Fragile X-associated tremor/ataxia syndrome (FXTAS)
FXTAS represents the most severe form of clinical involvement associated with premutation FMR1 alleles; its core features are intention tremor and/or ataxia, with peripheral neuropathy, autonomic dysfunction, and gradual cognitive decline beginning with memory and executive function deficits. Psychiatric features are often present, and may include anxiety, dysinhibition, depression, and apathy. MRI features of FXTAS include global brain atrophy, white matter disease in the subcortical, middle cerebellar peduncles (MCP) and periventricular regions.
MRI image - Jacquemont et al. (2003) Am J Hum Genet
FXTAS is associated with decreased brain volume. Increased signal (white lesions) in the middle cerebellar peduncles (MCP sign) reflects the disease process and is an important feature for the diagnosis of FXTAS. Approximately 60% of males with clinical findings consistent with FXTAS will demonstrate this feature.
A characteristic feature of FXTAS neuropathology is the presence of intranuclear inclusions
Inclusion image - Courtesy of Dr. Claudia Greco
in neurons and astrocytes in broad distribution throughout the brain and brainstem. The existence of both clinical and neuropathologic features of FXTAS within the premutation range (55-200 CGG repeats), where the FMR1 gene is active, but not in the full mutation range, where the gene is generally silent, led us to propose that FXTAS is due to an RNA "toxic gain-of-function," whereby the excess, CGG-expanded RNA itself leads to cellular dysregulation.
Since premutation carriers are relatively common in the general population, (up to 1 in 130 females and 250 males), as many as 1 in 3,000 males in the general population may develop clinical features of FXTAS at some point in their lives. Thus, from both the clinical and molecular perspective, FXTAS represents a logical objective for targeted therapy: the clinical impact would be high and the potential target (the FMR1 RNA itself) well defined.
The RNA "toxicity" model for the pathogenesis of FXTAS.
Features of the RNA "toxicity" model, as envisioned for FXTAS. Expanded CGG repeats (Gold), recruits one or more RNA-binding proteins. In another repeat expansion disorder, myotonic dystrophy [unbold], inability of the bound/sequestered proteins to carry out their normal functions loss of function of the sequestered proteins results in altered splicing of several other RNAs, leading in turn to specific features of the disease phenotype. An alternative model for FXTAS, currently being investigated, is that protein binding results in activation/signaling. Protein-RNA aggregation also leads to inclusion formation, which is not thought to be directly pathogenic.
- The disorder appears to be confined to carriers of active premutation alleles of the FMR1 gene; FXTAS has not been reported among older adults with fragile X syndrome, where the gene is transcriptionally silent.
- FMR1 mRNA levels are elevated by as much as eight-fold over the levels found for normal alleles.
- Animal models that harbor the CGG repeat expansions in the premutation range (~90 to 100 CGG repeats) manifest features of the neuropathology of FXTAS.
- FMR1 mRNA is found within the inclusions themselves Inclusion formation can be induced in neural cell models in which an expanded CGG repeat is expressed in front of an unrelated reporter gene.
Current research on FXTAS
Our laboratory is involved with a broad range of molecular and translational/clinical projects related to FXTAS, and this research effort forms the basis for our NTRI Consortium research effort; molecular efforts include:
- Development of oligonucleotide-based approaches to reduce FMR1 RNA in vivo.
- Defining the timing and reversibility of pathogenic responses to expression of the expanded-CGG-repeat RNA.
- Identification of the initial/early molecular events that couple expression of the expanded-CGG-repeat RNA to downstream processes (e.g., cellular stress response, breakdown of nuclear lamin A/C architecture) that are likely to lead to neurodegeneration.
- Characterization of the components of the intranuclear inclusions and the basis for inclusion formation.
- Development of approaches for delivery of therapeutic agents across the blood-brain-barrier.
- Understanding of the detailed molecular mechanisms by which the expanded-CGG repeat RNA triggers the pathogenic response in FXTAS.