Abstract
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a severe neurodegenerative movement disorder affecting over 40% of male and 16% of female FMR1 premutation carriers over the age of 50. However, there is a lack of prognostic biomarkers to aid early diagnosis and treatment planning. Therefore, this study aimed to assess the utility of the Magnetic Resonance Parkinson Index (MRPI) as a potential MRI biomarker for FXTAS. The four measurements required for the MRPI were assessed in 45 male premutation carriers at risk of developing FXTAS (Mean age = 59.54 years), 53 male patients with FXTAS (Mean age = 66.16 years) and 61 male controls (Mean age = 60.75 years), of which 73 participants had follow-up visits on average 1.96 years later. Middle cerebellar peduncle (MCP) width as well as midbrain and pons cross-sectional area were reduced in patients with FXTAS compared to both premutation carriers without FXTAS and controls. While these measurements were not found to change over time in the three-group analysis, age was an important predictor of midbrain cross-sectional area and pons/midbrain ratio. MCP width was initially reduced in a subset of premutation carriers who developed FXTAS symptoms between their initial and follow-up visits, which also decreased between visits, compared to age-matched premutation carriers who did not show any FXTAS symptom development over time. Therefore, while the MPRI may not be a useful biomarker for FXTAS, decreased MCP width may be one of the first notable signs of FXTAS, and therefore the first biomarker with the potential to identify those most at risk for the disorder.
Highlights
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a severe neurodegenerative movement disorder caused by premutation expansions (55–200 CGG repeats) in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene, located on the X-chromosome
Post-hoc pairwise comparisons revealed that patients with FXTAS demonstrated significantly reduced Middle cerebellar peduncle (MCP) width, midbrain and pons cross-sectional areas and increased pons/midbrain ratio compared to controls (Figure 2)
Perhaps more interestingly, decreasing MCP width appears to be sensitive to early structural changes associated with FXTAS development
Summary
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a severe neurodegenerative movement disorder caused by premutation expansions (55–200 CGG repeats) in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene, located on the X-chromosome. Studies suggest that ∼40% of male and 8–16% of female premutation carriers over the age of 50 years (RodriguezRevenga et al, 2009) have FXTAS, but these figures rise to 75% of male premutation carriers over the age of 70 years (Jacquemont et al, 2004). Despite the relatively high incidence, there is currently a lack of prognostic markers to detect the earliest neurodegenerative signs of FXTAS. The diagnostic criteria of FXTAS comprise three domains: clinical, radiological, and pathological (Jacquemont et al, 2003; Hall et al, 2014). Probable or possible, FXTAS diagnosis requires a degree of functional/clinical impairment. Other clinical features may include executive dysfunction, ranging from mild to dementia-like in severity, which often presents later in the disease course (Seritan et al, 2008)
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