Amino Acid Dysregulation Metabotypes: Potential Biomarkers for Diagnosis and Individualized Treatment for Subtypes of Autism Spectrum Disorder

Alan M. Smith, Joseph J. King, Paul R. West, Michael A. Ludwig, Elizabeth L.R. Donley, Robert E. Burrier, David G Amaral

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: Autism spectrum disorder (ASD) is behaviorally and biologically heterogeneous and likely represents a series of conditions arising from different underlying genetic, metabolic, and environmental factors. There are currently no reliable diagnostic biomarkers for ASD. Based on evidence that dysregulation of branched-chain amino acids (BCAAs) may contribute to the behavioral characteristics of ASD, we tested whether dysregulation of amino acids (AAs) was a pervasive phenomenon in individuals with ASD. This is the first article to report results from the Children's Autism Metabolome Project (CAMP), a large-scale effort to define autism biomarkers based on metabolomic analyses of blood samples from young children. Methods: Dysregulation of AA metabolism was identified by comparing plasma metabolites from 516 children with ASD with those from 164 age-matched typically developing children recruited into the CAMP. ASD subjects were stratified into subpopulations based on shared metabolic phenotypes associated with BCAA dysregulation. Results: We identified groups of AAs with positive correlations that were, as a group, negatively correlated with BCAA levels in ASD. Imbalances between these two groups of AAs identified three ASD-associated amino acid dysregulation metabotypes. The combination of glutamine, glycine, and ornithine amino acid dysregulation metabotypes identified a dysregulation in AA/BCAA metabolism that is present in 16.7% of the CAMP subjects with ASD and is detectable with a specificity of 96.3% and a positive predictive value of 93.5% within the ASD subject cohort. Conclusions: Identification and utilization of metabotypes of ASD can lead to actionable metabolic tests that support early diagnosis and stratification for targeted therapeutic interventions.

Original languageEnglish (US)
Pages (from-to)345-354
Number of pages10
JournalBiological Psychiatry
Volume85
Issue number4
DOIs
StatePublished - Feb 15 2019

Fingerprint

Biomarkers
Amino Acids
Branched Chain Amino Acids
Autistic Disorder
Metabolome
Therapeutics
Autism Spectrum Disorder
Ornithine
Metabolomics
Glutamine
Glycine
Early Diagnosis
Phenotype

Keywords

  • Amino acids
  • Autism
  • Biomarker
  • Diagnosis
  • Metabolomics
  • Metabotype

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Amino Acid Dysregulation Metabotypes : Potential Biomarkers for Diagnosis and Individualized Treatment for Subtypes of Autism Spectrum Disorder. / Smith, Alan M.; King, Joseph J.; West, Paul R.; Ludwig, Michael A.; Donley, Elizabeth L.R.; Burrier, Robert E.; Amaral, David G.

In: Biological Psychiatry, Vol. 85, No. 4, 15.02.2019, p. 345-354.

Research output: Contribution to journalArticle

Smith, Alan M. ; King, Joseph J. ; West, Paul R. ; Ludwig, Michael A. ; Donley, Elizabeth L.R. ; Burrier, Robert E. ; Amaral, David G. / Amino Acid Dysregulation Metabotypes : Potential Biomarkers for Diagnosis and Individualized Treatment for Subtypes of Autism Spectrum Disorder. In: Biological Psychiatry. 2019 ; Vol. 85, No. 4. pp. 345-354.
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abstract = "Background: Autism spectrum disorder (ASD) is behaviorally and biologically heterogeneous and likely represents a series of conditions arising from different underlying genetic, metabolic, and environmental factors. There are currently no reliable diagnostic biomarkers for ASD. Based on evidence that dysregulation of branched-chain amino acids (BCAAs) may contribute to the behavioral characteristics of ASD, we tested whether dysregulation of amino acids (AAs) was a pervasive phenomenon in individuals with ASD. This is the first article to report results from the Children's Autism Metabolome Project (CAMP), a large-scale effort to define autism biomarkers based on metabolomic analyses of blood samples from young children. Methods: Dysregulation of AA metabolism was identified by comparing plasma metabolites from 516 children with ASD with those from 164 age-matched typically developing children recruited into the CAMP. ASD subjects were stratified into subpopulations based on shared metabolic phenotypes associated with BCAA dysregulation. Results: We identified groups of AAs with positive correlations that were, as a group, negatively correlated with BCAA levels in ASD. Imbalances between these two groups of AAs identified three ASD-associated amino acid dysregulation metabotypes. The combination of glutamine, glycine, and ornithine amino acid dysregulation metabotypes identified a dysregulation in AA/BCAA metabolism that is present in 16.7{\%} of the CAMP subjects with ASD and is detectable with a specificity of 96.3{\%} and a positive predictive value of 93.5{\%} within the ASD subject cohort. Conclusions: Identification and utilization of metabotypes of ASD can lead to actionable metabolic tests that support early diagnosis and stratification for targeted therapeutic interventions.",
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