THE SPECTRUM OF SYNDROMIC DISORDERS ASSOCIATED WITH EXPANSION OF CGG-REPEATS IN THE FMR1 PROMOTER: PATHOGENETIC MECHANISMS AND CLINICAL SYMPTOMS

Fragile X spectrum disorders (FXSD) include Fragile X syndrome (FXS), Fragile X tremor ataxia syndrome (FXTAS), Fragile X premature ovarian insufficiency, fragile X associated neuropsychiatric disorders. They are caused by dynamic mutations of the FMR1 gene due to expansion of trinucleotide repeats in the gene promoter. Fragile X syndrome (mental retardation, ASD, ADHD) is caused by FMR1 full mutation (>200 CGG repeats) that results in full or partial suppression of FMRP expression. The clinical symptoms of FXTAS, FXPOI, FXAND can manifest in premutation carriers (CGG repeats from 55 to 200). The pathogenetic mechanism is associated with reduction of FMRP expression and excessive levels of FMR1 mRNA with excessive CGG-repeats number. In this review we focus on the phenotypes and genotypes of FX related disorders, analyzing the relationship between molecular mechanisms (FMRP deficit, atypical isoforms translation, FMR1 mRNA gain of function) and clinical presentation (cognitive level, severity of ASD, manifestation of FXTAS, FXPOI and FXAND).