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. In this study, 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 showed 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 there is Alzheimer pathology and perhaps a synergistic effect on the progression of the disease may occur.

Figure 1

A. Intranuclear inclusions in pyramidal cells in CA3b of Case 2. B. Intranuclear inclusions in granule cells of the medial blade of the dentate gyrus of Case 2. C. Intranuclear infusions in pyramidal cells and neurons in the hilus of case 6. c. Inset, intranuclear inclusion in neuron and astrocyte in the white matter adjacent to layer VI of the frontal cortex of Case 6. D. Intranuclear inclusion in an astrocye in layer II if the frontal cortex of Case 1. d. Inset, granule cell from layer IV of the frontal cortex in Case 1. All plates are at 1000X magnification. Scale bar = 50μm.