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Original Investigation
May 2018

Development of White Matter Circuitry in Infants With Fragile X Syndrome

Author Affiliations
  • 1Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill
  • 2Department of Educational Psychology, University of Minnesota, Minneapolis
  • 3Department of Psychiatry, University of North Carolina at Chapel Hill
  • 4Department of Computer Science, University of North Carolina at Chapel Hill
  • 5Department of Speech and Hearing Sciences, University of Washington, Seattle
  • 6Department of Computer Science and Engineering, New York University, Brooklyn
  • 7Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, Missouri
  • 8Department of Psychiatry, Washington University in St Louis, St Louis, Missouri
  • 9Department of Radiology, Washington University in St Louis, St Louis, Missouri
JAMA Psychiatry. 2018;75(5):505-513. doi:10.1001/jamapsychiatry.2018.0180
Key Points

Question  Is white matter development altered in infants with fragile X syndrome?

Findings  In this longitudinal imaging study of 27 infants with fragile X syndrome and 73 typically developing control infants, 12 of 19 major white matter tracts investigated were significantly diminished in infants with fragile X syndrome compared with controls.

Meaning  The effects of fragile X gene expression on the early development of white matter structural connectivity are well established at 6 months of age.

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 data were 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 pathways were 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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