Altered Metabolism of Mothers of Young Children with Autism Spectrum Disorder: A Case Control Study

Abstract

Background: Previous research studies have demonstrated abnormalities in the metabolism of mothers of young children with autism. Method: Metabolic analysis was performed on blood samples from 30 mothers of young children with Autism Spectrum Disorder (ASD-M) and from 29 mothers of young typically-developing children (TD-M). Targeted metabolic analysis focusing on the folate one-carbon metabolism (FOCM) and the transsulfuration pathway (TS) as well as broad metabolic analysis were performed. Statistical analysis of the data involved both univariate and multivariate statistical methods. Results: Univariate analysis revealed significant differences in 5 metabolites from the folate one-carbon metabolism and the transsulfuration pathway and differences in an additional 48 metabolites identified by broad metabolic analysis, including lower levels of many carnitine-conjugated molecules. Multivariate analysis with leave one-out cross validation allowed classification of samples as belonging to one of the two groups with 93% sensitivity and 97% specificity with five metabolites. Furthermore, each of these five metabolites correlated with 8-15 other metabolites indicating that there are five clusters of correlated metabolites. In fact, all but 5 of the 50 metabolites with the highest area under the receiver operating characteristic curve were associated with the five identified groups. Many of the abnormalities appear linked to low levels of folate, vitamin B12, and carnitine-conjugated molecules. Conclusions: Mothers of children with ASD have many significantly different metabolite levels compared to mothers of typically developing children at 2-5 years after birth.

Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models

“…17,85 Finally, the differences in maternal metabolites are consistent with previously known impacts on one-carbon metabolism. [14][15][16] Taken together, the correlations of the DUX4 co-methylation network in infant hippocampus demonstrate that the lean control and intervention groups had higher levels of methylation than obese pregnancies in the DUX4 co-methylation network, which significantly correlated with differences in behavior related to abstract stimuli and social stimuli recognition memory, higher PUFA concentrations in the brain, and differing levels of metabolites related to neurodevelopment. Furthermore, the higher methylation levels of this module significantly correlated with lower levels of maternal inflammatory cytokines/adipokines and differences in maternal one-carbon metabolism and metabolism of amino acids by the tricarboxylic acid cycle during pregnancy.…”

“…13 In humans, altered metabolites have been observed in the serum of mothers of young children with ASD, including those related to the one-carbon metabolism, critical for the epigenetic modification DNA cytosine methylation. 14 In mice, a perinatal high-fat diet was found to alter one-carbon metabolism and DNA methylation in the prefrontal cortex of male offspring. 15 The effect of maternal obesity on one-carbon metabolism in offspring was also seen in baboons fed a high-fat, high-energy diet.…”