Development of white matter circuitry in infants with fragile x syndrome

Meghan R. Swanson, Jason J. Wolff, Mark D. Shen, Martin Styner, Annette Estes, Guido Gerig, Robert C. McKinstry, Kelly N. Botteron, Joseph Piven, Heather C. Hazlett

    Research output: Contribution to journalArticle

    Abstract

    IMPORTANCE Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder and the most common inherited cause of intellectual disability in males. However, there are no published data on brain development in children with FXS during infancy. OBJECTIVE To characterize the development of white matter at ages 6, 12, and 24 months in infants with FXS compared with that of typically developing controls. DESIGN, SETTING, AND PARTICIPANTS Longitudinal behavioral and brain imaging datawere collected at 1 or more time points from 27 infants with FXS and 73 typically developing controls between August 1, 2008, and June 14, 2016, at 2 academic medical centers. Infants in the control group had no first- or second-degree relatives with intellectual or psychiatric disorders, including FXS and autism spectrum disorder. MAIN OUTCOMES AND MEASURES Nineteen major white matter pathwayswere defined in common atlas space based on anatomically informed methods. Diffusion parameters, including fractional anisotropy, were compared between groups using linear mixed effects modeling. Fiber pathways showing group differences were subsequently examined in association with direct measures of verbal and nonverbal development. RESULTS There were significant differences in the development of 12 of 19 fiber tracts between the 27 infants with FXS (22 boys and 5 girls) and the 73 infants in the control group (46 boys and 27 girls), with lower fractional anisotropy in bilateral subcortical-frontal, occipital-temporal, temporal-frontal, and cerebellar-thalamic pathways, as well as 4 of 6 subdivisions of the corpus callosum. For all 12 of these pathways, there were significant main effects between groups but not for the interaction of age × group, indicating that lower fractional anisotropy was present and stable from age 6 months in infants with FXS. Lower fractional anisotropy values in the uncinate fasciculi were correlated with lower nonverbal developmental quotient in the FXS group (left uncinate, F = 10.06; false discovery rate-corrected P = .03; right uncinate, F = 21.8; P = .004). CONCLUSIONS AND RELEVANCE The results substantiate in human infants the essential role of fragile X gene expression in the early development of white matter. The findings also suggest that the neurodevelopmental effects of FXS are well established at 6 months of age.

    Original languageEnglish (US)
    Pages (from-to)505-513
    Number of pages9
    JournalJAMA Psychiatry
    Volume75
    Issue number5
    DOIs
    StatePublished - May 1 2018

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    Fragile X Syndrome
    Anisotropy
    White Matter
    Control Groups
    Inborn Genetic Diseases
    Atlases
    Corpus Callosum
    Child Development
    Neuroimaging
    Intellectual Disability
    Psychiatry
    Age Groups
    Gene Expression

    ASJC Scopus subject areas

    • Psychiatry and Mental health

    Cite this

    Swanson, M. R., Wolff, J. J., Shen, M. D., Styner, M., Estes, A., Gerig, G., ... Hazlett, H. C. (2018). Development of white matter circuitry in infants with fragile x syndrome. JAMA Psychiatry, 75(5), 505-513. https://doi.org/10.1001/jamapsychiatry.2018.0180

    Development of white matter circuitry in infants with fragile x syndrome. / Swanson, Meghan R.; Wolff, Jason J.; Shen, Mark D.; Styner, Martin; Estes, Annette; Gerig, Guido; McKinstry, Robert C.; Botteron, Kelly N.; Piven, Joseph; Hazlett, Heather C.

    In: JAMA Psychiatry, Vol. 75, No. 5, 01.05.2018, p. 505-513.

