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BackgroundClinical 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.MethodsThirty-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.ResultsWe found that children with ASD had increased advanced glycation endproducts (AGEs), Nε-carboxymethyl-lysine (CML) and Nω-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.ConclusionsChanges 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.Electronic supplementary materialThe online version of this article (10.1186/s13229-017-0183-3) contains supplementary material, which is available to authorized users.

Subcortical band heterotopia (SBH) and classical lissencephaly (LIS) result from deficient neuronal migration which causes mental retardation and epilepsy. A single LIS/SBH locus on Xq22.3-q24 was mapped by linkage analysis and physical mapping of the breakpoint in an X;2 translocation. A recently identified gene, doublecortin ( DCX ), is expressed in fetal brain and mutated in LIS/SBH patients. We have identified four novel missense mutations in the gene, one familial mutation with LIS in a male and SBH in the carrier females, one de novo mutation in an SBH female, and two mutations in sporadic SBH female patients. The DCX gene is found to be expressed exclusively at a very high level in the adult frontal lobe. We have also cloned the X-linked mouse doublecortin (Dcx) gene. It encodes isoforms of a highly hydrophilic 40 kDa protein, homologous to its human counterpart and containing several potential phosphorylation sites. Both human and mouse DCX proteins are homologous to a CNS protein containing a Ca2+/calmodulin kinase domain, suggesting that the DCX protein may belong to a novel class of intracellular proteins involved in neuronal migration through Ca2+-dependent signaling.