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Review
.2013 Jul;126(1):1-19.
doi: 10.1007/s00401-013-1138-1. Epub 2013 Jun 21.

Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms

Affiliations
Review

Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms

Paul Hagerman. Acta Neuropathol.2013 Jul.

Abstract

Since its discovery in 2001, our understanding of fragile X-associated tremor/ataxia syndrome (FXTAS) has undergone a remarkable transformation. Initially characterized rather narrowly as an adult-onset movement disorder, the definition of FXTAS is broadening; moreover, the disorder is now recognized as only one facet of a much broader clinical pleiotropy among children and adults who carry premutation alleles of the FMR1 gene. Furthermore, the intranuclear inclusions of FXTAS, once thought to be a CNS-specific marker of the disorder, are now known to be widely distributed in multiple non-CNS tissues; this observation fundamentally changes our concept of the disease, and may provide the basis for understanding the diverse medical problems associated with the premutation. Recent work on the pathogenic mechanisms underlying FXTAS indicates that the origins of the late-onset neurodegenerative disorder actually lie in early development, raising the likelihood that all forms of clinical involvement among premutation carriers have a common underlying mechanistic basis. There has also been great progress in our understanding of the triggering event(s) in FXTAS pathogenesis, which is now thought to involve sequestration of one or more nuclear proteins involved with microRNA biogenesis. Moreover, there is mounting evidence that mitochondrial dysregulation contributes to the decreased cell function and loss of viability, evident in mice even during the neonatal period. Taken together, these recent findings offer hope for early interventions for FXTAS, well before the onset of overt disease, and for the treatment of other forms of clinical involvement among premutation carriers.

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Conflict of interest statement

Conflicts: Dr. Hagerman is an uncompensated collaborator with Pacific Biosciences regarding newFMR1 sequencing strategies; he holds patents forFMR1 genotyping and protein tests.

Figures

Fig. 1
Fig. 1
Schematic of the CGG-repeat element within the 5′ untranslated region (5′UTR) of theFMR1 gene. The modal number of CGG repeats in the general population is approximately 30; 45–54 CGG repeats are generally referred to as “gray zone” alleles. Premutation alleles are generally unmethylated (yellow); however, partially methylated alleles are observed near the upper end of the premutation range (indicated by red shading). Full mutation alleles are generally, although not always methylated. CDS, protein coding sequence.
Fig. 2
Fig. 2
Representative fragile X pedigree displaying intergenerational shift from premutation to full mutation alleles, and consequent increase in disease penetrance and severity (genetic anticipation), due to CGG-repeat instability during transmission. Numbers below family members indicate CGG-repeat size (two alleles for females); red dots, premutation; solid red symbols, full mutation/fragile X syndrome. Premutation alleles are associated with at least four phenotypic domains, with typical age ranges as indicated to the right side of the figure.
Fig. 3
Fig. 3
MRI images of white matter and structural abnormalities associated with FXTAS [1,3,23,30,162]. For each pair of images, a normal control (left) and FXTAS case (right) are represented. The white arrows indicate increased signal intensity on T2 turbo spin-echo sequences in the middle cerebellar peduncle (MCP) (a), sub-insular white matter (c), and cerebral white matter (d). Thinning and increased signal of the trunk and splenium of the corpus callosum (b; arrows) are from the T2 FLAIR sequence. Cases depicted in this figure are males, as follows: (a) 70 yr, FXTAS stage 3, 96 CGG repeats; (b) same asa; (c) 65 yr, stage 3, 91 CGG repeats; (d) 78 yr, stage 4, 116 CGG repeats. The control used for all images and comparisons was a 68-year-old man with 32 CGG repeats. Images kindly provided by Patrick Adams.
Fig. 4
Fig. 4
Schematic of the role of DGCR8 in the pathogenesis of FXTAS [139]. (a) DGCR8 binds to pri-miRNA in the nucleus, recruiting DROSHA (and other proteins) to form the “microprocessor” complex; binding of DGCR8 is cooperative and targets a specific (imperfect) helix region of the pri-miRNAs. Cleavage yields precursor miRNAs (pre-miRNAs), which exit the nucleus for further processing into mature miRNAs. NormalFMR1 alleles do not interact appreciably with DGCR8. (b) Expanded CGG-repeat RNA forms stable helical stems, which recruit (sequester) DGCR8, thus preventing normal levels of pri-miRNA processing. Consequently, nuclear pri-miRNA levels are increased and mature, cytoplasmic miRNAs are decreased. The 88 CGG-repeat allele depicted in the figure is near the modal value for individuals with FXTAS.
Fig. 4
Fig. 4
Schematic of the role of DGCR8 in the pathogenesis of FXTAS [139]. (a) DGCR8 binds to pri-miRNA in the nucleus, recruiting DROSHA (and other proteins) to form the “microprocessor” complex; binding of DGCR8 is cooperative and targets a specific (imperfect) helix region of the pri-miRNAs. Cleavage yields precursor miRNAs (pre-miRNAs), which exit the nucleus for further processing into mature miRNAs. NormalFMR1 alleles do not interact appreciably with DGCR8. (b) Expanded CGG-repeat RNA forms stable helical stems, which recruit (sequester) DGCR8, thus preventing normal levels of pri-miRNA processing. Consequently, nuclear pri-miRNA levels are increased and mature, cytoplasmic miRNAs are decreased. The 88 CGG-repeat allele depicted in the figure is near the modal value for individuals with FXTAS.
Fig. 5
Fig. 5
Representative examples of intranuclear inclusions inpost-mortem, non-CNS tissues/organs from FXTAS patients; for more details of the range of non-CNS tissues bearing inclusions in both humans and premutation KI mice, see text and Table 2 of Hunsaker et al. [86]. For each image, arrowheads point to inclusions. (a) Cardiomyocytes (ubiquitin; 400x); (b) cardiac autonomic ganglion cell (H&E, 600x); (c) pancreas (ubiquitin, 1000x); (d) intestinal wall (H&E, 400x); (e) adrenal medulla (H&E, 600x); (f) myenteric plexus, stomach (H&E, 400x); (g) anterior pituitary (H&E, 400x); (h) testicular Leydig cells (ubiquitin, 400x); (i) renal distal tubule (ubiquitin, 400x). Images kindly provided by Claudia Greco.
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