Abstract
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability (ID) and a known monogenic cause of autism spectrum disorder (ASD). It is a trinucleotide repeat disorder, in which more than 200 CGG repeats in the 5’ untranslated region (UTR) of the fragile X mental retardation 1 (FMR1) gene causes methylation of the promoter with consequent silencing of the gene, ultimately leading to the loss of the encoded fragile X mental retardation 1 protein, FMRP. FMRP is an RNA binding protein that plays a primary role as a repressor of translation of various mRNAs, many of which are involved in the maintenance and development of neuronal synaptic function and plasticity. In addition to intellectual disability, patients with FXS face several behavioral challenges, including anxiety, hyperactivity, seizures, repetitive behavior, and problems with executive and language performance. Currently, there is no cure or approved medication for the treatment of the underlying causes of FXS, but in the past few years, our knowledge about the proteins and pathways that are dysregulated by the loss of FMRP has increased, leading to clinical trials and to the path of developing molecular biomarkers for identifying potential targets for therapies. In this paper, we review candidate molecular biomarkers that have been identified in preclinical studies in the FXS mouse animal model and are now under validation for human applications or have already made their way to clinical trials.
Highlights
A biomarker is “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [1]
Tested in a recent randomized double-blind placebo-controlled crossover trial in children with Fragile X syndrome (FXS), aged 6–17, years, ganaxolone was found to be safe and have beneficial effects in some patients, for those with higher anxiety or lower cognitive abilities [108]. These preclinical and clinical studies strengthen the hypothesis of GABA receptors involved in the pathology of FXS and as they are the major inhibitory receptors in the brain, they point to the therapeutic potential of the GABA receptor for the behavioral and epileptic phenotypes associated with fragile X syndrome
Most of the FXS research in mammalian model systems is limited to two disease models, the Fmr1 KO mouse and Fmr1 KO drosophila animal model, but the central issue in using these models is variability and small effect size of the phenotype in the area of cognitive defects
Summary
A biomarker is “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [1]. FXSleading leading to to altered figure shows the molecular pathways targeted oror understudy, forfor thethe reversal of cognitive andand behavioral impairments in FXS patients. Observed patterns of brain [21], activity, including audiogenic phenotypes that resemble the human the disorder, including biochemistry electrophysiology [22], seizures, are similar to those in individuals affected by [25], these mice poorly mimic human neuropathology [23], and spine morphology [24]. 2. Candidate molecular biomarkers forXFXS include a number of targets and substrates of and several signaling pathways, in addition to fragile mental retardation. Fmr mRNA and fragile X mental retardation 1 protein (FMRP) expression, de models and in human FXS tissues. 2 (BMPR2), Kinase Kappa (Dgkκ), system (eCS), microRNA’s (miRNA’s), tyrosine phosphatase (STEP), glycogen synthase kinase-3 amyloid-β protein striatal-enriched precursor (APP),protein (miRNA’s), striatal-enriched protein tyrosine (GSK-3) cytokine and chemokine profiles, metabotropic glutamate receptor (mGluRs)
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