Neuropathological, clinical and molecular pathology in female fragile X premutation carriers with and without FXTAS

Abstract

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.

Cognitive Dysfunction in FMR1 Premutation Carriers

“…Of these four women, only three had received a clinical diagnosis of FXTAS. These results suggest that dementia is more common in female carriers than previously reported, and call into question the contribution of other neurodegenerative processes to the cognitive decline of premutation carriers [44]. Since the majority of studies have focused on male carriers as described in detail above, the sample of older women with FXTAS studied so far has been small.…”

“…Only a few women with FXTAS and dementia have been reported to date in the international literature, and in some cases, the etiology of their cognitive impairment was multifactorial [36,[39][40][41]. Interestingly, Tassone and colleagues found both AD lesions and FXTAS intranuclear inclusions on neuropathological exam in three women carriers with cognitive loss, while a fourth had Lewy bodies in addition to inclusions [44]. Of these four women, only three had received a clinical diagnosis of FXTAS.…”

Current research, diagnosis, and treatment of fragile X-associated tremor/ataxia syndrome

“…Dementia was found in 21-50% males with FXTAS (32,36). In females with FXTAS, however, dementia is far less common (36,37) and it has been reported in only a few cases (41)(42)(43)(44)(45). Females with FXTAS may also exhibit parkinsonism, although at a lower rate than in males with FXTAS (34).…”

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

“…This is not surprising since we have proven that a common denominator for those carriers of the premutation is compromise of the nervous system, and as such an impact on the psychological and psychiatric features of these patients may be expected. The main example of the psychiatric compromise of carriers occurs in those that develop FXTAS, which is not only a neurodegenerative disease as previously stated, but it is also considered to be a neuropsychiatric condition that often courses with dementia especially in male patients [42] which although previously believed to be rare in women with the premutation, increasing evidence is proving otherwise [43][44][45][46].…”