Editorial
Current Psychiatry Reviews, 2013, Vol. 9, No. 1
51
EDITORIAL
Fragile X Families: A Lifespan Perspective
This special issue discusses multiple aspects of fragile X-associated disorders across the lifespan. The fragile X mental
retardation (FMR1) gene is versatile. Typically consisting of less than 45 CGG triplet repeats, the FMR1 gene is susceptible to
expansions, especially when transmitted from mothers to their offspring [1, 2]. FMR1 mutations (over 200 CGG repeats) cause
silencing of the gene, which manifests clinically as the fragile X syndrome (FXS). Premutations (with higher CGG repeat
numbers than in typical individuals, but less than full mutation range) can cause multiple medical and psychiatric conditions.
Until 2001, the only clinical syndrome known to be associated with FMR1 gene premutations was premature ovarian failure
(later renamed primary ovarian insufficiency). There was great resistance from the scientific community to accept that gene
premutations, not just mutations, could lead to complex clinical involvement. No other premutation carries such serious and
varied consequences.
The fragile X-associated disorders are intriguing because they span all ages, highlight poignant gender differences, and
combine neurodevelopmental and neurodegenerative processes. Abnormalities of this single gene can cause a plethora of
medical, emotional, functional, and socio-economic consequences for individuals and their caregivers. In many families,
multiple members are affected with either the mutation or the premutation. Thus, abnormalities of the FMR1 gene can serve as
exemplars of chronic diseases with tremendous impact on patients and their loved ones, and are in great need of further
research and understanding by the health science community.
This collection of articles is intended for practicing psychiatrists, purposely minimizing basic sciences research data, which
are abundant in this field. Premutation-related brain changes may start during prenatal stages of development. Neuronal
migration defects were discovered in the neocortex of the premutation knock-in mouse model, providing evidence that the
FMR1 premutation has a neurodevelopmental component [3]. Interestingly, these neurodevelopmental changes pave the way
for a late-onset neurodegenerative disease, fragile X-associated tremor ataxia syndrome (FXTAS). FXTAS is a movement
disorder characterized by intention tremor and gait ataxia which occurs in older individuals with the premutation. Men are
affected more often than women, although women have more varied presentations. Psychiatric disorders associated with
FXTAS were reviewed in this issue [4], along with a pilot study focused on postpartum depression in women carriers [5].
Women premutation carriers are known to be more susceptible to mood disorders than women in the general population [6, 7].
Obadia et al. explored whether mothers of children with FXS are at higher risk for postpartum depression than carriers with
unaffected children [5].
An interesting question, as in any illness with a life-long constellation of symptoms, is whether psychiatric symptoms
precede neurological impairment, constituting a prodrome of FXTAS. In Ages of onset of mood and anxiety disorders in fragile
X premutation carriers, preliminary results are presented, suggesting that is the case, at least for major depression [8]. This
brings up an additional question: is a lifelong history of depression a risk factor for future cognitive impairment, similar to
Alzheimer’s disease [9]? Although it is not yet clear what risk factors predispose premutation carriers to cognitive deficits,
FXTAS is often accompanied by short-term memory loss, executive dysfunction, and in some cases a mixed corticalsubcortical dementia. The current knowledge on cognitive changes in premutation carriers was reviewed by Seritan et al. [10].
Despite much greater awareness of health care providers about FXS physical phenotypes, little is known about psychiatric
presentations in individuals with full mutations. Wadell and colleagues contributed a thorough review, including an informed
perspective on assessment strategies and emerging therapies for FXS [11]. The challenges of caring for those with FXS extend
into late life, since these individuals are rarely able to function independently. Iosif et al. explored the burden experienced by
family caregivers in caring for people with FXS and FXTAS [12]. The families’ struggle with the educational and health
systems is heartbreaking. Access to resources, such as speech therapy or vocational therapy for the youth, and home health
services or long-term care planning for elderly patients, is limited. Few providers are educated on the fragile X spectrum
illnesses. There is a great need for interprofessional and multidisciplinary teams in assessing and addressing the needs of
affected individuals.
This special issue is an effort to disseminate the knowledge regarding fragile X spectrum disorders accumulated over the
past decade. There is still a lot to be learned, but this is a small step towards improving the care of fragile X families.
ACKNOWLEDGEMENT
I am very grateful to Heather Young, Ph.D., R.N., F.A.A.N., for her helpful editorial comments.
REFERENCES
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Tassone F, Hagerman RJ, Taylor AK, Gane LW, Godfrey TE, Hagerman PJ. Elevated levels of FMR1 mRNA in carrier males: a new mechanism of
involvement in fragile X syndrome. Am J Hum Genet 2000; 66: 6-15.
Willemsen R, Levenga J, Oostra BA. CGG repeat in the FMR1 gene: size matters. Clin Genet 2011; 80:214-25.
Cunningham CL, Martinez Cerdeno V, Navarro Porras E, et al. Premutation CGG-repeat expansion of the FMR1 gene impairs mouse neocortical
development. Hum Mol Genet 2011; 20: 64-79.
Seritan AL, Ortigas M, Seritan S, Bourgeois JA, Hagerman R. FXTAS and related psychiatric disorders. Current Psychiatry Reviews
Obadia RW, Iosif AM, Seritan AL. Postpartum depression in women with the FMR1 premutation. Current Psychiatry Reviews
52 Current Psychiatry Reviews, 2013, Vol. 9, No. 1
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Editorial
Roberts JE, Bailey D, Mankowski J, et al. Mood and anxiety disorders in females with the FMR1 premutation. Am J Med Genet Neuropsychiatr Genet
2009; 150B: 130-9.
Bourgeois JA, Seritan AL, Casillas M, et al. Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers. J Clin Psychiatry
2011; 72: 175-82.
Seritan AL, Bourgeois JA, Schneider A, Mu Y, Hagerman RJ, Nguyen DV. Ages of onset of mood and anxiety disorders in fragile X premutation
carriers. Current Psychiatry Reviews
Rapp MA, Schnaider-Beeri M, Wysocki M, et al. Cognitive decline in patients with dementia as a function of depression. Am J Geriatr Psychiatry
2011; 19:357-63.
Seritan AL, Cogswell J, Grigsby J. Cognitive dysfunction in FMR1 premutation carriers. Current Psychiatry Reviews
Wadell PM, Hagerman RJ, Hessl DR. Fragile X syndrome: Psychiatric manifestations, assessment, and emerging therapies. Current Psychiatry
Reviews
Iosif AM, Sciolla AF, Brahmbhatt K, Seritan AL. Caregiver burden in fragile X families. Current Psychiatry Reviews
Andreea L. Seritan, M.D.
(Guest Editor)
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