Abstract
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and is associated with increased risk for autism spectrum disorder (ASD), anxiety, ADHD, and epilepsy. While our understanding of FXS pathophysiology has improved, a lack of validated blood-based biomarkers of disease continues to impede bench-to-bedside efforts. To meet this demand, there is a growing effort to discover a reliable biomarker to inform treatment discovery and evaluate treatment target engagement. Such a marker, amyloid-beta precursor protein (APP), has shown potential dysregulation in the absence of fragile X mental retardation protein (FMRP) and may therefore be associated with FXS pathophysiology. While APP is best understood in the context of Alzheimer disease, there is a growing body of evidence suggesting the molecule and its derivatives play a broader role in regulating neuronal hyperexcitability, a well-characterized phenotype in FXS. To evaluate the viability of APP as a peripheral biological marker in FXS, we conducted an exploratory ELISA-based evaluation of plasma APP-related species involving 27 persons with FXS (mean age: 22.0 ± 11.5) and 25 age- and sex-matched persons with neurotypical development (mean age: 21.1 ± 10.7). Peripheral levels of both Aβ(1–40) and Aβ(1–42) were increased, while sAPPα was significantly decreased in persons with FXS as compared to control participants. These results suggest that dysregulated APP processing, with potential preferential β-secretase processing, may be a readily accessible marker of FXS pathophysiology.
Highlights
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the most common monogenic cause of autism spectrum disorder (Kosinovsky et al, 2005)
FXS is caused by a CGG repeat expansion in the promoter region of the fragile X mental retardation 1 gene (FMR1), resulting in silencing of the gene and amyloid-beta precursor protein (APP) in FXS
Analytes showing differential expression in the FXS group compared to typically developing controls (TDC) group are described here. sAPPα levels were significantly reduced in FXS relative to TDC (p = 0.0003, d∗ = 1.13)
Summary
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the most common monogenic cause of autism spectrum disorder (Kosinovsky et al, 2005). FXS is an X-linked disorder affecting 1 in 4,000 males and 1 in 6,000–8,000 females, with all males and some females having significant developmental disability as well as increased risk for autism, anxiety, ADHD, and epilepsy. FMRP is an RNA binding and carrier protein that plays a role in the transport, localization, and translational repression of at least hundreds of target mRNAs (Darnell et al, 2011; Ascano et al, 2012; Westmark, 2018). One of the obstacles preventing the development of disease-modifying treatments for FXS is a lack of useful readily accessible markers of pathophysiology. There have been efforts to identify either a single or combination of molecular markers in FXS
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