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.

Keywords: TUBB3; TUBB3 E410K syndrome; arcuate fasciculus (AF); autism; cingulum (Cing); corpus callosum (CC); corticospinal tract (CST); diffusion imaging; dorsal language network (DLN); genetics; inferior fronto-occipital fasciculus (IFOF); inferior longitudinal fasciculus (ILF); intellectual disability, magnetic resonance imaging (MRI); medial lemniscus (ML); misguidance; structural connectivity; superior longitudinal fasciculus (SLF); tractography; uncinate fasciculus (UF); ventral language network (VLN).

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Figures

Figure 1.

Gyral-based FA values. Scatter plots of FA value for the connections between the first (short-range), second and third (middle-range), and fourth and higher (long-range) neighboring gyri in pediatric and adult subjects versus controls (*corrected P < 0.05). Pediatric subjects have significantly lower FA in middle to long-range connections compared with pediatric controls, while adult subjects show no significant differences compared with adult controls.

Figure 2.

FA values of major white matter tracts. Scatter plots of FA value for major white matter tracts in pediatric and adult groups (*corrected P < 0.05). FA values are significantly lower for CST, ML, CC, right DLN.ant and right DLN.post VLN.IFOF, and cingulate-reconstructed tracts in the pediatric subjects compared with controls, and in the CST, CC, DLN.ant, VLN.IFOF, and right ML-reconstructed tracts in the adult subjects compared with controls. Note that the DTI sequence was performed with b = 1000 s/mm2 in S1 and all of the pediatric controls. DTI was performed with b = 700 s/mm2 for S2–S7 and all of the adult controls. CST = corticospinal tract, ML = medial lemniscus, CC = corpus callosum, DLN.ant = anterior segment of the dorsal language network, DLN.post = posterior segment of the dorsal language network, VLN.ILF = inferior longitudinal fasciculus of the ventral language network, VLN.IFOF = inferior fronto-occipital fasciculus of the ventral language network, VLN.UF = uncinate fasciculus of the ventral language network, Cing = cingulum.

Figure 3.

FA color maps, CST, and ML. Each row represents images for a single individual with row 1: pediatric control (PC7); rows 2–5: pediatric subjects S1–S4; rows 6–8: adult subjects S5–S7; row 9: adult control (AC2). The pseudocolored fibers are overlaid on each individual’s coregistered sagittal MPRAGE shown in radiological convention in columns B–G. Column A: Axial FA color map of the midpons (typical radiological convention with left on the right and anterior at top of image), highlighting expected locations of pontine CST (bilateral anterior blue regions, anterior arrows in PC, column A) and pontine ML (bilateral posterior blue regions, posterior arrowheads in PC, column A). Note the variability in size and shape of the anterior and posterior blue regions in S1–S7 compared with controls. Color scheme represents the dominant direction of the principal eigenvector in each voxel; as per standard RGB convention for fiber direction, red corresponds to right/left, green corresponds to anterior posterior, and blue corresponds to superior/inferior. Column B: Fibers captured by one ROI placed in the left cerebral peduncle and another ROI in the ipsilateral anterior and posterior pons, anticipated to capture the left CST. Column C: Fibers captured by one ROI placed in the right cerebral peduncle and another ROI in the ipsilateral anterior and posterior pons, anticipated to capture the right CST. Note the variable CST reconstruction in subjects compared with controls in columns B and C. Column D: Fibers captured by an exclusion ROI placed in the left cerebral peduncle and an inclusion ROI placed in the ipsilateral anterior and posterior pons, anticipated to capture the left ML. Column E: Fibers captured by an exclusion ROI placed in the right cerebral peduncle and an inclusion ROI placed in the ipsilateral anterior and posterior pons, anticipated to capture the right ML. Column F: Fibers captured by two inclusions ROIs; one in the left cerebral peduncle and the other in the ipsilateral posterior pons. Column G: Fibers captured by two inclusions ROIs; one in the right cerebral peduncle and the other in the ipsilateral posterior pons. Note how in both columns F and G, there are no fibers captured in controls while subjects show abnormal tracts. See Supplementary Fig. 3A, B for pediatric and adult controls, respectively.

Figure 4.

