Clinical, Genetic and Imaging Findings Identify New Causes for Corpus Callosum Development Syndromes

Timothy J. Edwards; Elliott H. Sherr ; A. James Barkovich; Linda J. Richards


Brain. 2014;137(6):1579-1613. 

In This Article

Abstract and Introduction


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.


The corpus callosum is the largest of the interhemispheric white matter tracts in the brain. It comprises >190 million topographically organized axons, each forming homotopic or heterotopic connections, often between distant regions of cerebral cortex (Wahl et al., 2007, 2009). These connections participate in an array of cognitive functions including language, abstract reasoning, and the integration of complex sensory information between the hemispheres (Brown et al., 1999; Paul et al., 2003). The corpus callosum is classically divided into four distinct segments based on early histological studies (Witelson, 1989; see Figure 1). Recent advances in diffusion tensor imaging and tractography have provided remarkable insight into the diversity of interhemispheric callosal connections within each segment, and has helped to clarify what happens to these connections when embryonic or foetal development is disturbed (Wahl et al., 2007, 2009).

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.

Agenesis of the corpus callosum (ACC) is an exceedingly heterogeneous condition that can result from disruption of numerous developmental steps from early midline telencephalic patterning to neuronal specification and guidance of commissural axons. It can occur as an isolated finding on MRI, but is more commonly associated with a broader disorder of brain development (Schell-Apacik et al., 2008; Tang et al., 2009). Accordingly, the cognitive and neurological consequences in patients with ACC vary considerably from mild behavioural problems to severe neurological deficits. Deficits in problem solving and social skills are common, and these often fall within the autistic spectrum (Lau et al., 2013; Siffredi et al., 2013). Interestingly, isolated ACC predominantly carries a favourable prognosis (Moutard et al., 2003; Sotiriadis et al., 2012) and these individuals exhibit a different cognitive outcome from the disconnection syndrome characterized in commissurotomy patients Paul et al., 2007). Individuals with ACC therefore provide a unique opportunity to study not only the mechanisms of callosal development, but also the broader principles that determine how the brain responds to disruptions in neurodevelopment.

The increased use and resolution of comparative genomic hybridization have implicated many more genes and genomic loci in corpus callosum development (O'Driscoll et al., 2010), and have revealed a great diversity of genetic causes for ACC syndromes. At present, however, the cause of 55–70% of cases with ACC cannot be identified by clinical evaluation {Bedeschi et al., 2006; Schell-Apacik et al., 2008). The apparently sporadic nature of ACC makes genetic studies difficult (Sherr et al., 2005; Schell-Apacik et al., 2008), and it is possible that the cause of ACC in a proportion of these patients is non-genetic, such as foetal exposure to alcohol. Indeed, it is often the associated brain abnormalities found on imaging that point to the underlying developmental process that is disturbed.

Syndromes incorporating ACC can be broadly classified by the stage in development that is primarily affected using an approach similar to previous classifications of cortical malformations (Barkovich et al., 2012). ACC can occur in association with disorders of neuronal and/or glial proliferation, neuronal migration and/or specification, midline patterning, axonal growth and/or guidance, and post-guidance development. Much of what is known about normal corpus callosum formation has emerged from studies using mouse models of callosal agenesis. Indeed, our understanding of the processes underpinning callosal development in mice has served as a foundation for much of what is currently known about human patients with ACC. The purpose of this review is to systematically outline the clinical features of all human syndromes associated with ACC, and relate these to the genetic causes and developmental processes likely to be disturbed.