Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes

Abstract

The corpus callosum is the largest fibre tract in the brain, connecting the two cerebral hemispheres, and thereby facilitating the integration of motor and sensory information from the two sides of the body as well as influencing higher cognition associated with executive function, social interaction and language. Agenesis of the corpus callosum is a common brain malformation that can occur either in isolation or in association with congenital syndromes. Understanding the causes of this condition will help improve our knowledge of the critical brain developmental mechanisms required for wiring the brain and provide potential avenues for therapies for callosal agenesis or related neurodevelopmental disorders. Improved genetic studies combined with mouse models and neuroimaging have rapidly expanded the diverse collection of copy number variations and single gene mutations associated with callosal agenesis. At the same time, advances in our understanding of the developmental mechanisms involved in corpus callosum formation have provided insights into the possible causes of these disorders. This review provides the first comprehensive classification of the clinical and genetic features of syndromes associated with callosal agenesis, and provides a genetic and developmental framework for the interpretation of future research that will guide the next advances in the field.

Keywords: axon guidance; corpus callosum; midline patterning; neurogenesis; neuronal specification.

© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Figures

Figure 1

T1-weighted sagittal MRI scans showing the structure of the normal human corpus callosum in the full-term infant (A), 8-month-old (B), 2-year-old (C), 8-year-old (D) and adult (E). (A) At birth, the corpus callosum has assumed its general shape but is thinner throughout. The thickness of the corpus callosum (vertical dimension) increases generally throughout childhood and adolescence. Growth in the anterior sections is most pronounced within the first 10 years of life (compare C with D), and posterior growth predominates during adolescence (compare D with E). There is also marked interindividual variation in corpus callosum size and shape. (E) Normal adult corpus callosum, showing subdivisions established by Witelson (1989). The corpus callosum is initially divided into genu, rostrum, body and splenium. The body can be further subdivided into the isthmus, and the anterior, middle and posterior segments. RB = rostral body; AMB = anterior midbody; PMB = posterior midbody; Is = isthmus.

Figure 2

Neuroanatomical features revealed by T1-weighted midsagittal and coronal MRI in patients with corpus callosum abnormalities. (A and D) Patient with complete ACC associated with dorsal expansion of the third ventricle (asterisk), absence of the cingulate gyrus and sulcus, and absence of the septum pellucidum. (B and E) Patient with partial ACC; the splenium is absent and the rostrum is not fully formed (arrows). In addition, the leaves of the septum pellucidum are unfused (E; arrowheads). (C and F) Patient with hypoplasia of the corpus callosum. All segments are present but are diffusely thinned; there is also markedly reduced cerebral white matter volume (F).

Figure 3

T1-weighted midsagittal MRI and diffusion tensor imaging tractography of two patients with partial ACC (pACC) and a normal corpus callosum control. (A, C and F) T1-weighted midsagittal MRI scans. (B, D and G) High-angular-resolution diffusion imaging. Arrows indicate callosal fragments present in partial patients with ACC. (E and H) Q-ball tractography of partial patients with ACC reveals callosal connections between homotopic and heterotopic cortical regions. Homotopic connections between anterior frontal lobes are conserved in both partial patients with ACC (blue streamlines in E and H; orange streamlines in H), but the degree of temporal and occipital connectivity varies. Both patients also show ‘sigmoid bundles’ (yellow streamlines in E and H), which connect the anterior frontal lobe with the contralateral parieto-occipital region. Images adapted from Wahl et al. (2009).

Figure 4

Processes underpinning midline patterning in the human foetal brain extrapolated from studies in mouse. Initial expression of the morphogen FGF8 at the midline is necessary for early forebrain patterning, and subsequent development of the commissural plate through which all forebrain commissures pass. The commissural plate can be divided molecularly into four distinct subdomains, each specified by midline patterning molecules that likely act downstream of FGF8. Each forebrain commissure correlates anatomically with a specific subdomain. The corpus callosum (CC) passes through a domain of EMX1 and NFIA expression; the hippocampal commissure (HC) passes through domains expressing NFIA, ZIC2 and SIX3, and the anterior commissure (AC) passes through a SIX3-expressing domain in the septum. Sagittal section at 13 weeks gestation adapted from Rakic and Yakovlev (1968).

