Altered White Matter Organization in the TUBB3 E410K Syndrome

Abstract

Seven unrelated individuals (four pediatric, three adults) with the TUBB3 E410K syndrome, harboring identical de novo heterozygous TUBB3 c.1228 G>A mutations, underwent neuropsychological testing and neuroimaging. Despite the absence of cortical malformations, they have intellectual and social disabilities. To search for potential etiologies for these deficits, we compared their brain's structural and white matter organization to 22 controls using structural and diffusion magnetic resonance imaging. Diffusion images were processed to calculate fractional anisotropy (FA) and perform tract reconstructions. Cortical parcellation-based network analysis and gyral topology-based FA analyses were performed. Major interhemispheric, projection and intrahemispheric tracts were manually segmented. Subjects had decreased corpus callosum volume and decreased network efficiency. While only pediatric subjects had diffuse decreases in FA predominantly affecting mid- and long-range tracts, only adult subjects had white matter volume loss associated with decreased cortical surface area. All subjects showed aberrant corticospinal tract trajectory and bilateral absence of the dorsal language network long segment. Furthermore, pediatric subjects had more tracts with decreased FA compared with controls than did adult subjects. These findings define a TUBB3 E410K neuroimaging endophenotype and lead to the hypothesis that the age-related changes are due to microscopic intrahemispheric misguided axons that are pruned during maturation.

Tractography of the Cerebellar Peduncles in Second- and Third-Trimester Fetuses

“…32,33 Tractography of the cerebellar peduncles and other posterior fossa tracts could also help in the identification of a variety of axonal guidance disorders (eg, tubulinopathies, pontine tegmental cap dysplasia), which are known to harbor aberrations in white matter connections. 34,35 Tractography could also improve our understanding of the emerging abnormalities in the fetal cerebellum in disorders such as congenital heart disease and intrauterine growth restriction, which are known to impact cerebellar development. 6,36 Even though the existing literature focuses on volumetric analysis of these structures, the distinct physiology of SCP and MCP could provide insights into the specific networks that have been affected, such is the case of longterm follow-up of white matter injury of prematurity, in which abnormalities in the SCP correlate with motor outcomes and abnormalities in the MCP correlate with a lower intelligence quotient at 7 years of age.…”

Identification of neuronal structures and pathways corresponding to clinical functioning in galactosemia

“…Diffusion Toolkit (trackvis.org/dtk/) was used to reconstruct the white matter tracts using Diffusion Tensor Imaging (DTI) imaging model and the Fiber Assignment by Continuous Tracking (FACT) reconstruction algorithm, with an angle threshold of 45°, no FA threshold. TrackVis (trackvis.org) was used to create the fiber pathways with the manual placement of ROIs, as explained in detail in our previous work, 44 using color‐FA, FA, and ADC maps and T1‐to‐b0 anatomical images to ensure tract segmentation accuracy 44 . We investigated white matter abnormalities in: corpus callosum (Figures 1A and S1), bilateral cingulum (Figures 1B and S2), bilateral corticospinal tracts (CST) (Figures 1C and S3), bilateral dorsal and ventral language networks (VLN).…”

Brain Characteristics Noted Prior to and Following Cranial Orthotic Treatment

“…To create the posterior segment (yellow), an ROI was placed posterior to ROI’s for the long and anterior segments in the axial plane. 20,24 All DLN tracts were reconstructed bilaterally.…”

“…13 We also added an exclusion mask to remove corpus callosum fibers that run in close proximity to the cingulum. 20 Cingulum tracts were reconstructed in both hemispheres.…”

“…To create the posterior segment (yellow), an ROI was placed posterior to ROI's for the long and anterior segments in the axial plane. 20,24 All DLN tracts were reconstructed bilaterally. Ventral Language Network (VLN): To segment the IFOF (red), an ROI was placed in the sagittal plane to identify the main fiber pathway.…”