Delayed Motor Milestones Achievement in Infancy Associates with Perturbations of Amino Acids and Lipid Metabolic Pathways.

Rebecca Kofod Vinding,Daniela Rago,Klaus Bønnelykke,Scott T Weiss,Bo Lund Chawes,Jakob Stokholm,Hans Bisgaard,Jessica Lasky-Su,Augusto A Litonjua,Gözde Gürdeniz,Morten Arendt Rasmussen,Rachel S Kelly

doi:10.3390/metabo10090337

Abstract

The relationship between developmental milestone achievement in infancy and later cognitive function and mental health is well established, but underlying biochemical mechanisms are poorly described. Our study aims to discover pathways connected to motor milestone achievement during infancy by using untargeted plasma metabolomic profiles from 571 six-month-old children in connection with age of motor milestones achievement (Denver Developmental Index) in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) mother–child cohort. We used univariate regression models and multivariate modelling (Partial Least Squares Discriminant Analysis: PLS-DA) to examine the associations and the VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort for validation. The univariate analyses showed 62 metabolites associated with gross-motor milestone achievement (p < 0.05) as well as the PLS-DA significantly differentiated between slow and fast milestone achievers (AUC = 0.87, p = 0.01). Higher levels of tyramine-O-sulfate in the tyrosine pathway were found in the late achievers in COPSAC (p = 0.0002) and in VDAART (p = 0.02). Furthermore, we observed that slow achievers were characterized by higher levels of fatty acids and products of fatty acids metabolism including acyl carnitines. Finally, we also observed changes in the lysine, histidine, glutamate, creatine and tryptophan pathways. Observing these metabolic changes in relation to gross-motor milestones in the first year of life, may be of importance for later cognitive function and mental health.

Highlights

The brain is the most complex organ of the body and undergoes developmental changes throughout life, where the earliest phases of maturation during fetal development and childhood are the most important for later mental health [1]
Thereafter, we investigated whether the metabolic signature of age at motor milestone achievement in the child was dependent on the maternal metabolic profile during pregnancy; i.e., gestational week 24 and 1 week postpartum
Mothers of the children, who were excluded based on incomplete data were more likely to be nulliparous, to have antibiotic treatment during pregnancy and were slightly older when giving birth

Summary

Introduction

The brain is the most complex organ of the body and undergoes developmental changes throughout life, where the earliest phases of maturation during fetal development and childhood are the most important for later mental health [1]. Skills, such as smiling, grasping, crawling, the first walking steps, Metabolites 2020, 10, 337; doi:10.3390/metabo10090337 www.mdpi.com/journal/metabolites. During infancy there is a rapid increase in motor abilities: the child learns to reach, grasp, sit, stand and walk These motor abilities or milestones in early life are universal and the WHO has classified the age ranges at which these developmental milestones are normally achieved [2]. It has been shown that delayed motor development associates with psychopathological disorders such as schizophrenia, autism and neurosis [7,10]

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Results

Conclusion