This work is dedicated to the memory of Matteo.
Neuropathological, clinical and molecular pathology in female fragile X premutation carriers with and without FXTAS
Article first published online: 6 APR 2012
© 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society
Genes, Brain and Behavior
Volume 11, Issue 5, pages 577–585, July 2012
How to Cite
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. and Hagerman, R. J. (2012), Neuropathological, clinical and molecular pathology in female fragile X premutation carriers with and without FXTAS. Genes, Brain and Behavior, 11: 577–585. doi: 10.1111/j.1601-183X.2012.00779.x
- Issue published online: 2 JUL 2012
- Article first published online: 6 APR 2012
- Accepted manuscript online: 30 MAR 2012 12:00AM EST
- Received 18 December 2011, revised 14 February 2012 and 2 March 2012, accepted for publication 5 March 2012
- Activation ratio;
- Alzheimer disease;
- FMR1 premutation;
- RNA toxicity
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.