Fragile X syndrome and associated disorders: Clinical aspects and pathology

Abstract

This review aims to assemble many years of research and clinical experience in the fields of neurodevelopment and neuroscience to present an up-to-date understanding of the clinical presentation, molecular and brain pathology associated with Fragile X syndrome, a neurodevelopmental condition that develops with the full mutation of the FMR1 gene, located in the q27.3 loci of the X chromosome, and Fragile X-associated tremor/ataxia syndrome a neurodegenerative disease experienced by aging premutation carriers of the FMR1 gene. It is important to understand that these two syndromes have a very distinct clinical and pathological presentation while sharing the same origin: the mutation of the FMR1 gene; revealing the complexity of expansion genetics.

Keywords: FMR1 gene; FXTAS; Fragile X syndrome; Fragile X-associated tremor/ataxia syndrome; Neuropathology.

Figure 1.. FMR1 GGG repeat length and gene expression.

Overview of the relationship between CGG repeat length (A,B,C) within the FMR1 gene (left column) and its effects on FMR1 mRNA (middle) and FMRP protein synthesis (right). A) FMR1 alleles bearing less than 45 CGG repeats are considered in the normal range. B) CGG repeat expansion into the premutation range (containing 55–200 CGG repeats) causes an upregulation in FMR1 mRNA transcripts. For most premutation cases FMRP levels (black shapes) are not altered, although some individuals may show a modest reduction. Additionally, RAN translation of FMR1 mRNA produces toxic FMRpolyG protein species (red shapes). C) CGG repeat expansion into the full mutation range (200+ repeats) causes hypermethylation of the FMR1 gene, resulting in full transcriptional and translational silencing. Figure Key: FMR1 Gene: Open reading frame indicated with solid blue, non-coding 5’ and 3’ regions indicated with shaded black pattern. CGG repeat is located in the 5’ untranslated region (red shaded in A and B, white shaded in C to represent hypermethylation of the gene). FMR1 mRNA transcripts indicated with curved blue lines. FMRP protein represented as black shapes and FMRpolyG is represented as red shapes.

Figure 2.. FXTAS Neuropathology.

Postmortem neuropathological analysis from human FXTAS cases show a characteristic neurodegenerative phenotype which includes ventricular enlargement (A); focal white matter lesions (B,C); ubiquitinated intranuclear inclusion bodies (D,E – ubiquitin IHC with hematoxylin nuclear counterstain); patches of astrogliosis (F,G - GFAP IHC); and excessive iron accumulation (H,I – ferric iron stained using Perl’s method, Eosin counterstain).