Cognitive Dysfunction in FMR1 Premutation Carriers

Abstract

Premutation carriers of the fragile X mental retardation gene (especially men) older than 50 may develop a neurodegenerative disease, the fragile X-associated tremor/ataxia syndrome (FXTAS). Carriers may present with varied cognitive impairments. Attention, working memory, declarative and procedural learning, information processing speed, and recall are among the cognitive domains affected. Executive dysfunction is a prominent deficit, which has been demonstrated mostly in men with FXTAS. In more advanced stages of FXTAS, both men and women may develop a mixed cortical-subcortical dementia, manifested by psychomotor slowing and deficits in attention, retrieval, recall, visuospatial skills, occasional apraxia, as well as overt personality changes. Studies have shown dementia rates as high as 37-42% in older men with FXTAS, although more research is needed to understand the prevalence and risk factors of dementia in women with FXTAS. Neuropsychiatric symptoms are common and reflect the dysfunction of underlying frontal-subcortical neural circuits, along with components of the cerebellar cognitive affective syndrome. These include labile or depressed mood, anxiety, disinhibition, impulsivity, and (rarely) psychotic symptoms. In this paper we review the information available to date regarding the prevalence and clinical picture of FXTAS dementia. Differential diagnosis may be difficult, given overlapping motor and non-motor signs with several other neurodegenerative diseases. Anecdotal response to cholinesterase inhibitors and memantine has been reported, while symptomatic treatments can address the neuropsychiatric manifestations of FXTAS dementia.

Prevalence and predictors of subjective memory complaints in adult male carriers of the FMR1 premutation

“…These findings are in contrast to previous research using the same measure of memory function in larger samples Grigsby et al, 2008), where significant group differences in objective memory performance were observed when comparing PM males with and without FXTAS to controls. It is likely that the small number of PM males in the FXTAS group (n = 7) resulted in insufficient power to detect significant group effects in the current study, particularly given the inter-individual variability in cognitive features in PM males with FXTAS Seritan, Cogswell, & Grigsby, 2013;Seritan et al, 2008).…”

The cognitive neuropsychological phenotype of carriers of the FMR1 premutation

“…On the Mini Mental State Exam [9], a measure of general mental status, the difference in mean scores of FXTAS patients and controls was statistically, but not clinically, significant (27.6 vs 29.2). Nevertheless, a subset of individuals with FXTAS - most with advanced disease - demonstrates frank dementia [10,11]. Performance on measures of declarative memory is impaired, likely reflecting the effects of executive dysfunction (that is, problems with active learning and active retrieval) rather than a primary memory disorder.…”

Towards An Understanding of Neuropsychiatric Manifestations In Fragile X Premutation Carriers

“…This pattern of deficits indicates that FXTAS dementia is a mixed cortical-subcortical dementias, similarly to corticobasal degeneration and dementia with Lewy bodies, which also have parkinsonism as a prominent feature [65,71]. Due to the overlap of clinical signs and symptoms and the limited body of knowledge available to date, FXTAS dementia is difficult to distinguish from other dementias with movement disorders [71].…”

“…Due to the overlap of clinical signs and symptoms and the limited body of knowledge available to date, FXTAS dementia is difficult to distinguish from other dementias with movement disorders [71]. FXTAS may be mistaken for Parkinson’s disease (PD) or spinocerebellar ataxia (SCA) in some cases, although studies have identified the FMR1 premutation in less than 1% of men clinically diagnosed with multiple system atrophy, PD or SCA [72–74].…”