Corpus Callosum (CC): Each row represents images for a single individual with row 1: pediatric control (PC1); rows 2–5: pediatric subjects S1–S4; rows 6–8: adult subjects S5–S7; row 9: adult control (AC2). The pseudocolored fibers are overlaid on each individual’s coregistered structural MPRAGE image presented in standard radiology convention in columns A and C. In column E, anterior is to the right. Column A: Axial view of five CC segments of equal length and psuedocolored as follows: green = anterior CC, turquoise = mid-anterior CC, red = central CC, dark blue = mid-posterior CC, yellow = posterior CC. Column B: Axial central segment of the CC from superior (left) and inferior (right) views, with ellipsoids showing orientation and organization of the fibers using standard RGB conventions for fiber direction. Column C: Left sagittal view of five pseudocolored CC segments as per column A. Column D: Sagittal view of the CC with anterior to the left and with ellipsoids showing orientation and organization of the fibers using standard RGB conventions for fiber direction. Column E: Right sagittal view of five pseudocolored CC segments as per columns A and C. Columns B and D created via 3D Slicer via the Slicer DMRI Project (dmri.slicer.org) (Norton et al. 2017). See Supplementary Fig. 4A,B for pediatric and adult controls, respectively.

Figure 5.

Dorsal Language Network (DLN). Each row represents images for a single individual with row 1: pediatric control (PC2); rows 2–5: pediatric subjects S1–S4; rows 6–8: adult subjects S5–S7; row 9: adult control (AC12). Column A: Coronal view of color FA maps at the level of the body of the CC (typical radiological convention with left on the right and anterior at top of image). Column B: Axial view of FA color maps at the level of the body of the CC. Note the absence of the DLN.long green region and smaller size of the DLN.ant green region in S1–S7 compared with controls. Color scheme represents the dominant direction of the principal eigenvector in each voxel; as per standard RGB convention for fiber direction, red corresponds to right/left, green corresponds to anterior posterior, and blue corresponds to superior/inferior. The pseudocolored fibers are overlaid on each individual’s structural MPRAGE image, presented in standard radiological convention in columns C and D, while in column E anterior is to the right. Column C: Axial view showing the reconstructed segments of the DLN bilaterally; anterior segment (DLN.ant; green); long segment (DLN.long; red); posterior segment (DLN.post; yellow). Column D: Sagittal view of the left hemisphere shows reconstructed segments of the left DLN. Column E: Sagittal view of the right hemisphere shows reconstructed segments of the right DLN. Note that in all subjects the DLN.long could not be reconstructed. See Supplementary Fig. 5A,B for pediatric and adult controls, respectively.

Figure 6.

Ventral Language Network (VLN). Each row represents images for a single individual with row 1: pediatric control (PC2); rows 2–5: pediatric subjects S1–S4; rows 6–8: adult subjects S5–S7; row 9: adult control (AC12). The pseudocolored fibers are overlaid on each individual’s’ structural MPRAGE image, presented in standard radiological convention in columns A and B, while in column C, anterior is to the right. Column A: Axial view showing the bilateral inferior longitudinal fasciculus (VLN.ILF; green), inferior fronto-occipital fasciculus (VLN.IFOF; red), and uncinate fasciculus (VLN.UF; yellow). Column B: Left hemisphere showing the VLN. Column C: Right hemisphere showing the VLN. Note that fibers are more disorganized and in most cases fewer in number in subjects compared with controls. See Supplementary Fig. 6A,B for pediatric and adult controls, respectively.

Figure 7.

Cingulum. Each row represents images for a single individual with row 1: pediatric control (PC2); rows 2–5: pediatric subjects S1–S4; rows 6–8: adult subjects S5–S7; row 9: adult control (AC12). The pseudocolored fibers are overlaid on each individual’s’ structural MPRAGE image, presented in standard radiological convention in columns A and B, while in column C, anterior is to the right. Column A: Axial view of the Cing bilaterally. Column B: Left hemisphere showing the Cing. Column C: Right hemisphere showing the Cing. Note that fibers are more disorganized and in most cases fewer in number in subjects compared with controls. See Supplementary Fig. 7A,B for pediatric and adult controls, respectively.