Structural brain abnormalities in a single gene disorder associated with epilepsy, language impairment and intellectual disability

Abstract

Childhood speech and language deficits are highly prevalent and are a common feature of neurodevelopmental disorders. However, it is difficult to investigate the underlying causal pathways because many diagnostic groups have a heterogeneous aetiology. Studying disorders with a shared genetic cause and shared cognitive deficits can provide crucial insight into the cellular mechanisms and neural systems that give rise to those impairments. The current study investigated structural brain differences of individuals with mutations in ZDHHC9, which is associated with a specific neurodevelopmental phenotype including prominent speech and language impairments and intellectual disability. We used multiple structural neuroimaging methods to characterise neuroanatomy in this group, and observed bilateral reductions in cortical thickness in areas surrounding the temporo-parietal junction, parietal lobule, and inferior frontal lobe, and decreased microstructural integrity of cortical, subcortical-cortical, and interhemispheric white matter projections. These findings are compared to reports for other genetic groups and genetically heterogeneous disorders with a similar presentation. Overlap in the neuroanatomical phenotype suggests a common pathway that particularly affects the development of temporo-parietal and inferior frontal areas, and their connections.

Keywords: Cognitive development; Cortical morphology; Diffusion-weighted imaging; Human genetics; Language.

Fig. 1

Vertex-wise analysis of cortical volume and thickness comparing the ZDHCC9 and control group. Statistical analysis was based on a paired t-tests and false discovery rate adjustment for multiple comparison including both hemispheres. Decreased cortical thickness was found in the ZDHHC9 group, particularly in areas surrounding the temporo-parietal junctions and parietal lobule.

Fig. 2

Overview of tract-based spatial statistics (TBSS) results comparing fractional anisotropy (FA) between patients with ZDHHC9 mutation and typical controls adjusted for participant age. Results are presented superimposed on the T1-weighted MNI152 brain at 1 mm³ resolution. The top figure shows significant reductions in FA on p < 0.05 significance level in the ZDHHC9 case group compared to the control group are shown in red. The bottom rows show significant increases in MD and RD in the ZDHHC9 case group. Green lines show the location of the mean FA skeleton. The numbers indicate the axial position with reference to the MNI coordinate system. Annotations highlight key white matter structures. Abbreviations: Arc: arcuate fasciculus, CC: corpus callosum, Cing: cingulate, CST: cortico-spinal tract, IC: internal capsule, ILF: inferior longitudinal fasciculus, Fx: Fornix, SLF: superior longitudinal fasciculus, Unc: Uncinate fasciculus. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Visualisation of projections of the corpus callosum (cc) in segments in the Hofer and Frahm (2006) parcellation scheme for a control participant. Projections of the anterior segment of the cc mainly contain fibres of the prefrontal cortex. The second segment consists of fibres crossing between premotor and supplementary motor cortex. The third segment holds motor cortex projections. The fourth segment is made up of fibres projecting to sensory areas of the parietal lobe. The most posterior segments contain fibres of the parietal, temporal, and occipital lobe (Hofer and Frahm, 2006).

Fig. 4

Visualisation of thalamic projections to cortical target areas. Projections from the thalamus to frontal, pre-central, post-central, parietal, temporal, and occipital cortical target areas were distinguished. ROIs were mutually exclusive, i.e. pre-central projections were not included in frontal projections, and post-central projections were not included in the parietal ones.

Fig. 5

Visualisation of tractography reconstruction of the arcuate fasciculus (AF), cortico-spinal tract (CST), and uncinate fasciculus (UF) in the left hemisphere for a representative participant in the control group.