Objective: FMR1 premutation carriers of both genders have a high lifetime prevalence of anxiety and
depressive disorders, however little is known regarding the onset ages of these conditions. This study compared onset ages
of mood and anxiety disorders in premutation carriers with typical onset ages of the same disorders in the general
Methods: Eighty-one premutation carriers (42% men; average age 62, SD 10) with and without FXTAS completed the
Structured Clinical Interview for DSM-IV-TR. Onset ages of mood and anxiety disorders were compared to the
corresponding typical population onset ages using the signed rank test.
Results: Overall median onset ages of MDD (46 years old, p < 0.0001), panic disorder (40 years old, p = 0.0067), and
specific phobia (11.5 years old, p = 0.0003) were significantly higher in premutation carriers compared to the general
population. Median MDD onset ages in male carriers (52 years old) and those with FXTAS (49.5 years old) were
significantly higher relative to the general population (median 32, both p < 0.0001). Tremor and ataxia emerged
significantly later than MDD and the anxiety disorders studied.
Conclusion: Depressive and anxiety disorders in premutation carriers have a later onset compared to the general
population, but precede the onset of motor symptoms. This may be due to progressive mRNA toxicity in the limbic
system, white matter changes leading to neuronal dysconnectivity, and interaction with environmental factors.
Psychosocial factors may be protective. Further research is needed to understand the full spectrum of psychiatric
phenotypes in FMR1 premutation carriers.