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Psychopathology Increases With Age in Fragile X Carrier Mothers

  • Randi Hagerman
    Correspondence
    Address correspondence to: Randi Hagerman, M.D., MIND Institute UCDMC, 2825 50th Street, Sacramento, CA 95817; .
    Affiliations
    UC Davis MIND Institute, Department of Pediatrics, UC Davis Medical Center, University of California, Davis, Sacramento, California
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      The saga of psychiatric problems in FMR1 premutation carriers (55–200 CGG repeats) has come a long way over the last 15 years, informed by advances in molecular biology, neuroimaging, and detailed phenotypic assessments within psychiatric and neuropsychological studies. Initially, in the 1990s, female premutation carriers were considered unaffected by psychiatric problems, although epidemiologic studies demonstrated an increased rate of early menopause in carriers compared with the general population. Early menopause in female premutation carriers has been confirmed by many centers and renamed fragile X–associated primary ovarian insufficiency (
      • Sullivan S.D.
      • Welt C.
      • Sherman S.
      FMR1 and the continuum of primary ovarian insufficiency.
      ). The emergence of several molecular mechanisms to explain clinical involvement in premutation carriers, particularly the aging problem of fragile X–associated tremor ataxia syndrome (FXTAS), has colored the way we interpret psychological and psychiatric problems in carriers. The molecular problem of elevated FMR1 messenger RNA (mRNA) in premutation carriers is the opposite of what occurs in males in fragile X syndrome (FXS), where little or no FMR1 mRNA is produced because the gene is usually methylated when the CGG repeat number is >200 repeats (full mutation). The elevated FMR1 mRNA occurs throughout life in the carriers. Although the level of fragile X mental retardation protein is usually normal, avoiding intellectual disability, the problems of psychopathology often begin in childhood (
      • Hagerman P.J.
      • Hagerman R.J.
      Fragile X-associated tremor/ataxia syndrome.
      ), and, as Roberts et al. (
      • Roberts J.E.
      • Tonnsen B.L.
      • McCary L.M.
      • Ford A.L.
      • Golden R.N.
      • Bailey Jr., DB
      Trajectory and predictors of depression and anxiety disorders in mothers with the FMR1 premutation.
      ) have shown in this issue of Biological Psychiatry, the psychopathology rate increases with age in adulthood. This elegant study followed 83 carrier mothers (mean age, 38.4 years) and their children with FXS who were assessed at two time points separated by a 3-year interval. The frequency of mood disorders increased from 45.7% at the first time point to 60.2% at the second time point, whereas anxiety disorders increased from 27.1% at the first time point to 34.9% at the second time point, even in the face of a high rate of psychotropic medication use (41%). These women experience substantial psychological problems beyond problems associated with raising difficult children with FXS, as the mood and anxiety disorders begin for many before they have children. Roberts et al. have teased apart the additive burden of experiencing severe behavioral problems in their children, having multiple children with FXS, being a divorced or single parent, and experiencing the hormonal effects of fragile X–associated primary ovarian insufficiency, all of which add complexity to the overall presence of psychopathology. Perhaps the most severe stress that these mothers experience is having a child who is regularly aggressive toward them, leaving them bruised black and blue or occasionally with major injuries and emergency department visits.
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