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 journalArticlepeer-review

21 Scopus citations


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
Issue number5
StatePublished - May 2018

Bibliographical note

Funding Information:
Additional Contributions: We thank the children and their families for their ongoing participation in this longitudinal study, as well as the numerous research assistant and volunteers who have worked on this project. Lisa Flake, MSW, Washington University in St Louis, assisted with data collection, K. Y. Truong, PhD, University of North Carolina at Chapel Hill, consulted on the statistical methods and approach, Rachel G. Smith, BA, University of North Carolina at Chapel Hill, and Clement Vachet, MS, previously at the University of Utah, developed the imaging processing pipelines. Lisa Flake, Rachel Smith, and Clement Vachet were research assistants on the IBIS project with salary paid from the National Institutes of Health grant supporting this project. K. Y. Truong was not compensated.

Funding Information:
Funding/Support: This work was supported by grants R01-HD059854 (Dr Hazlett), R01-HD055741 (Dr Piven), R01-HD055741-S1 (Dr Piven), P30-HD003110 (Dr Piven), and U54-EB005149 from the National Institutes of Health and Simons Foundation Autism Research Initiative grant 140209 from the Simons Foundation. Dr Swanson was supported by a Pathway to Independence Award (K99-MH108700) from the National Institute of Mental Health and a National Research Service Award (T32-HD40127) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Dr Wolff was supported by grant K01-MH101653from the National Institute of Mental Health.

Funding Information:
Group Information: The Infant Brain Imaging Study (IBIS) Network is a National Institutes of Health– funded Autism Center of Excellence project and consists of a consortium of 8 universities in the United States and Canada. Clinical Sites: University of North Carolina: Joseph Piven, MD (IBIS Network principal investigator), Heather C. Hazlett, PhD, and C. Chappell, MS; University of Washington: Stephen Dager, MD, Annette Estes, PhD, and Dennis Shaw, MD; Washington University in St Louis: Kelly N. Botteron, MD, Robert C. McKinstry, MD, PhD, John Constantino, MD, and John Pruett Jr, MD, PhD; The Children’s Hospital of Philadelphia: Robert T. Schultz, PhD, and Sarah Paterson, PhD; University of Alberta: Lonnie Zwaigenbaum, MD, MSc; University of Minnesota: Jed T. Elison, PhD, and Jason J. Wolff, PhD; Data Coordinating Center: Montreal Neurological Institute: Alan C. Evans, PhD, D. Louis Collins, PhD, G. Bruce Pike, PhD, Vladimir Fonov, PhD, Penelope Kostopoulos, PhD, and Samir Das, BSc; Image Processing Core: New York University: Guido Gerig, PhD; and University of North Carolina: Martin Styner, PhD; and Statistical Analysis Core: University of North Carolina: Hongbin Gu, PhD.

Publisher Copyright:
© 2018 American Medical Association.


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