Agenesis of the corpus callosum (AgCC), a failure to develop the large bundle of fibres that connect the cerebral hemispheres, occurs in 1:4000 individuals. Genetics, animal models and detailed structural neuroimaging are now providing insights into the developmental and molecular bases of AgCC. Studies using neuropsychological, electroencephalogram and functional MRI approaches are examining the resulting impairments in emotional and social functioning, and have begun to explore the functional neuroanatomy underlying impaired higher-order cognition. The study of AgCC could provide insight into the integrated cerebral functioning of healthy brains, and may offer a model for understanding certain psychiatric illnesses, such as schizophrenia and autism.

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Agenesis of the corpus callosum: genetic, developmental and functional aspects of connectivity

Autistic-spectrum conditions and psychotic-spectrum conditions (mainly schizophrenia, bipolar disorder, and major depression) represent two major suites of disorders of human cognition, affect, and behavior that involve altered development and function of the social brain. We describe evidence that a large set of phenotypic traits exhibit diametrically opposite phenotypes in autistic-spectrum versus psychotic-spectrum conditions, with a focus on schizophrenia. This suite of traits is inter-correlated, in that autism involves a general pattern of constrained overgrowth, whereas schizophrenia involves undergrowth. These disorders also exhibit diametric patterns for traits related to social brain development, including aspects of gaze, agency, social cognition, local versus global processing, language, and behavior. Social cognition is thus underdeveloped in autistic-spectrum conditions and hyper-developed on the psychotic spectrum. We propose and evaluate a novel hypothesis that may help to explain these diametric phenotypes: that the development of these two sets of conditions is mediated in part by alterations of genomic imprinting. Evidence regarding the genetic, physiological, neurological, and psychological underpinnings of psychotic-spectrum conditions supports the hypothesis that the etiologies of these conditions involve biases towards increased relative effects from imprinted genes with maternal expression, which engender a general pattern of undergrowth. By contrast, autistic-spectrum conditions appear to involve increased relative bias towards effects of paternally expressed genes, which mediate overgrowth. This hypothesis provides a simple yet comprehensive theory, grounded in evolutionary biology and genetics, for understanding the causes and phenotypes of autistic-spectrum and psychotic-spectrum conditions.

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Psychosis and autism as diametrical disorders of the social brain

White matter tracts of the brain allow neurons and neuronal networks to communicate and function with high efficiency The aim of this review is to briefly introduce diffusion tensor imaging methods that examine white matter tracts and then to give an overview of the studies that have investigated white matter integrity in the brains of individuals with autism spectrum disorder (ASD) From the 48 studies we reviewed, persons with ASD tended to have decreased fractional anisotropy and increased mean diffusivity in white matter tracts spanning many regions of the brain but most consistently in regions such as the corpus callosum, cingulum, and aspects of the temporal lobe This decrease in fractional anisotropy was often accompanied by increased radial diffusivity Additionally, the review suggests possible atypical lateralization in some white matter tracts of the brain and a possible atypical developmental trajectory of white matter microstructure in persons with ASD Clinical implications and future research directions are discussed

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Diffusion Tensor Imaging in Autism Spectrum Disorder: A Review

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.

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

A Meta-Analysis of the Corpus Callosum in Autism

Archival data from a survey of parent observations was used to determine the prevalence of social and behavioral problems in children with agenesis of the corpus callosum (ACC). Parent observations were surveyed using the Child Behavior Checklist (CBCL) for 61 children with ACC who were selected from the archive based on criteria of motor development suggesting a relatively high general level of functioning. Younger children with ACC (ages 2-5) were rated as primarily having problems with sleep. Older children with ACC (ages 6-11) manifested problems in attention, social function, thought, and somatic complaints. The older children with ACC were also compared to CBCL data from 52 children with autism who were selected from a previous study. Children with ACC were generally less impaired than children with autism on nearly all scales, with significantly less severe problems in the areas of attention, anxiety/depression, social function, and unusual thoughts. A further questionnaire related to diagnostic criteria for autism indicated that some children with ACC had traits that are among those that contribute to the diagnosis of autism within the domains of social interaction and social communication, but fewer who manifest repetitive and restricted behaviors.

/pdf/social-and-behavioral-problems-of-children-with-agenesis-of-45k18sby4r.pdf

Social and Behavioral Problems of Children with Agenesis of the Corpus Callosum

Objectives To explore and compare the prevalence and expression of specific health-related variables in a large survey sample of persons with agenesis of the corpus callosum (ACC) and their siblings.



Methods  Caregiver surveys of individuals with ACC (n = 189) and their siblings (n = 189) provided data regarding diagnoses, physical features, neurological and sensory information, feeding, elimination and sleep concerns, and some behavioural features.



Results  Compared with their siblings, individuals with ACC had more concurrent conditions and were more likely to have altered pain perception and sensitivity to touch. In addition, individuals with ACC had more sensory deficits and abnormalities as well as altered patterns of feeding/eating, elimination and sleep.



Conclusions  These data raise important questions for future research and suggest the need for increased vigilance by caregivers and health-care professionals of individuals with callosal disorders. Early detection and intervention may help prevent or ameliorate health problems in this population.

Health-related issues in individuals with agenesis of the corpus callosum

Background The study objective was to develop a profile of characteristics and diagnostic indicators of agenesis of the corpus callosum (ACC) using a large sample of individuals with ACC and their siblings. Very few previous studies have been able to access large populations in order to develop a comprehensive profile.

Methods  Caregivers of 720 individuals with ACC and 219 siblings, the largest sample studied to date, provided surveys with data on diagnoses, physical characteristics, developmental patterns and physical functioning.

Results  Compared with siblings, individuals with ACC exhibited a pattern of delayed motor development, difficulty with balance and bimanual movements, large head size, poor muscle tone, poor depth perception, reduced pain perception, sleeping difficulties and an increased proportion of left and mixed handedness.

Conclusions  These results extend previous descriptions but are also consistent with published reports that used small samples and single case studies. The data provide a profile that has implications for early detection and intervention of individuals with ACC as well as for highlighting future research directions to extend knowledge about ACC.

Physical, motor, sensory and developmental features associated with agenesis of the corpus callosum.

Absence of the corpus callosum is often associated with cognitive deficits, autism, and epilepsy. Using a genomic microarray, the authors analyzed DNA from 25 patients with radiographically confirmed callosal anomalies and identified three patients with de novo copy number changes in chromosome regions 2q37, 6qter, and 8p. Chromosomal deletions and duplications may be a relatively common cause of cerebral malformations.

Genomic microarray analysis identifies candidate loci in patients with corpus callosum anomalies.

Twenty-three years of observation and testing of the communication skills of a male participant with agenesis of the corpus callosum (ACC) and normal IQ revealed initial weakness in content and form of language. While his general ability to communicate improved over time, difficulties with fluent speech in conversations and pragmatic language skills persisted into young adulthood. With intensive intervention, communication and academic skills developed by late adolescence, which allowed the participant to complete a regular high school program. Discussion includes similarities and differences between this longitudinal case study and other reports of individuals with ACC with respect to communication skills. A clinical intervention approach based on collaboration between client, school, and the client's family is described.

Kathryn J. Schilmoeller

Papers

Social and Behavioral Problems of Children with Agenesis of the Corpus Callosum

Health-related issues in individuals with agenesis of the corpus callosum

Physical, motor, sensory and developmental features associated with agenesis of the corpus callosum.

Genomic microarray analysis identifies candidate loci in patients with corpus callosum anomalies.

A 23-Year Review of Communication Development in an Individual with Agenesis of the Corpus Callosum.