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Abstract Developmental delays have been associated with metabolic disturbances in children. Previous research in the childhood autism risk from genetics and the environment (CHARGE) case–control study identified neurodevelopment-related plasma metabolites in children, suggesting disturbances in the energy-related tricarboxylic acid (TCA) cycle and 1-carbon metabolism (1CM). Here, we investigated associations between children’s neurodevelopmental outcomes and their mothers’ plasma metabolite profiles in a subset of mother–child dyads from CHARGE, including those with autism spectrum disorder (ASD, n = 209), Down syndrome (DS, n = 76), idiopathic developmental delay (iDD, n = 64), and typically developed (TD, n = 185) controls. Multiple linear regression revealed associations between child neurodevelopmental outcomes and maternal plasma metabolites related to the TCA cycle, 1CM, and lipid metabolism. Despite profound metabolic disturbances in children with DS reported previously, few of these differences were observed in the mothers, which might reflect differences in gene dosage between children with DS and their euploid mothers. Notably differences in maternal metabolism related to ASD and iDD followed similar patterns of disturbance in previously reported metabolic signatures in children but were generally smaller in magnitude. Similar patterns of metabolic disturbances observed in mothers and their children with ASD or iDD could reflect shared genetic, mitochondrial, and/or environmental risk factors.

Blood is a rich biological sample routinely collected in clinical and epidemiological studies. With advancements in high throughput -omics technology, such as metabolomics, epidemiology can now delve more deeply and comprehensively into biological mechanisms involved in the etiology of diseases. However, the impact of the blood collection tube matrix of samples collected needs to be carefully considered to obtain meaningful biological interpretations and understand how the metabolite signatures are affected by different tube types. In the present study, we investigated whether the metabolic profile of blood collected as serum differed from samples collected as ACD plasma, citrate plasma, EDTA plasma, fluoride plasma, or heparin plasma. We identified and quantified 50 metabolites present in all samples utilizing nuclear magnetic resonance (NMR) spectroscopy. The heparin plasma tubes performed the closest to serum, with only three metabolites showing significant differences, followed by EDTA which significantly differed for five metabolites, and fluoride tubes which differed in eleven of the fifty metabolites. Most of these metabolite differences were due to higher levels of amino acids in serum compared to heparin plasma, EDTA plasma, and fluoride plasma. In contrast, metabolite measurements from ACD and citrate plasma differed significantly for approximately half of the metabolites assessed. These metabolite differences in ACD and citrate plasma were largely due to significant interfering peaks from the anticoagulants themselves. Blood is one of the most banked samples and thus mining and comparing samples between studies requires understanding how the metabolite signature is affected by the different media and different tube types.

Background: Developmental disabilities are defined by delays in learning, language, and behavior, yet growing evidence has revealed disturbances in metabolic systems that may also be present. Little is known about whether these metabolic issues contribute to the symptoms or severity of these disabilities, or whether sex plays a role in these associations, given that boys are disproportionately affected by some developmental disabilities. Here we sought to investigate the correlation between psychometric scores, sex, and the plasma metabolome.Methods: The plasma metabolomes of children with autism spectrum disorder (ASD; n = 167), idiopathic developmental delay (i-DD; n = 51), Down syndrome (DS; n = 31), and typically developing controls (TD; n = 193) were investigated using NMR spectroscopy. Spearman rank correlations and multiple linear regression models (adjusted for child's neurodevelopmental diagnosis, child's sex, child's age, child's race/ethnicity, maternal age at child's birth, and parental homeownership) were used to examine the association between plasma metabolites and sex in relation to psychometric measures of cognitive skills, adaptive behavior, and maladaptive behavior in our study population.Results: Higher levels of metabolites involved in cellular energy and mitochondrial function among children with ASD (fumarate and cis-aconitate), DS (lactate), and TD (pyruvate) are associated with poorer cognitive and adaptive subscales. Similarly, higher o-acetylcarnitine associated with deficits in cognitive subscales among all DS cases and TD boys, and carnitine correlated with increased maladaptive behavior among girls with ASD and girls with DS. Among children with DS, elevated myo-inositol, ornithine, and creatine correlated with poorer scores across several subscales. Even among TD cases, elevated 3-hydroxybutyrate correlated with decreased receptive language. In contrast, higher levels of glutamate were associated with better socialization skills among ASD cases. Even after adjusting for the child's neurodevelopmental diagnosis, sex, and other possible confounders, key metabolites including glycolysis metabolites (lactate and pyruvate), ketone bodies (3-hydroxybutyrate and acetoacetate), TCA cycle metabolites (cis-aconitate and fumarate), as well as ornithine were associated with deficits in multiple domains of cognitive function, adaptive skills, and aberrant behaviors.Conclusions: Our results highlight that some plasma metabolites may relate to specific functional subdomains within cognitive, adaptive, and behavioral development with some variation by diagnosis and sex.

Background: Compared to breast-fed (BF), formula-fed (FF) infants exhibit more rapid weight gain, a different fecal microbial profile, as well as elevated serum insulin, insulin growth factor 1 (IGF-1), and branched chain amino acids (BCAAs). Since infant formula contains more protein and lower free amino acids than breast milk, it is thought that protein and/or free amino acids may be key factors that explain phenotypic differences between BF and FF infants.Methods: Newborn rhesus monkeys (Macaca mulatta) were either exclusively BF or fed regular formula or reduced protein formula either supplemented or not with a mixture of amino acids. Longitudinal sampling and clinical evaluation were performed from birth to 16 weeks including anthropometric measurements, intake records, collection of blood for hematology, serum biochemistry, hormones, and metabolic profiling, collection of urine for metabolic profiling, and collection of feces for 16s rRNA fecal microbial community profiling.Results: Reducing protein in infant formula profoundly suppressed intake, lowered weight gain and improved the FF-specific metabolic phenotype in the first month of age. This time-dependent change paralleled an improvement in serum insulin. All lower protein FF groups showed reduced protein catabolism with lower levels of blood urea nitrogen (BUN), urea, ammonia, albumin, creatinine, as well as lower excretion of creatinine in urine compared to infants fed regular formula. Levels of fecal microbes (Bifidobacterium and Ruminococcus from the Ruminococcaceae family), that are known to have varying ability to utilize complex carbohydrates, also increased with protein reduction. Adding free amino acids to infant formula did not alter milk intake or fecal microbial composition, but did significantly increase urinary excretion of amino acids and nitrogen-containing metabolites. However, despite the lower protein intake, these infants still exhibited a distinct FF-specific metabolic phenotype characterized by accelerated weight gain, higher levels of insulin and C-peptide as well as elevated amino acids including BCAA, lysine, methionine, threonine and asparagine.Conclusions: Reducing protein and adding free amino acids to infant formula resulted in growth and metabolic performance of infants that were more similar to BF infants, but was insufficient to reverse the FF-specific accelerated growth and insulin-inducing high BCAA phenotype.