Altered White Matter Organization in the TUBB3 E410K Syndrome

Cereb Cortex. 2019 Jul 22;29(8):3561-3576. doi: 10.1093/cercor/bhy231.


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).

MeSH terms

  • Adult
  • Age Factors
  • Anisotropy
  • Autism Spectrum Disorder / diagnostic imaging*
  • Autism Spectrum Disorder / genetics
  • Autism Spectrum Disorder / pathology
  • Autism Spectrum Disorder / physiopathology
  • Brain / diagnostic imaging
  • Brain / pathology
  • Case-Control Studies
  • Cerebral Cortex / diagnostic imaging*
  • Cerebral Cortex / pathology
  • Child
  • Corpus Callosum / diagnostic imaging*
  • Corpus Callosum / pathology
  • Diffusion Magnetic Resonance Imaging
  • Diffusion Tensor Imaging
  • Endophenotypes
  • Female
  • Fibrosis / diagnostic imaging
  • Fibrosis / genetics
  • Fibrosis / pathology
  • Fibrosis / physiopathology
  • Heterozygote
  • Humans
  • Intellectual Disability / diagnostic imaging*
  • Intellectual Disability / genetics
  • Intellectual Disability / pathology
  • Intellectual Disability / physiopathology
  • Kallmann Syndrome / diagnostic imaging
  • Kallmann Syndrome / genetics
  • Kallmann Syndrome / pathology
  • Kallmann Syndrome / physiopathology
  • Male
  • Mutation
  • Neural Pathways / diagnostic imaging
  • Neural Pathways / pathology
  • Neuropsychological Tests
  • Ophthalmoplegia / diagnostic imaging
  • Ophthalmoplegia / genetics
  • Ophthalmoplegia / pathology
  • Ophthalmoplegia / physiopathology
  • Organ Size
  • Pyramidal Tracts / diagnostic imaging*
  • Pyramidal Tracts / pathology
  • Syndrome
  • Tubulin / genetics*
  • White Matter / diagnostic imaging*
  • White Matter / pathology
  • Young Adult


  • TUBB3 protein, human
  • Tubulin

Supplementary concepts

  • Congenital Fibrosis of the Extraocular Muscles