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
- 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
) 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.