Investigators at the University of Queensland, Brisbane, Australia, and the University of California, Benioff Children's Hospital, studied the clinical features of syndromes associated with agenesis of the corpus callosum (ACC) and their relation to the genetic causes and developmental processes involved. ACC syndromes can be classified by the stage of development primarily affected. Axonal growth continues until 2 months after birth, and structural changes continue post-natally, the thickness of the CC increasing anteriorly through childhood and posteriorly during adolescence. Early perturbations of CC development (weeks 14 and 15 post conception) result in complete agenesis, and later developmental disturbances (weeks 18 and 19) result in partial agenesis confined to the posterior CC. ACC can occur with disorders of neuronal and/or glial proliferation, telencephalic midline patterning, and axonal growth or guidance, similar to that observed in the mouse model. Copy number variations (e.g. 1q42-q44 deletion) and single gene mutations are present in some ACC syndromes, but a clear genetic cause is not identified in the majority. Neuroimaging has extended the number and variety of syndromes recognized in association with ACC and these include the major ciliopathies: Joubert syndrome (molar tooth sign, vermis hypoplasia); Meckel syndrome (occipital encephalocele, absence of olfactory bulbs); hydrolethalus syndrome (severe hydrocephalus); acrocallosal syndrome (exencephaly, hydrocephalus); Bardet-Biedl syndrome (molar tooth sign, retinitis pigmentosa). [1]

COMMENTARY. This review provides a comprehensive classification of the clinical and genetic features of syndromes associated with callosal agenesis. In a clinical reference guide to neurological syndromes [2], among approximately 250 syndromes listed, 18 have an associated CC dysgenesis. Seizures, especially infantile spasms, as in Aicardi syndrome, are an established complication of ACC whereas behavioral and cognitive impairments as isolated deficits are less well documented.

ACC and autism. About one third of a group of 26 adults with ACC presented with autism whereas in childhood only 3 of the group had met criteria for a diagnosis of autism spectrum disorder [3]. Parent ratings of childhood behavior indicate that children with agenesis are less likely to be autistic but as adults ACC is a risk factor for developing autism. Both genetic and environmental factors may be involved in the cause of ACC and its autistic features.