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Am J Med Genet A. 2009 Mar;149A(3):403-7. doi: 10.1002/ajmg.a.32697.

Cholinergic dysfunction in fragile X syndrome and potential intervention: a preliminary 1H MRS study.

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Center for Interdisciplinary Brain Sciences Research, Stanford University School of Medicine, Stanford, California 94305-5795, USA.


Males with fragile X syndrome (FRAX) are at risk for significant cognitive and behavioral deficits, particularly those involving executive prefrontal systems. Disruption of the cholinergic system secondary to fragile X mental retardation protein deficiency may contribute to the cognitive-behavioral impairments associated with fragile X. We measured choline in the dorsolateral prefrontal cortex of nine males with FRAX and 9 age-matched typically developing controls using (1)H magnetic resonance spectroscopy. Right choline/creatine was significantly reduced in the fragile X group compared to controls. In controls, both left and right choline was significantly positively correlated with intelligence and age was significantly negatively correlated with left choline. There were no correlations in the fragile X group. Subjects with FRAX participating in a pilot open-label trial of donepezil, an acetylcholinesterase inhibitor, demonstrated significantly improved cognitive-behavioral function. Studies utilizing biochemical neuroimaging techniques such as these have the potential to significantly impact the design of treatment strategies for FRAX and other genetic disorders by helping identify neurochemical targets for intervention as well as serving as metrics for treatment efficacy.

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