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Brain Advance Access published online on December 12, 2006
Brain, doi:10.1093/brain/awl338
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© The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received June 1, 2006
Revised September 18, 2006
Accepted November 7, 2006

Article

Amygdala dysfunction in men with the fragile X premutation

David Hessl 1 *, Susan Rivera 2, Kami Koldewyn 3, Lisa Cordeiro 4, John Adams 4, Flora Tassone 5, Paul J. Hagerman 5, and Randi J. Hagerman 6

1 Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California-Davis, Medical Center, Sacramento, CA, USA; Department of Psychiatry and Behavioral Sciences, University of California-Davis, Medical Center, Sacramento, CA, USA
2 Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California-Davis, Medical Center, Sacramento, CA, USA; Department of Psychology, University of California-Davis, Davis, CA, USA
3 Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California-Davis, Medical Center, Sacramento, CA, USA; Center for Neuroscience, University of California-Davis, Davis, CA, USA
4 Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California-Davis, Medical Center, Sacramento, CA, USA
5 Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California-Davis, Medical Center, Sacramento, CA, USA; Department of Biochemistry and Molecular Medicine, University of California-Davis, School of Medicine, Davis, CA, USA
6 Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, University of California-Davis, Medical Center, Sacramento, CA, USA; Department of Pediatrics, University of California-Davis, Medical Center, Sacramento, CA, USA

* To whom correspondence should be addressed.
David Hessl, E-mail: david.hessl{at}ucdmc.ucdavis.edu


  Abstract

Premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are associated with autism spectrum disorder in childhood, premature ovarian failure, and the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS, and perhaps the other clinical presentations among carriers, are thought to be due to toxic gain-of-function of elevated levels of the expanded-repeat FMR1 mRNA. Previous structural MRI studies have implicated the amygdala as a potential site of dysfunction underlying social deficits and/or risk for FXTAS. As a preliminary investigation of this possible association, adult males with the premutation, and male controls matched for IQ, age and education, completed three protocols that probe amygdala and sympathetic function: (i) a functional MRI paradigm that measures brain response to fearful faces; (ii) a fear-potentiated startle paradigm that differentiates responses to fearful faces and fearful non-social images and (iii) measurement of skin conductance level during a brief social encounter. Compared with controls, men with the FMR1 premutation demonstrated diminished brain activation in the amygdala and several brain areas that mediate social cognition while viewing fearful faces. The reduced amygdala activation in the premutation group was significantly associated with self-report of psychological symptoms on the Symptom Checklist-90--Revised. These men also displayed a lack of startle potentiation while viewing fearful faces and showed reduced skin conductance response when greeting an unfamiliar experimenter in comparison with the control group. The current findings may be related to social cognition deficits reported previously in children and adults with the premutation. The aetiology for this dysfunction may be elevated FMR1 mRNA or reduced FMR1 protein that occurs in carriers with higher premutation CGG repeat alleles.

Keywords: FMR1 gene; FXTAS; fragile X; face perception; social cognition.
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