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Cited by 86Autism Spectrum Disorder ResearchAdvanced Glycation End Products researchChild Nutrition and Feeding Issues

Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism - a source of biomarkers for clinical diagnosis

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Anwar, Attia, Abruzzo, Provvidenza Maria, Pasha, Sabah, Rajpoot, Kashif, Bolotta, Alessandra, Ghezzo, Alessandro, Marini, Marina, Posar, Annio +3 more·2018·Molecular Autism
DOI 10.1186/s13229-017-0183-3PMC PMC5817812
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Abstract

Background: Clinical chemistry tests for autism spectrum disorder (ASD) are currently unavailable. The aim of this study was to explore the diagnostic utility of proteotoxic biomarkers in plasma and urine, plasma protein glycation, oxidation, and nitration adducts, and related glycated, oxidized, and nitrated amino acids (free adducts), for the clinical diagnosis of ASD. Methods: Thirty-eight children with ASD (29 male, 9 female; age 7.6 ± 2.0 years) and 31 age-matched healthy controls (23 males, 8 females; 8.6 ± 2.0 years) were recruited for this study. Plasma protein glycation, oxidation, and nitration adducts and amino acid metabolome in plasma and urine were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Machine learning methods were then employed to explore and optimize combinations of analyte data for ASD diagnosis. Results: -carboxymethylarginine (CMA), and increased oxidation damage marker, dityrosine (DT), in plasma protein, with respect to healthy controls. We also found that children with ASD had increased CMA free adduct in plasma ultrafiltrate and increased urinary excretion of oxidation free adducts, alpha-aminoadipic semialdehyde and glutamic semialdehyde. From study of renal handling of amino acids, we found that children with ASD had decreased renal clearance of arginine and CMA with respect to healthy controls. Algorithms to discriminate between ASD and healthy controls gave strong diagnostic performance with features: plasma protein AGEs-CML, CMA-and 3-deoxyglucosone-derived hydroimidazolone, and oxidative damage marker, DT. The sensitivity, specificity, and receiver operating characteristic area-under-the-curve were 92%, 84%, and 0.94, respectively. Conclusions: Changes in plasma AGEs were likely indicative of dysfunctional metabolism of dicarbonyl metabolite precursors of AGEs, glyoxal and 3-deoxyglucosone. DT is formed enzymatically by dual oxidase (DUOX); selective increase of DT as an oxidative damage marker implicates increased DUOX activity in ASD possibly linked to impaired gut mucosal immunity. Decreased renal clearance of arginine and CMA in ASD is indicative of increased arginine transporter activity which may be a surrogate marker of disturbance of neuronal availability of amino acids. Data driven combination of these biomarkers perturbed by proteotoxic stress, plasma protein AGEs and DT, gave diagnostic algorithms of high sensitivity and specificity for ASD.

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  • Plasma CML levels were increased in children with autism spectrum disorders (n = 38) compared with healthy children (n = 31), measured by LC-MS/MS.

    “| Autism spectrum disorders | Plasma | Healthy children (n = 31) vs. children with autism spectrum disorders (n = 38) | LC-MS/MS | Increased plasma CML levels in children with autism spectrum disorders | [143] |”

    From Protein oxidation - Formation mechanisms, detection and relevance as biomarkers in human diseases (2021) · cites this paper as [143]

    The Results report increased CML in plasma protein from children with ASD, and the Methods say plasma-protein adducts were measured by LC-MS/MS. Although the Subject recruitment section lists 38 children with ASD and 31 typically developing children, Results Table 2 gives 27 and 21, respectively, for the plasma-protein measurements. The cited row therefore uses the recruitment totals rather than the numbers underlying the reported CML increase. (LLM, conf=0.90)

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Authors
Anwar, A., Abruzzo, P. M., Pasha, S., Rajpoot, K., Bolotta, A., Ghezzo, A., Marini, M., Posar, A., Visconti, P., Thornalley, P. J., & Rabbani, N.
Affiliations
  • University Hospital Coventry (GB)
  • Don Carlo Gnocchi Foundation (IT)
  • University of Birmingham (GB)
  • University of Bologna (IT)
  • Institute of Neurological Sciences (IT)
Corresponding author
Rabbani, Naila
ORCID
Venue
Molecular Autism
Publisher
Springer Science and Business Media LLC
Published
2018-02-19
Volume
9
Issue
1
Pages
3-3
ISSN
2040-2392 (ISSN-L)
DOI
10.1186/s13229-017-0183-3
PMC
PMC5817812
OpenAlex
W2782785236
Cited by
86
References
3
Citations by year
2026: 6 · 2025: 13 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 13 · 2020: 12 · 2019: 14 · 2018: 11
FWCI
7.45
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Autism (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
  • Warwick Research Archive Portal (University of Warwick) (submittedVersion)
Funders
  • Warwick Impact Fund award
  • Fondazione del Monte di Bologna e Ravenna,
  • Fondazione Nando Peretti
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Health Sciences › Medicine › Psychiatry and Mental health › Child Nutrition and Feeding Issues
Keywords
autism spectrum disorder, advanced glycation end products, dityrosine, biomarkers, oxidative damage, alpha-aminoadipic semialdehyde, dual oxidase, 3-deoxyglucosone, glyoxal, amino acid metabolism
MeSH terms
Machine Learning, Arginine, Autistic Disorder, Child, Female, Humans, Lysine, Male, Sensitivity and Specificity, Tyrosine, Biomarkers, Glycation End Products, Advanced, Oxidative Stress, Amino Acid Transport Systems, Basic

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