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Development of White Matter Circuitry in Infants with Fragile X Syndrome

Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, NC, USA.
Publication Date:
JAMA Psychiatry
Volume Number:
Issue Number:
JAMA Psychiatry. 2018 May 1;75(5):505-13.
PubMed ID:
Appears in Collections:
U54 EB005149/EB/NIBIB NIH HHS/United States
P30 HD003110/HD/NICHD NIH HHS/United States
T32 HD040127/HD/NICHD NIH HHS/United States
K99 MH108700/MH/NIMH NIH HHS/United States
R01 HD059854/HD/NICHD NIH HHS/United States
L30 HD085276/HD/NICHD NIH HHS/United States
K01 MH101653/MH/NIMH NIH HHS/United States
R01 HD055741/HD/NICHD NIH HHS/United States
Generated Citation:
Swanson M.R., Wolff J.J., Shen M.D., Styner M., Estes A., Gerig G., McKinstry R.C., Botteron K.N., Piven J., Hazlett H.C. Development of White Matter Circuitry in Infants with Fragile X Syndrome. JAMA Psychiatry. 2018 May 1;75(5):505-13. PMID: 29617515. PMCID: PMC6026861.
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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.