Psychiatric Disorders Associated with FXTAS

Abstract

Carriers of the FMR1 premutation (with 55-200 CGG repeats) may present with multiple medical and psychiatric disorders. Middle-aged carriers (males more often than females) may suffer from fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is a newly discovered neurodegenerative disease characterized by intention tremor and ataxia, along with several other neurological features. Psychiatric manifestations are common in premutation carriers of both genders and include attention deficits, anxiety, depression, irritability, impulse dyscontrol, and substance abuse or dependence. Major depressive disorder, panic disorder with or without agoraphobia, generalized anxiety disorder, social phobia, and specific phobia are among the psychiatric diagnoses often encountered in premutation carriers, including those with FXTAS. Later in the course of the illness, cognitive deficits (including dementia) may occur. In this paper, we discuss common psychiatric phenotypes in FXTAS, based on a thorough review of the literature, as well as our own research experience. Symptomatic pharmacologic treatments are available, although disease modifying agents have not yet been developed.

Trajectory and Predictors of Depression and Anxiety Disorders in Mothers With the FMR1 Premutation

“…Rates of MDD and anxiety disorders did not differ between women over age 40 with and without premature ovarian insufficiency, consistent with previous reports (17). Given that none of our participants were 50 years or older and all reported the absence of a FXTAS diagnosis, these findings are not attributed to FXTAS as has been reported in other studies (34; 37). Thus, the accelerating, elevated rates of mood and anxiety disorders we observed do not appear to be secondary effects of medical experiences, underscoring the developmentally complex nature of vulnerabilities.…”

“…Both our study and others (1; 20; 27; 29) note the subtlety of the relationships between mid-level CGG repeats and psychiatric symptoms that are challenging to detect given the relatively small samples of women with larger premutation alleles and a failure to intentionally examine non-linear effects in the presence of linear effects. The lack of replication of these findings in some studies may be due, in part, to these factors as many conduct simple correlations or exclusively linear analyses which obscure detection of non-linear effects and preclude detecting a potential relationship between mid-range repeats and psychiatric symptomology (33; 34). …”

“…Alternatively, undiscovered genetic or epigenetic factors and mediating cognitive or environmental factors are rival hypotheses given evidence of differential sensitivity to stressful life events in relation to depressive and anxious symptomology in women with midsize CGG repeats (21) and recent discoveries of novel methylation markers associated with anxiety mediated by executive functioning in women with the premutation (33) Progressive mRNA toxicity is an associated putative explanatory mechanism with recognition of the cumulative effects of stress and the presence of protective factors as contributory factors (34). …”

The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology

“…In late-stage FXTAS, frank dementia, primary memory deficits, and signs of cortical impairment, are often observed (Seritan et al, 2013). Emotional and behavioral symptoms are common, and include apathy, anxiety, agitation, and depression, as well as obsessive-compulsive symptoms (Birch et al, 2014; Bourgeois et al, 2009; Grigsby et al, this issue; Hessl et al, 2005).…”

Risk Factors for Cognitive Impairment in Fragile X-Associated Tremor/Ataxia Syndrome

“…45,46 The mechanisms through which obstructive sleep apnea affects cognition are not yet clear; cerebrovascular insult and cortisol dysregulation have been implicated. 46,47 …”