Abstract
Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5’-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult “gain-of-function” syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.
Highlights
Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), 11009 Cádiz, Spain; Unidad de Investigación, Hospital Universitario Puerta del Mar, Av
Some authors have suggested that all clinical manifestations associated with the PM of the Fragile X Mental Retardation 1 (FMR1) gene constitute a spectrum of varying degrees of penetrance and severity of these clinical signs, in which the final diagnosis of Fragile X-associated tremor-ataxia syndrome (FXTAS) or Fragile X-associated primary ovarian insufficiency (FXPOI) may represent extreme forms of cognitive and endocrine impairment that may be present in other PM carriers in a milder manner
This vast catalogue of mitochondrial alterations has been proposed to be caused by the interaction between FMRpolyG-containing aggregates and the mitochondrial membrane, which was concomitant to negative effects on membrane potential, ATP synthesis, assembly of respiratory chain supercomplexes composed by complexes I, III and IV, and gene expression of mitochondrial mRNAs, in the absence of altered mitochondrial DNA (mtDNA) content in in vitro preparations [150]
Summary
The Fragile X Mental Retardation 1 (FMR1) gene is located on the X chromosome and encodes the polysome-associated RNA-binding protein FMRP, which plays key roles in neuronal development and synaptic plasticity through the regulation of mRNAs at the level of traffic, stability, splicing and both somatic and presynaptic translation [1]. The risk to develop FXTAS (OMIM #300623) is higher in men than in women: from 17% to 75% of the PM male carriers as age increases, and only from 8 to 16% in PM carrier women [6,7] who exhibit a diverse phenotype much milder than those observed in men, possibly due to the female inactivation of chromosome X [8]. More prevalent in women is the development of the Fragile X-associated primary ovarian insufficiency (FXPOI, OMIM #311360): 24% of the PM women whereas the prevalence of POI in the general population is 1% [17] This form is the most common inheritable ovarian dysfunction, which symptoms include irregular menstruation cycles, reduced fertility and early menopause onset [18]. This review is focused on the adult Fragile X-associated syndromes, starting with a brief description of the molecular pathogenic mechanisms caused by the CGG expansion, followed by a discussion about how some molecular and cellular alterations can be monitored at the peripheral level, mainly through the assessment of blood and derivatives: serum, plasma and peripheral blood mononuclear cells (PBMCs)
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