Association Between Plasma Metabolites and Psychometric Scores Among Children With Developmental Disabilities: Investigating Sex-Differences

Abstract

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.

Central Nervous System Metabolism in Autism, Epilepsy and Developmental Delays: A Cerebrospinal Fluid Analysis

“…Specifically, in those with DD, we found involvement of ATP and other energy metabolites. Previous studies show elevations in the TCA and energy pathway metabolites in both urine [ 21 ] and plasma [ 13 , 14 ]. Studies examining the characteristics of those with ASD and mitochondrial disorder demonstrate a high incidence of DD, particularly motor delay [ 25 ].…”

“…Children with DD have been shown to have increased glycolic and 3-hydroxyisobutyric acid and decreased palmitic acid [ 21 ] in urine and elevated acetate, glutamate, lactate and tricarboxylic acid (TCA) cycle metabolites in plasma [ 13 ]. Interestingly, one study that included DD and ASD participants demonstrated that cognitive function, adaptive skills, and aberrant behavior were related to some of these same metabolites [ 14 ].…”

Metabolomic Signatures of Autism Spectrum Disorder

“…The repeated association of energy metabolism with many aspects of ASD is not surprising given the high rate of mitochondrial dysfunction associated with ASD [ 10 , 11 ]. Furthermore, the link to neurodevelopment and language is not surprising as previous studies have linked developmental delays to abnormal CAC and energy pathway biomarkers in urine [ 54 ], plasma [ 55 , 56 ], and CSF [ 34 ]. Children with ASD and mitochondrial disease appear to have two developmental profiles, those with developmental delays, including motor delay, and those that manifest NDR [ 10 ].…”

Maternal Plasma Metabolic Profile Demarcates a Role for Neuroinflammation in Non-Typical Development of Children

“…For example, one could imagine two metabolites that have the same concentrations in TD and ASD, but whose correlation changes with age or other conditions (e.g, diet; example [ 48 ]). Much of the literature on biomarkers of ASD and/or IDD has focused on the search for individual molecules, or statistical combinations of molecules, which are predictive of ASD-related morbidity or diagnosis [ 16 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 ]. However, few metabolomic studies have moved beyond individual, isolated biomarkers, focusing instead on metabolic pathway analysis, in which whole metabolic pathways are analyzed for significant changes.…”