In utero activation of fetal genes that predispose to the development of autism are triggered by maternal inflammation

Controlling the maternal inflammation may be key to autism prevention

Several lines of evidences suggest that both genetic and environmental factors contribute to autism development.
A subset of autism cases are linked to rare genetic variation such as copy-number variation (CNV), which are structural alterations of the DNA in the genome resulting in more (duplication) or fewer (deletion) number copies on certain chromosomes.

A recent study, grouping multiple laboratories over the world (8 countries including USA) under the Autism Genome Project, analyzed 2,446 ASD-affected families. The results showed an increase of specific genetic deletions and duplications in affected versus control groups associated with ASD and intellectual disability.

Several animal studies have demonstrated that maternal inflammation during pregnancy, in particular the secretion of IL-6, could alter fetal neurodevelopment and lead to autism in the offspring. More interestingly, other studies investigated the effects of maternal immune activation (MIA) on pups of control mothers (typical strain with no predisposition to behavioral impairment) and pups from an inbred strain predisposed to exhibit ASD-like behaviors. Results showed greater impairments in pups with both genetic susceptibility and exposure to MIA than in pups with either risk factor alone. This strongly highlights the fact that genetic predisposition when combined with a strong immune reaction (inflammation) during gestation result in a higher risk to develop ASD and an increase in autism severity.

In human, a new study published in the latest issue of the Journal of Developmental and Behavioral Pediatrics , clearly demonstrates that maternal immune activation unravels the genetic predispositions such as CNV to induce the development of autism . In that report, they analyzed 1971 children of the Simons Simplex Collection Sample with a diagnosis of ASD and explore the relation of ASD-associated copy number variants (CNVs) with environmental risks for the condition such as prenatal maternal infection inducing inflammation.

Maternal infections and febrile episodes during pregnancy were reported by parent interview.

Results showed a strong correlation between the presence of ASD-related CNV and maternal infection. But most mothers who experienced fever or infections during pregnancy do not give birth to a future autistic child.

This suggests that individuals carrying these specific genetic variants are more susceptible to the effects of maternal infection and are at higher risk to develop severe autism behaviors.

These recent works clearly demonstrate and confirmed our postulate “ Maternal systemic inflammation resulting from an infection or an autoimmune disease could disrupt fetal neurodevelopment, which is more severely affected when combined to genetic predisposition and could lead to autism”.

Thus the prevention or reduction of maternal inflammation during pregnancy, through an early immune profile screening and subsequent therapies, could minimize the risks of having a future autistic child.

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