Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP)

Authors

  • Doron Gothelf MD,

    1. Behavioral Neurogenetics Center, Child Psychiatry Department, Schneider Children's Medical Center of Israel, Petah Tiqwa
    2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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  • Joyce A. Furfaro PhD,

    1. Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA
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  • Fumiko Hoeft MD, PhD,

    1. Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA
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  • Mark A. Eckert PhD,

    1. Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC
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  • Scott S. Hall PhD,

    1. Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA
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  • Ruth O'Hara PhD,

    1. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA
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  • Heather W. Erba PhD,

    1. Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA
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  • Jessica Ringel BS,

    1. Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA
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  • Kiralee M. Hayashi BS,

    1. Laboratory of Neuroimaging, Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles
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  • Swetapadma Patnaik MS,

    1. Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA
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  • Brenda Golianu MD,

    1. Department of Anesthesia, Stanford University School of Medicine, Stanford, CA
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  • Helena C. Kraemer PhD,

    1. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA
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  • Paul M. Thompson PhD,

    1. Laboratory of Neuroimaging, Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles
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  • Joseph Piven MD,

    1. Department of Psychiatry, University of North Carolina, Chapel Hill, NC
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  • Allan L. Reiss MD

    Corresponding author
    1. Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA
    • Center for Interdisciplinary Brain Science, Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, 401 Quarry Road, Stanford, CA 94305-5795
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Abstract

Objective

To determine how neuroanatomic variation in children and adolescents with fragile X syndrome is linked to reduced levels of the fragile X mental retardation-1 protein and to aberrant cognition and behavior.

Methods

This study included 84 children and adolescents with the fragile X full mutation and 72 typically developing control subjects matched for age and sex. Brain morphology was assessed with volumetric, voxel-based, and surface-based modeling approaches. Intelligence quotient was evaluated with standard cognitive testing, whereas abnormal behaviors were measured with the Autism Behavior Checklist and the Aberrant Behavior Checklist.

Results

Significantly increased size of the caudate nucleus and decreased size of the posterior cerebellar vermis, amygdala, and superior temporal gyrus were present in the fragile X group. Subjects with fragile X also demonstrated an abnormal profile of cortical lobe volumes. A receiver operating characteristic analysis identified the combination of a large caudate with small posterior cerebellar vermis, amygdala, and superior temporal gyrus as distinguishing children with fragile X from control subjects with a high level of sensitivity and specificity. Large caudate and small posterior cerebellar vermis were associated with lower fragile X mental retardation protein levels and more pronounced cognitive deficits and aberrant behaviors.

Interpretation

Abnormal development of specific brain regions characterizes a neuroanatomic phenotype associated with fragile X syndrome and may mediate the effects of FMR1 gene mutations on the cognitive and behavioral features of the disorder. Fragile X syndrome provides a model for elucidating critical linkages among gene, brain, and cognition in children with serious neurodevelopmental disorders. Ann Neurol 2007

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