    Research output: Contribution to journalArticle

    Swanson, MR, Wolff, JJ, Shen, MD, Styner, M, Estes, A, Gerig, G, McKinstry, RC, Botteron, KN, Piven, J & Hazlett, HC 2018, 'Development of white matter circuitry in infants with fragile x syndrome', JAMA Psychiatry, vol. 75, no. 5, pp. 505-513. https://doi.org/10.1001/jamapsychiatry.2018.0180
    Swanson MR, Wolff JJ, Shen MD, Styner M, Estes A, Gerig G et al. Development of white matter circuitry in infants with fragile x syndrome. JAMA Psychiatry. 2018 May 1;75(5):505-513. https://doi.org/10.1001/jamapsychiatry.2018.0180
    Swanson, Meghan R. ; Wolff, Jason J. ; Shen, Mark D. ; Styner, Martin ; Estes, Annette ; Gerig, Guido ; McKinstry, Robert C. ; Botteron, Kelly N. ; Piven, Joseph ; Hazlett, Heather C. / Development of white matter circuitry in infants with fragile x syndrome. In: JAMA Psychiatry. 2018 ; Vol. 75, No. 5. pp. 505-513.
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    abstract = "IMPORTANCE Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder and the most common inherited cause of intellectual disability in males. However, there are no published data on brain development in children with FXS during infancy. OBJECTIVE To characterize the development of white matter at ages 6, 12, and 24 months in infants with FXS compared with that of typically developing controls. DESIGN, SETTING, AND PARTICIPANTS Longitudinal behavioral and brain imaging datawere collected at 1 or more time points from 27 infants with FXS and 73 typically developing controls between August 1, 2008, and June 14, 2016, at 2 academic medical centers. Infants in the control group had no first- or second-degree relatives with intellectual or psychiatric disorders, including FXS and autism spectrum disorder. MAIN OUTCOMES AND MEASURES Nineteen major white matter pathwayswere defined in common atlas space based on anatomically informed methods. Diffusion parameters, including fractional anisotropy, were compared between groups using linear mixed effects modeling. Fiber pathways showing group differences were subsequently examined in association with direct measures of verbal and nonverbal development. RESULTS There were significant differences in the development of 12 of 19 fiber tracts between the 27 infants with FXS (22 boys and 5 girls) and the 73 infants in the control group (46 boys and 27 girls), with lower fractional anisotropy in bilateral subcortical-frontal, occipital-temporal, temporal-frontal, and cerebellar-thalamic pathways, as well as 4 of 6 subdivisions of the corpus callosum. For all 12 of these pathways, there were significant main effects between groups but not for the interaction of age × group, indicating that lower fractional anisotropy was present and stable from age 6 months in infants with FXS. Lower fractional anisotropy values in the uncinate fasciculi were correlated with lower nonverbal developmental quotient in the FXS group (left uncinate, F = 10.06; false discovery rate-corrected P = .03; right uncinate, F = 21.8; P = .004). CONCLUSIONS AND RELEVANCE The results substantiate in human infants the essential role of fragile X gene expression in the early development of white matter. The findings also suggest that the neurodevelopmental effects of FXS are well established at 6 months of age.",
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    AU - Wolff, Jason J.

    AU - Shen, Mark D.

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    AU - Estes, Annette

    AU - Gerig, Guido

    AU - McKinstry, Robert C.

    AU - Botteron, Kelly N.

    AU - Piven, Joseph

    AU - Hazlett, Heather C.

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    N2 - IMPORTANCE Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder and the most common inherited cause of intellectual disability in males. However, there are no published data on brain development in children with FXS during infancy. OBJECTIVE To characterize the development of white matter at ages 6, 12, and 24 months in infants with FXS compared with that of typically developing controls. DESIGN, SETTING, AND PARTICIPANTS Longitudinal behavioral and brain imaging datawere collected at 1 or more time points from 27 infants with FXS and 73 typically developing controls between August 1, 2008, and June 14, 2016, at 2 academic medical centers. Infants in the control group had no first- or second-degree relatives with intellectual or psychiatric disorders, including FXS and autism spectrum disorder. MAIN OUTCOMES AND MEASURES Nineteen major white matter pathwayswere defined in common atlas space based on anatomically informed methods. Diffusion parameters, including fractional anisotropy, were compared between groups using linear mixed effects modeling. Fiber pathways showing group differences were subsequently examined in association with direct measures of verbal and nonverbal development. RESULTS There were significant differences in the development of 12 of 19 fiber tracts between the 27 infants with FXS (22 boys and 5 girls) and the 73 infants in the control group (46 boys and 27 girls), with lower fractional anisotropy in bilateral subcortical-frontal, occipital-temporal, temporal-frontal, and cerebellar-thalamic pathways, as well as 4 of 6 subdivisions of the corpus callosum. For all 12 of these pathways, there were significant main effects between groups but not for the interaction of age × group, indicating that lower fractional anisotropy was present and stable from age 6 months in infants with FXS. Lower fractional anisotropy values in the uncinate fasciculi were correlated with lower nonverbal developmental quotient in the FXS group (left uncinate, F = 10.06; false discovery rate-corrected P = .03; right uncinate, F = 21.8; P = .004). CONCLUSIONS AND RELEVANCE The results substantiate in human infants the essential role of fragile X gene expression in the early development of white matter. The findings also suggest that the neurodevelopmental effects of FXS are well established at 6 months of age.

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