Women with Fragile X–associated Tremor/Ataxia Syndrome

Background: Fragile X–associated tremor and ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder linked to the FMR1 premutation. Objectives: FXTAS in women is far less common than in men, and this study represents the largest sample reported to date. Methods: A total of 53 female premutation carriers with FXTAS (mean_age, 66.83 years; FXTAS stages 2–5) and 55 age-matched and demographic background–matched control participants (mean_age, 61.94 years) underwent a comprehensive molecular, physiological, neuropsychological, and psychiatric assessment. Results: The large sample of female premutation carriers showed a wide range of variability of clinical signs and symptom progression. The imaging results showed a middle cerebellar peduncles sign in only 6 patients; another symptom included high-signal intensity in the splenium of the corpus callosum, and diffuse cerebral deep white matter changes (e.g., in the pons) are more common. The rate of psychiatric disorders, especially depression, is higher than in the general population. There is a clear impairment in executive functioning and fine motor skills in connection with a higher FXTAS stage. Conclusions: The manifestation of FXTAS symptoms in female carriers can be diverse with a milder phenotype and a lower penetrance than those observed in male premutation carriers. The middle cerebellar peduncles sign is present in only a small percentage of the sample, and we propose that the imaging criteria for FXTAS in women need to be expanded.