Figure 5

Processes extrapolated from mouse studies necessary for specification of callosal neurons, correct guidance of axons across the midline, and target identification in the contralateral cortex. Midline zipper glia develop in the septum and may play a role in fusion of the midline, which is correlated with corpus callosum development. As axons reach the midline, they encounter and must correctly interpret multiple attractive and repulsive guidance cues expressed by the glial wedge and indusium griseum. The first axons to cross the midline arise from the cingulate cortex, and these pioneering neurons appear to be necessary for the subsequent crossing of the majority of callosal axons, arising from the neocortex (A). Callosal neurons originate from layers I, II/III, V and VI of the cortex. However, the layer that a neuron resides in is not sufficient for specification as a callosally projecting neuron, and callosal neuron identity seems to coincide with expression of the transcription factor SATB2. These neurons project an axon radially towards the intermediate zone, which must then decide to turn medially rather than laterally (B). Once axons reach the contralateral hemisphere, they must recognize their target area and synapse with target neurons, presumably through molecular-recognition and activity-dependent mechanisms (C). Exuberant axonal growth continues after birth and is accompanied by axonal pruning which continues throughout childhood and adolescence. SVZ = subventricular zone; VZ = ventricular zone.

Figure 6

Major mechanisms underlying neurogenesis in the telencephalon relevant to ACC in humans. Many molecules involved in neurogenesis have multiple functions, and genetic mutations can therefore result in complex neurodevelopmental disorders. Many midline patterning genes functionally interact with primary cilia, and mutations in these genes give rise to a group of overlapping syndromes termed ‘ciliopathies’, which can feature ACC. Genes in red are associated with a human syndrome; genes in blue have a mouse model with ACC but have not yet been associated with a human ACC syndrome, and genes in grey (ligands in black) have not been implicated in either human or mouse ACC.

Figure 7

Major mechanisms that potentially underlie guidance of callosal axons in humans. Guidance receptors are expressed on the growth cone of commissural axons, and when bound to their ligand/s, influence microtubule and actin dynamics through second messengers including RHOA, RAC1 and CDC42. Some guidance receptors, such as DCC, have multiple ligands, and the effects of receptor activation depend on the bound ligand. Whereas most ligands are secreted from midline glial populations into the surrounding extracellular matrix, ephrin ligands are membrane-bound and can initiate reverse signalling. The effects of ephrin receptors vary depending on the subtype of receptor activated, and ligands expressed. Genes in red are associated with a human syndrome; genes in blue have a mouse model with ACC but are not associated with a human ACC syndrome, and genes in grey (ligands in black) have not been implicated in human or mouse ACC. 1, based on overexpression studies, NGEF increases RHOA activity relative to RAC1 and CDC42.

Figure 8

Associated malformations commonly seen in patients with ACC. (A) T1-weighted axial MRI scan showing complete ACC associated with a third ventricle cyst (asterisk) and periventricular nodular heterotopia (arrowheads). (B) T2-weighted axial MRI scan showing ACC (asterisk) associated with polymicrogyria (PMG) (arrowheads) and copolcephaly (+). (C) T2-weighted axial MRI scan showing ACC with subcortical heterotopia (SCH) (arrowheads) and marked asymmetry of the cerebral hemispheres. Midsagittal (D) and axial (E) T1-weighted MRI scan of a patient with Aicardi syndrome revealing a constellation of neuroradiological features, including complete ACC (arrow), grey matter heterotopia (white arrowhead), cystic dilation of the left lateral ventricle (asterisk) and enlarged fourth ventricle (+). In addition, there is marked asymmetry of the cerebral hemispheres.