Background
The fragile X premutation provides a unique opportunity for the study of genetic and
brain mechanisms of behavior and cognition in the context of neurodevelopment and
neurodegeneration. Although the neurodegenerative phenotype, fragile X-associated
tremor/ataxia syndrome, is well described, evidence of a causal link between the premutation
and psychiatric disorder earlier in life, clear delineation of a behavioral/cognitive
phenotype, and characterization of the physiological basis of observed symptoms have
been elusive.
Methods
We completed functional magnetic resonance imaging targeting the amygdala with an
emotion-matching task and concurrent infrared eye tracking, FMR1 molecular genetic testing, and neuropsychological assessment in 23 men with the premutation
(mean age = 32.9 years) and 25 male control subjects (mean age = 30.1 years).
Results
Premutation carriers had significantly smaller left and right amygdala volume and
reduced right amygdala activation during the task relative to control subjects. Although
both elevated FMR1 messenger RNA and reduced fragile X mental retardation protein (FMRP) were associated
with the reduced activation, multiple regression analysis suggested that reduced FMRP
is the primary factor. Premutation carriers also had higher ratings of autism spectrum
symptoms than control subjects, which were associated with the reduced amygdala response.
Conclusions
Although prior studies have emphasized a toxic gain-of-function effect of elevated
messenger RNA associated with the premutation, the current results point to the role
of reduced FMRP in alterations of brain activity and behavior.
Key Words
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Article info
Publication history
Published online: July 25, 2011
Accepted:
May 27,
2011
Received in revised form:
April 15,
2011
Received:
October 12,
2010
Identification
Copyright
© 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
