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

• Published in: Genes, brain and behavior Vol. 11; no. 5; pp. 577 - 585
• Main Authors: Tassone, F., Greco, C. M., Hunsaker, M. R., Seritan, A. L., Berman, R. F., Gane, L. W., Jacquemont, S., Basuta, K., Jin, L.‐W., Hagerman, P. J., Hagerman, R. J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2012; John Wiley & Sons, Inc
• Subjects: Activation ratio; Aged; Aged, 80 and over; Alleles; Alzheimer disease; Alzheimer's disease; Amyloid; Ataxia; Ataxia - genetics; Ataxia - pathology; Autonomic nervous system; Basal ganglia; Brain - pathology; Cancer; Central nervous system diseases; Cerebellum; Cognitive ability; Dementia - genetics; Dementia - pathology; Dementia disorders; Female; Females; FMR1 premutation; fragile X mental retardation protein; Fragile X Mental Retardation Protein - genetics; Fragile X syndrome; Fragile X Syndrome - genetics; Fragile X Syndrome - pathology; FXTAS; gait; Humans; Inclusion bodies; Intranuclear Inclusion Bodies - genetics; Intranuclear Inclusion Bodies - pathology; Lewy bodies; Mental retardation; Middle Aged; Motivation; Movement disorders; Neurodegenerative diseases; Neurofibrillary tangles; Neurons - pathology; Pathology; Plaques; RNA toxicity; Syndrome; tremor; Tremor - genetics; Tremor - pathology
• ISSN: 1601-1848; 1601-183X; 1601-183X
• DOI: 10.1111/j.1601-183X.2012.00779.x

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.