title: Oxidative stress-related biomarkers in autism: systematic review and meta-analyses.
abstract: Autism spectrum disorders (ASDs) are rarely diagnosed in children younger than 2 years, because diagnosis is based entirely on behavioral tests. Oxidative damage may play a central role in this pathogenesis, together with the interconnected transmethylation cycle and transsulfuration pathway. In an attempt to clarify and quantify the relationship between oxidative stress-related blood biomarkers and ASDs, a systematic literature review was carried out. For each identified study, mean biomarker levels were compared in cases and controls providing a point estimate, the mean ratio, for each biomarker. After meta-analysis, the ASD patients showed decreased blood levels of reduced glutathione (27%), glutathione peroxidase (18%), methionine (13%), and cysteine (14%) and increased concentrations of oxidized glutathione (45%) relative to controls, whereas superoxide dismutase, homocysteine, and cystathionine showed no association with ASDs. For the C677T allele in the methylene tetrahydrofolate reductase gene (MTHFR), homozygous mutant subjects (TT) showed a meta-OR of 2.26 (95% CI 1.30-3.91) of being affected by ASD with respect to the homozygous nonmutant (CC). Case-control studies on blood levels of vitamins suggest a lack of association (folic acid and vitamin B12) or rare association (vitamins A, B6, C, D, E). Sparse results were available for other biomarkers (ceruloplasmin, catalase, cysteinylglycine, thiobarbituric acid-reactive substances, nitric oxide) and for polymorphisms in other genes. Existing evidence is heterogeneous and many studies are limited by small sample size and effects. In conclusion, existing evidence suggests a role for glutathione metabolism, the transmethylation cycle, and the transsulfuration pathway, although these findings should be interpreted with caution, and larger, more standardized studies are warranted.
authors.affiliation: Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, 00166 Roma, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Frustaci
authors.forename: Monica
authors.initials: M
authors.lastname: Neri
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cesario
authors.forename: James B
authors.initials: JB
authors.lastname: Adams
authors.forename: Enrico
authors.initials: E
authors.lastname: Domenici
authors.forename: Bernardo
authors.initials: B
authors.lastname: Dalla Bernardina
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonassi
mesh_terms: D015415:Biomarkers / Q000097:blood*; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D002675:Child, Preschool; D005978:Glutathione / Q000097:blood / Q000378:metabolism; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D018384:Oxidative Stress; D014815:Vitamins / Q000097:blood
chemical_list: D015415:Biomarkers; D014815:Vitamins; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D005978:Glutathione