Agenesis of Corpus Callosum

Background of Agenesis of Corpus Callosum

Corpus callosum is the largest cerebral commissure that connects neocortical areas with a cardinal role in the execution of physical, cognitive and affective functions. Agenesis of corpus callosum (ACC) can be partial or complete, isolated or associated with other malformations. The incidence of ACC has not been well defined, varying in surveys of patients undergoing neuroimaging. In 135 children (aged 3 months to 15 years) with structural defects of the central nervous system found on magnetic resonance imaging, agenesis of the corpus callosum was evident in 7. ACC is one of the most commonly occurring brain malformations found in 2-3% of individuals with intellectual disability.

Etiology and Diagnosis of Agenesis of Corpus Callosum

ACC is a heterogeneous condition that can be caused by either chromosomal, infectious, vascular or toxic disorders. It can be part of chromosomal syndromes (trisomy 8, 13, 18, or 21), as well as a number of X-linked syndromes, in particular Aicardi’s syndrome. The most frequent causes of ACC are gene mutations that are related to pathways of axon guidance, ciliary development, cell adhesion, proliferation, differentiation and migration, such as the gene Netrin receptor DCC, CDK10, ephrin B1 (EFNB1), mediator complex subunit 12 (MED12). Diagnosis of callosal agenesis is established by characteristic changes seen on ultrasound and magnetic resonance imaging (MRI). MRI analyses of fetal cerebral sulcal development showed that “isolated” ACC is associated with a broad alteration in cerebral sulcal development that can be detected in the second and third trimester.

The Role of ARID1B in Agenesis of Corpus Callosum

Haploinsufficiency of ARID1B (AT-rich interaction domain 1B) is involved in corpus callosum agenesis. The ARID1B gene encodes a subunit of the BRG1-associated factors (BAF) chromatin remodeling complex that regulates gene expression via nucleosome remodeling. Wnt/β-catenin target genes were upregulated in individuals harboring ARID1B mutations, and in vitro studies showed that ARID1B functions as a repressor of Wnt/β-catenin signaling, it may be an appropriate target for gene therapy in disorders of growth and development. Preclinical studies have identified the use of a positive allosteric modulator of the GABAA receptor as an effective treatment for some ARID1B haploinsufficiency-related behavioral phenotypes, and there is potential for the refinement of this therapy in order to translate it into clinical use.

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