Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

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.

Narrative Review: Update on the Molecular Diagnosis of Fragile X Syndrome

“…PM carriers are at increased risk for a spectrum of conditions: fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI, OMIM 311360), fragile X-associated neuropsychiatric conditions (FXANC), and other anomalies (autoimmune disorders, fibromyalgia, and thyroid dysfunctions) [20]. FXTAS is a late-onset neurodegenerative disorder characterized by progressive intention tremor, cerebellar ataxia, neuropathy, autonomic dysfunction, parkinsonism, and cognitive decline [9,21,22]. FXPOI is defined as hypergonadotropic hypogonadism and oligo/amenorrhea before 40 years of age.…”

A Glimpse of Molecular Biomarkers in Huntington’s Disease

“…MicroRNAs (miRNAs) are of special interest as biomarkers because they can be obtained not only from whole blood as cellular transcripts but also from the plasma and serum fractions [ 124 ], as they are strikingly stable as constituents of extracellular vesicles and lipoproteins and RNA-binding protein complexes [ 125 , 126 ]. In the case of HD, variations in circulating miR-10b-5p and miR-486-5p in plasma resemble those observed in brain miRNAs [ 127 ], certain miRNAs (miR-122-5p, miR-100-5p, miR-641 and miR-330-3p) can be associated with the functional capabilities of patients [ 128 ], and their levels can be modified after diet-based interventions (e.g., miR-338-3p, miR-128-3p, miR-23a-3p and miR-24-3p [ 129 ]).…”

Identification of microRNAs associated with human fragile X syndrome using next-generation sequencing

“…Regarding American College of Medical Genetics (ACMG) in FXS, CGG triplet is repeated more than 200 times (that is known as a “full” mutation); those with a premutation and intermediate genotype carry a 55–200 and 45–54 of CGG repeats respectively, while this DNA segment is normally repeated between 5 and 44 times 2 . The carriers of premutation show a much lesser extent FXS phenotype 3 , but are at risk of developing a neurodegenerative disorder in adulthood in male, called fragile X tremor-ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency, or FXPOI among female carriers 4 , 5 .…”