Abstract
Recent advances in neurobiology have provided several molecular entrees for targeted treatments for Fragile X syndrome (FXS). However, the efficacy of these treatments has been demonstrated mainly in animal models and has not been consistently predictive of targeted drugs’ response in the preponderance of human clinical trials. Because of the heterogeneity of FXS at various levels, including the molecular level, phenotypic manifestation, and drug response, it is critically important to identify biomarkers that can help in patient stratification and prediction of therapeutic efficacy. The primary objective of this study was to assess the ability of molecular biomarkers to predict phenotypic subgroups, symptom severity, and treatment response to metformin in clinically treated patients with FXS. We specifically tested a triplex protein array comprising of hexokinase 1 (HK1), RAS (all isoforms), and Matrix Metalloproteinase 9 (MMP9) that we previously demonstrated were dysregulated in the FXS mouse model and in blood samples from patient with FXS. Seventeen participants with FXS, 12 males and 5 females, treated clinically with metformin were included in this study. The disruption in expression abundance of these proteins was normalized and associated with significant self-reported improvement in clinical phenotypes (CGI-I in addition to BMI) in a subset of participants with FXS. Our preliminary findings suggest that these proteins are of strong molecular relevance to the FXS pathology that could make them useful molecular biomarkers for this syndrome.
Highlights
Fragile X Syndrome (FXS) is the leading single-gene cause of Autism Spectrum Disorder (ASD)and intellectual disability (ID) caused by a CGG trinucleotide expansion in the FMR1 (Fragile X mental retardation 1) gene
We have investigated whether plasma abundance levels of RAS, hexokinase 1 (HK1), and Matrix Metalloproteinase 9 (MMP9) were sensitive to metformin treatment in individuals with Fragile X syndrome (FXS) and whether they correlated with changes in commonly used clinical measures Clinical Global Impression (CGI) and Body
We have previously reported that MMP9 protein levels are significantly higher in FXS patient plasma while RAS and HK1 protein level are significantly lower in FXS patients compared to age- and gender-matched typically developing (TD) individuals. [10,13,25]
Summary
Fragile X Syndrome (FXS) is the leading single-gene cause of Autism Spectrum Disorder (ASD)and intellectual disability (ID) caused by a CGG trinucleotide expansion in the FMR1 (Fragile X mental retardation 1) gene. Fragile X Syndrome (FXS) is the leading single-gene cause of Autism Spectrum Disorder (ASD). Remaining FXS cases that do not meet the criteria of ASD diagnosis demonstrate many behaviors that go along with the broader autism spectrum [1,2,3,4,5,6,7]. The overlap between FXS and ASD diagnoses and symptoms underscores the importance of FXS as a model population Brain Sci. 2020, 10, 361; doi:10.3390/brainsci10060361 www.mdpi.com/journal/brainsci. Brain Sci. 2020, 10, 361 for ASD therapeutic development. FXS is associated with an increase in Body Mass Index (BMI), and a subgroup of patients with FXS can develop severe hyperphagia, obesity, and hypogonadism or delayed puberty [8,9]. There are no FDA-approved pharmacological therapies for FXS, despite its status as an orphan disease and its potential importance to inform about ASD treatments
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