carriers.

Cecilia Giulivi,Randi Hagerman,Flora Tassone,Eleonora Napoli,Julian Halmai

doi:10.3389/fnmol.2016.00071

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.

Highlights

A modestly expanded CGG nucleotide repeats (55–200) in the 5 UTR of the fragile X mental retardation gene, fragile X mental retardation 1 (FMR1) (Kogan et al, 2008; Tassone et al, 2012; Battistella et al, 2013), is the hallmark of premutation carriers
A list of single metabolites was identified as being potential biomarkers of the premutation, from which only those with an AUROC of ≥0.8 and p-values ≤ 0.05 were selected (Figure 1A). These metabolites were classified based on their biological role as follows: biogenic amines, bioactive fatty acids, organic carboxylic acids, monosaccharides, and others
To the best of our knowledge, this is the first study in which an untargeted serum metabolomic profiling approach combined with sequential metabolite ratio analysis has been applied to discriminate plasma biomarkers in plasma of premutation and Fragile X-associated tremor ataxia syndrome (FXTAS)-carriers

Summary

Introduction

A modestly expanded CGG nucleotide repeats (55–200) in the 5 UTR of the fragile X mental retardation gene, FMR1 (Kogan et al, 2008; Tassone et al, 2012; Battistella et al, 2013), is the hallmark of premutation carriers. Fibroblasts from premutation carriers (humans or Plasma Biomarkers in FMR1 Premutation animal models of the premutation) are generally accompanied by high FMR1 gene expression, normal or lower levels of its translation product FMRP (fragile X mental retardation protein) and mitochondrial dysfunction (Ross-Inta et al, 2010; Napoli et al, 2011). It is currently unknown which carriers of the premutation (over 1.5 million women and men in the United States) will develop FXTAS, as clinical diagnosis fails to identify carriers before significant neurological symptoms are evident.

Methods

Results

Conclusion