Urine Organic Acids as Metabolic Indicators for Global Developmental Delay/Intellectual Disability in Chinese Children

Abstract

Objective: The purpose of this study was to search for differential metabolites in urine organic acids, and to characterize metabolic features that can be used to identify metabolites for exploration of global developmental delay (GDD)/intellectual disability (ID) etiology and pathogenesis.Methods: We screened positive test results that could explain GDD/ID from 1,253 cases, and the major differential metabolites in 132 urine organic acids from the 1,230 cases with negative results (863 GDD cases, 367 ID cases), and 100 typically developing children (TD). Non-supervisory principal component analysis and orthogonal partial least squares discriminant analysis were used to develop models to distinguish GDD/ID from TD children, and to detect major differential metabolites.Results: We get 23 positive results that could identify the cause of GDD/ID from 1253 cases diagnosed with GDD/ID. Among 1,230 negative results, we get the differential metabolites of the GDD group and the ID group had the same trend compared with the TD group. Twenty four differential metabolites were obtained from the GDD group, and 25 from the ID group (VIP > 1.0, p < 0.01). These differential metabolites were mainly related to the following pathways: the synthesis and degradation of ketone bodies, citrate cycle, alanine, aspartate and glutamate metabolism, pyrimidine metabolism, butanoate metabolism, pyruvate metabolism, fatty acid biosynthesis, valine, leucine and isoleucine degradation.Conclusion: The use of metabolomics research methods to detect urine organic acids of children with GDD/ID can discover differential metabolites, which might be valuable for future research on the etiology, pathogenesis, prognosis and possible interventions of GDD/ID. The significantly altered differential metabolites indicators could therefore be potential diagnostic biomarkers for GDD/ID.

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 ].…”

Comprehensive evaluation of the child with global developmental delays or intellectual disability

“…However, it is imperative to consider metabolic disorders such as congenital hypothyroidism, phenylketonuria, and methylmalonic acidemia as potential underlying causes of GDD/ID. 14,15) In addition to central nervous system malformations, brain injury leading to neurodevelopmental disabilities can stem from pre-and postnatal complications such as asphyxia, congenital and acquired infections, kernicterus, and head trauma. 16,17) Uncontrolled maternal medical conditions and environmental exposure during pregnancy can precipitate GDD/ID.…”