Summary
Autism Spectrum Disorders (ASD) is a prenatal disorder which originates in the first trimester of pregnancy. It affects 78 million people worldwide and has high heritability, which may reflect genetic vulnerability to shared environmental exposures. Major concerns for subjects with suspected ASD, their parents, and carers are timely access to clinical diagnosis. ASD diagnosis is based on assessments in structured observations, interviews and examinations, medical/developmental review, and assessment instruments. These assessments are made by a multidisciplinary team of child and adolescent psychiatrists, child neurologists, developmental-behavioral pediatricians, or child psychologists. It is currently standardized to the Diagnostic and Statistical Manual of Mental Disorders-5 criteria (DSM-5) with recommended duration of the diagnostic procedure of 3 to 6 months. Due to a global shortage of specialists trained to assess suspected children using these established criteria, and the growing prevalence of the condition, diagnosis is often preceded by a long delay, in some cases greater than one year, from first referral to expert team evaluation.
There is an unmet clinical need for diagnostic techniques based on biomarkers which corroborate well with diagnosis of ASD by experts in child development. To meet this we developed a blood test for autism based in protein glycation and oxidation adduct content of plasma protein.
In 2018, we reported a discovery study of a blood test which met the American Psychiatry Association (APA) Work Group threshold classification criteria of ≥80% sensitivity and specificity. Our test was based on an algorithm with features of four plasma protein glycation and oxidation adducts – namely Nε-carboxymethyl-lysine (CML), Nω-carboxymethyl-arginine (CMA), 3-deoxyglucosone-derived hydroimidazolone (3DG-H) and dityrosine (DT). The test had accuracy 88%, sensitivity 92% and specificity 84% in children 5 – 12 years old.
Plasma protein glycation and oxidation adducts occur mostly in albumin, accounting for 60% of plasma protein, which has a half-life of 3 weeks. Plasma protein glycation and oxidation adduct levels thereby reflect changes in precursor glycation and oxidation processes occurring over the 3 – 4 weeks preceding blood sampling. Albumin in cerebrospinal fluid (CSF) exchanges relatively rapidly with albumin in plasma (half-life 3.3 h), so albumin modifications detected in plasma have contributions from those occurring in CSF.
In 2023 we reported successful clinical validation of this test in a large international multicenter independent clinical cohort (N = 478) with application to a wider age range of 1.5 – 12 years old children. ASD severity, as assessed by ADOS-2 score, correlated positively with plasma protein glycation adducts derived from methylglyoxal, hydroimidazolone MG-H1 and Nε(1-carboxyethyl)lysine (CEL).
The successful validation may indicate that the algorithm modifiable features are mechanistic risk markers linking ASD to increased lipid peroxidation, neuronal plasticity and proteotoxic stress. The correlation of ASD severity to methylglyoxal-derived glycation adducts of plasma protein may indicate severe symptoms are related to exposure to increased methylglyoxal. The food supplement which decreases clinical levels of methylglyoxal, glyoxalase 1 inducer trans-resveratrol and hesperetin in combination (tRES+HESP), deserves evaluation for alleviate of severe ASD.
Summary scheme
Footnote: Data and classification outcomes are from the discovery phase study – Anwar et al. (2018) Molecular Autism 9, 3.
Principal publications
Anwar, A., Abruzzo, P.M., Pasha, S., Rajpoot, K., Bolotta, A., Ghezzo, A., Marini, M., Posar, A., Visconti, P., Thornalley, P.J. and Rabbani, N. (2018) Advanced glycation endproducts, dityrosine and arginine transporter dysfunction in autism – a source of biomarkers for clinical diagnosis Molecular Autism 9, 3.
Al-Saei, A.N.J.M., Eldine, W.N., Rajpoot, K., Arshad, N., Al-Shammari, A.R., Kamal, M., Al-Shabeeb Akil, A., Fakhro, K.A., Thornalley, P.J. and Rabbani, N. (2023) Validation of plasma protein glycation and oxidation biomarkers for the diagnosis of autism. Molecular Psychiatry, https://doi.org/10.1038/s41380-023-02357-9.