Objective The authors studied the lifetime prevalence of DSM-IV-TR psychiatric disorders in a population of adults with the fragile X premutation. Methods Structured Clinical Interview for DSM-IV (SCID) were conducted on 85 individuals with the fragile X premutation, 47 with the fragile X-associated tremor/ataxia syndrome (FXTAS; 33 male, 14 female, mean age 66) and 38 without FXTAS (16 male, 22 female, mean age 52). Lifetime prevalence for mood and anxiety disorders among carriers with and without FXTAS was compared to available age-specific population estimates from the National Comorbidity Survey Replication (NCS-R). Results Among subjects with FXTAS, 30 cases (65%) met lifetime DSM-IV-TR criteria for mood disorder; 24 cases (52%) met lifetime DSM-IV-TR criteria for anxiety disorder. Among the non-FXTAS subjects, there were 15 cases (42%) of lifetime mood disorder and 18 cases (47%) of lifetime anxiety disorder. When compared to age-specific NCS-R data, the lifetime prevalence of any mood disorder, major depressive disorder, any anxiety disorder, panic disorder, specific phobia, and PTSD were significantly higher in subjects with FXTAS. The lifetime rates of social phobia in individuals with the premutation without FXTAS were significantly higher than NCS-R data. Conclusions This sample of carriers of the fragile X premutation had a notably high lifetime risk of mood and anxiety disorders. Mood and anxiety disorders may be part of the clinical phenotype of the fragile X premutation conditions, especially in carriers with FXTAS. Clinicians encountering these patients are advised to consider FXTAS as a neuropsychiatric syndrome as well as a neurological disorder.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder associated with premutation alleles of the fragile X mental retardation 1 (FMR1) gene. Approximately 40% of older male premutation carriers, and a smaller proportion of females, are affected by FXTAS; due to the lower penetrance the characterization of the disorder in females is much less detailed. Core clinical features of FXTAS include intention tremor, cerebellar gait ataxia, and frequently parkinsonism, autonomic dysfunction, and cognitive deficits progressing to dementia in up to 50% of males. Here, we report the clinical, molecular, and neuropathological findings of eight female premutation carriers. Significantly, four of these women had dementia; of the four, three had FXTAS plus dementia. Post mortem examination revealed the presence of intranuclear inclusions in all eight cases, which included one asymptomatic premutation carrier who died from cancer. Among the four subjects with dementia, three had sufficient number of cortical amyloid plaques and neurofibrillary tangles to make Alzheimer’s disease a highly likely cause of dementia and a fourth case had dementia with cortical Lewy bodies. Dementia appears to be more common than originally reported in females with FXTAS. Although further studies are required, our observation suggests that in a portion of FXTAS cases and Alzheimer pathologies a synergistic effect on the progression of the disease may occurs.

Background-Neurocognitive deficits in fragile X-associated tremor/ataxia syndrome (FXTAS) involve attentional control, working memory, executive functioning, and declarative and procedural learning. To date, no studies comparing FXTAS with other dementias have been done. We characterize the dementia in FXTAS, comparing it with Alzheimer's disease.

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Objective To investigate the nature of cognitive impairments and underlying brain mechanisms in older female fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome (FXTAS). Methods Extensive neuropsychological testing and cognitive event-related brain potentials (ERPs, particularly, the auditory P300) were examined in 84 female participants: 33 fragile X premutation carriers with FXTAS (mean age = 62.8), 25 premutation carriers without FXTAS (mean age = 55.4) and 26 normal healthy controls (mean age = 59.3). Results Both premutation groups exhibited executive dysfunction on the Behavioral Dyscontrol Scale (BDS), with subtle impairments in inhibition and performance monitoring in female carriers without FXTAS, and more substantial deficits in FXTAS women. However, the female carrier group without FXTAS showed more pronounced deficiencies in working memory. Abnormal ERPs were recorded over the frontal lobes, where FXTAS patients showed both P300 amplitude reduction and latency prolongation, while only decreased frontal P300 amplitudes were found in carriers without FXTAS. These frontal P3 measures correlated with executive function and information processing speed. Interpretation The neuropsychological testing and ERP results of the present study provide support for the hypothesis that executive dysfunction is the primary cognitive impairment among older female premutation carriers both with and without FXTAS, although these deficits are relatively mild compared to those in FXTAS males. These findings are consistent with a synergistic effect of the premutation and aging on cognitive impairment among older female fragile X premutation carriers, even in those without FXTAS symptoms.