Conclusion

It is proposed that dysregulated calcium signalling, mainly through disturbances in VGCC function and downstream signalling pathways, is the central molecular event that leads to pathologies of autism.

Various genetic and external factors are capable of perturbing calcium homeostasis during critical stages of development. As concordance of autism in monozygotic twins is less than 100% and the phenotypic expression of the disorder varies widely, it is concluded that non-genetic mechanisms could greatly contribute to the onset of autism.

Environmental influences and risk factors mentioned in this paper, such as perinatal hypoxia and exposure to infectious agents and various environmental toxins, are proposed as possible etiological agents. Furthermore, genetic polymorphism related to immune function and inflammatory reactions, such as MIF, and expression of chemokine receptors, such as CCR2 and others, would make for additional risk factors, raising vulnerability following exposure in critical stages of development. A combination of such influences, or combinations with inherited mutations in calcium signalling pathways or closely linked proteins, would account for the complexity of autistic phenotype and severity of symptoms.

Involvement of chemokines, chemokine receptors and their signalling in inflammatory and neurological disease has become more evident in recent years. It is becoming increasingly clear that, beyond their involvement in neuroinflammation, these proteins play an important role in brain development and function, due in great part to their ability to modulate functioning of ion channels. In addition to neurons and brain glia, chemokine receptors are widely expressed on immune and endothelial cells, and have been proposed to serve as a bridge linking the immune and nervous systems. Targeting specific chemokines and chemokine receptors, either directly or indirectly through activation of related opioid, adenosine, and vasointestinal peptide receptors, is a novel therapeutic strategy in both inflammatory and infectious disease. Apart from AIDS-dementia, Alzheimer's disease and the neuroinflammation associated with multiple sclerosis, desensitation and/or antagonism of specific chemokine receptors have been proposed as treatment targets in inflammatory disorders of gastrointestinal tract. Polymorphisms in genes that encode these receptors are now known to determine susceptibility to neurological dysfunction in HIV-infected individuals, and special attention should be paid to these factors considering that the symptoms and onset of AIDS-dementia in children are often identical to more common forms of autism [16101548, 16204635, 11456467, 16594639].

Lastly, antibodies to voltage-gated calcium channels, as well as to proteins that are able to modulate their function, such as for example maternal antibodies directed against angiotensin II type I receptors, could also play an etiological role in autism. Possiblity of perinatal infection that develops into latent, subclinical infection, and potential reactivation following an external stressor, such as vaccination, should not be discounted. Apart from the risk of reactivation, persistent low-level infection could have major implications during development due to possible modulation of calcium signalling pathways in host cell.

Note: in a recent small scale preliminary study by Whittemore Peterson Institute around 40% of children with autism tested postive for xenotropic murine leukaemia virus-related virus (XMRV) DNA, with nearly 60% showing presence of antibodies to the virus (unpublished data). According to latest research the presence of XMRV retrovirus in general healthy populat 4%. Larger scale studies to establish presence of this retrovirus in individuals with autism are currently under way. (Jan 2010). For details and references on HIV retrovirus induced autism and physiopathological parallels to idiopatic autism go to HIV_and_autism page.