Fragile X–Associated Tremor/Ataxia Syndrome

Age‐ and CGG repeat‐related slowing of manual movement in fragile X carriers: A prodrome of fragile X‐associated tremor ataxia syndrome?

“…This slowing could not be explained by any observable tremor or bradykinesia by blinded neurological exam by an experienced movement disorder specialist. One interpretation of this finding is that early-developing cerebellar or fronto-cerebellar tract changes in carriers 8, 40 underlie the motor slowing seen in the RTI tasks. These changes could be occurring before the appearance of intention tremor in high risk individuals.…”

“…8–19 It is notable that in some studies a subgroup of premutation carriers who do not yet meet diagnostic criteria for FXTAS exhibit subtle weaknesses in executive function and frontal-executive motor control that are very similar to the more pervasive and robust deficits in patients with the fully developed syndrome. 1 These observations raise a critical question whether milder EF weaknesses are in fact early markers of later frank neurodegeneration in FXTAS disease progression.…”

Abnormal trajectories in cerebellum and brainstem volumes in carriers of the fragile X premutation

“…In FXTAS cerebellar structural damage becomes clinically observable, with MRI signal hyperintensities in the MCP being used as a diagnostic criterion (Brunberg et al , 2002). The central role of cerebellum in FXTAS pathology is further highlighted by the evidence of a negative relationship between cerebellar volume and postural sway (Birch et al , 2015) and the associations of superior cerebellar peduncle with behavioral regulation and fine motor skills in premutation carriers (Wang et al , 2013c). …”

“…This participant was excluded in the analyses because he became an outlier in the regression models. Of the remaining 322 participants, 96 have been included in our previous studies (Wang et al , 2012, Wang et al , 2013a, Wang et al , 2013b, Wang et al , 2013c, Leow et al , 2014). A trained physician (RJH) scored FXTAS severity for premutation carriers using the FXTAS stage.…”

Risk Factors for Cognitive Impairment in Fragile X-Associated Tremor/Ataxia Syndrome

“…5–9 Underlying neurobiological correlates are not yet clear, although progressive mRNA toxicity, production of polyglycine- FMR1 protein, and altered connectivity in white matter tracts that serve cognitive, emotional, and motor functions have been found and postulated to be related or causal to FXTAS. 2,5,10–12 The longitudinal trajectory of FXTAS and the approximate timeline of clinical progression have yet to be elucidated. Previous studies have shown that up to 42% of men with FXTAS may develop dementia.…”