Here we report five cases of male FMR1 premutation carriers who present without clinical symptoms of the fragile X-associated tremor/ataxia syndrome (FXTAS), but who on MRI demonstrate white matter hyperintensities in the middle cerebellar peduncles (MCP sign) and other brain regions, a rare finding. MCP sign is the major radiological feature of FXTAS; it is therefore remarkable to identify five cases in which this MRI finding is present in the absence of tremor and ataxia, the major clinical features of FXTAS. Subjects underwent a detailed neurological evaluation, neuropsychological testing, molecular testing, and MRI evaluation utilizing T2 imaging described here. Additional white matter disease was present in the corpus callosum in four of the five cases. However, all cases were asymptomatic for motor signs of FXTAS.
Early-developing cerebellar or fronto-motor tract white matter changes, previously documented in MRI studies, may underlie motor slowing that occurs before clinically observable neurological symptoms associated with FXTAS. © 2018 International Parkinson and Movement Disorder Society.
Background Carriers of the FMR1 premutation are at increased risk of developing a late-onset progressive neurodegenerative disease, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by intention tremor, gait ataxia, and cognitive decline. Cross-sectional studies to date have provided evidence that neuropsychological changes, such as executive function alterations, or subtle motor changes, may precede the onset of formal FXTAS, perhaps characterizing a prodromal state. However, the lack of longitudinal data has prevented the field from forming a clear picture of progression over time within individuals, and we lack consensus regarding early markers of risk and measures that may be used to track response to intervention. Methods This was a longitudinal study of 64 male FMR1 premutation carriers (Pm) without FXTAS at study entry and 30 normal controls (Nc), aged 40 to 80 years (Pm M = 60.0 years; Nc M = 57.4 years). Fifty of the Pm and 22 of the Nc were re-assessed after an average of 2.33 years, and 37 Pm and 20 Nc were re-assessed a third time after an average of another 2.15 years. Eighteen of 64 carriers (28%) converted to FXTAS during the study to date. Neuropsychological assessments at each time point, including components of the Cambridge Neuropsychological Test Automated Battery (CANTAB), tapped domains of episodic and working memory, inhibitory control, visual attention, planning, executive control of movement, and manual speed and dexterity. Age-based mixed models were used to examine group differences in change over time on the outcomes in the full sample, and differences were further evaluated in 15 trios (n = 45; 15 Pm “converters,” 15 Pm “nonconverters,” 15 Nc) that were one-one matched on age, education, and socioeconomic status. Results Compared to Nc, Pm showed significantly greater rates of change over time in visual working memory, motor dexterity, inhibitory control, and manual movement speed. After multiple comparison correction, significant effects remained for motor dexterity. Worsening inhibitory control and slower manual movements were related to progression in FXTAS stage, but these effects became statistically non-significant after correcting for multiple comparisons. Higher FMR1 mRNA correlated with worsening manual reaction time but did not survive multiple comparisons and no other molecular measures correlated with neuropsychological changes. Finally, trio comparisons revealed greater rate of decline in planning and manual movement speed in Pm converters compared to Pm nonconverters. Conclusions Accelerated decline in executive function and subtle motor changes, likely mediated by frontocerebellar circuits, may precede, and then track with the emergence of formal FXTAS symptoms. Further research to develop and harmonize clinical assessment of FMR1 carriers across centers is needed to prepare for future prophylactic and treatment trials for this disorder.
Background Quantitative measurement of eye movements can reveal subtle progression in neurodegenerative diseases. Objective To determine if quantitative measurements of eye movements may reveal subtle progression of fragile X‐associated tremor and ataxia (FXTAS). Methods Prosaccade (PS) and antisaccade (AS) behavior was analyzed in 25 controls, 57 non‐FXTAS carriers, and 46 carriers with FXTAS. Results Symptomatic individuals with FXTAS had longer AS latencies, increased rates of AS errors, and increased AS dysmetria relative to non‐FXTAS carriers and controls. These deficits, along with PS latency and velocity, were greater in advanced FXTAS stages. Conclusion AS deficits differentiated FXTAS from non‐FXTAS premutation carriers implicating top‐down control and frontostriatal deterioration. However, the absence of group differences between non‐FXTAS carriers and controls in AS and PS markers suggests saccade performance may not be a sensitive enough measure for detecting conversion to FXTAS, but instead more helpful as translational biomarkers of FXTAS progression.
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