indolylacryloylglycine and Autistic-Disorder

A novel explanation is proposed for the metabolic differences underlying two distinct rat urinary compositional phenotypes i.e. that these may arise from differences in the gut microbially-mediated metabolism of phenylalanine. As part of this hypothesis, it is further suggested that elements of the mammalian gut microbiota may convert phenylalanine to cinnamic acid, either by means of an ammonia lyase-type reaction or by means of a three step route via phenylpyruvate and phenyllactate. The wider significance of such conversions is discussed with similar metabolism of tryptophan and subsequent glycine conjugation potentially explaining the origin of trans-indolylacryloylglycine, a postulated marker for autism.

Topics: Animals; Autistic Disorder; Bacterial Proteins; Biomarkers; Chlorogenic Acid; Clostridium; Disease Models, Animal; Fungal Proteins; Glycine; Hippurates; Humans; Intestines; Phenylalanine; Phenylalanine Ammonia-Lyase; Rats; Stereoisomerism; Systems Biology; Tryptophan; Tyrosine; Yeasts

An autism spectrum disorder (ASD) diagnosis is based on clinical behaviours as there are no validated biological diagnostic tools. Indolyl-3-acryloylglycine (IAG) is a chemical produced by gut microflora and there are conflicting reports as to whether urinary levels are elevated in children with ASD compared with controls. Urinary IAG levels in morning urine samples were statistically significantly higher in children with ASD whose caregivers reported the presence of chronic gastrointestinal (GI) disturbance than children with ASD without chronic GI disturbance. Urinary IAG, however, was not statistically significantly higher in children with ASD, compared with siblings or unrelated controls without ASD.

Topics: Autistic Disorder; Biomarkers; Child; Child Development Disorders, Pervasive; Creatinine; Female; Gastrointestinal Diseases; Glycine; Humans; Male

To test whether the presence of indolyl-3-acryloylglycine (IAG) is associated with autism, we analyzed urine from population-based, blinded cohorts. All children in York, UK with autism spectrum disorders (ASDs), diagnosed using ICD-10 research diagnostic criteria, were invited to participate. Fifty-six children on the autism spectrum (mean age 9y 8mo, SD 3y 8mo; 79% male) agreed to participate, as did 155 children without ASDs (mean age 10y, SD 3y 2mo; 54% male) in mainstream and special schools (56 of whom were age-, sex-, and school-matched to children with ASDs). IAG was found at similar levels in the urine of all children, whether IAG concentrations or IAG:creatinine ratios were compared. There was no significant difference between the ASD and the comparison group, and no difference between children at mainstream schools and those at special schools. There is no association between presence of IAG in urine and autism; therefore, it is unlikely to be of help either diagnostically or as a basis for recommending therapeutic intervention with dietary manipulation. The significance of the presence of IAG in urine has yet to be determined.

Topics: Adolescent; Autistic Disorder; Child; Child, Preschool; Cohort Studies; Diagnosis, Differential; Education, Special; Female; Glycine; Humans; Mainstreaming, Education; Male; Predictive Value of Tests; Reference Values; Syndrome

Autism is a heterogeneous pervasive developmental disorder with a poorly defined aetiology and pathophysiology. There are indications that the incidence of the disease is rising but still no definitive diagnostic biochemical markers have been isolated. Here we have addressed the hypothesis that urinary levels of trans -indolyl-3-acryloylglycine (IAG) are abnormal in patients diagnosed with autism spectrum disorders (ASD) compared to age-matched controls.. Urine samples were collected on an opportunistic basis and analysed for IAG concentration (normalised against creatinine content to account for changes in urinary volume) using reversed phase HPLC with UV detection.. Statistical analysis (Mann-Whitney tests) showed highly significant increases (p=0.0002) in the levels of urinary IAG in the ASD group (median 942 microV per mmol/L of creatinine [interquartile range 521-1729], n=22) compared to asymptomatic controls (331 [163-456], n=18). Detailed retrospective analysis showed that gender (boys 625 microV per mmol/L of creatinine [294-1133], n=29; girls 460 [282-1193], n=11: P=0.79) and age (control donor median 10 years [8-14], n=15; ASD median 9 years [7-11] n=22: P=0.54) were not significantly correlated with IAG levels in this non-blinded volunteer study.. Our results strongly suggest that urinary titres of IAG may constitute an objective diagnostic indicator for ASD. Mechanisms for the involvement of IAG in ASD are discussed together with future strategies to address its specificity.

Topics: Adolescent; Adult; Age Factors; Autistic Disorder; Biological Assay; Child; Child, Preschool; Chromatography, High Pressure Liquid; Cohort Studies; Creatine; Creatinine; Developmental Disabilities; Female; Glycine; Humans; Male; Sensitivity and Specificity; Ultraviolet Rays

HPLC analysis of the urine of autistic subjects indicated the presence of an unidentified component in greatly increased concentrations. We have reported the isolation of this component by HPLC and its identification. Mass spectrometry, NMR and UV spectroscopy identified the peak as corresponding to indolyl-3-acryloylglycine (IAG, 3), and this has been confirmed by an independent synthesis.

Topics: Autistic Disorder; Chromatography, High Pressure Liquid; Glycine; Humans; Magnetic Resonance Spectroscopy; Spectrometry, Mass, Electrospray Ionization; Spectrophotometry, Ultraviolet