Association Between Plasma Metabolites and Psychometric Scores Among Children With Developmental Disabilities:
Jennie Sotelo-Orozco1, Leonard Abbeduto2,3, Irva Hertz-Picciotto1
1Department of Public Health Sciences, University of California, Davis, Davis, CA, United States.
Insights
Metabolic disturbances in children with developmental disabilities correlate with cognitive and behavioral deficits. Specific plasma metabolites are linked to poorer outcomes, with variations observed based on diagnosis and sex.
Area of Science:
- Biochemistry and Neuroscience
- Metabolomics in Neurodevelopmental Disorders
Background:
- Developmental disabilities are characterized by learning, language, and behavioral delays.
- Emerging evidence suggests co-occurring metabolic system disturbances in these conditions.
- The role of sex in metabolic associations with developmental disabilities remains understudied.
Purpose of the Study:
- To investigate the correlation between plasma metabolome, psychometric scores, and sex in children.
- To examine associations between specific metabolites and cognitive, adaptive, and maladaptive behaviors.
Main Methods:
- Plasma metabolomes analyzed using NMR spectroscopy in children with autism spectrum disorder (ASD), idiopathic developmental delay (i-DD), Down syndrome (DS), and typically developing controls (TD).
- Statistical analyses included Spearman correlations and multiple linear regression, adjusting for diagnosis, sex, age, race/ethnicity, maternal age, and homeownership.
- Psychometric measures assessed cognitive skills, adaptive behavior, and maladaptive behavior.
Main Results:
- Elevated metabolites linked to cellular energy and mitochondrial function (e.g., fumarate, lactate, pyruvate) correlated with poorer cognitive and adaptive scores across diagnoses.
- Specific metabolites like o-acetylcarnitine and carnitine showed associations with cognitive deficits and maladaptive behaviors, respectively, with sex-specific patterns observed.
- Glutamate levels were associated with better socialization in ASD cases, while other metabolites like myo-inositol and ornithine correlated with poorer outcomes in DS.
Conclusions:
- Plasma metabolites are associated with specific functional subdomains in cognitive, adaptive, and behavioral development.
- Metabolic associations show variation depending on the neurodevelopmental diagnosis and sex of the child.
- These findings highlight potential biomarkers and therapeutic targets within metabolic pathways for developmental disabilities.
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.
