Oxidative stress-related biomarkers in autism: systematic review and meta-analyses

Free Radic Biol Med. 2012 May 15;52(10):2128-41. doi: 10.1016/j.freeradbiomed.2012.03.011. Epub 2012 Apr 18.


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.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Biomarkers / blood*
  • Child
  • Child Development Disorders, Pervasive / enzymology
  • Child Development Disorders, Pervasive / genetics
  • Child Development Disorders, Pervasive / metabolism*
  • Child, Preschool
  • Glutathione / blood
  • Glutathione / metabolism
  • Humans
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Oxidative Stress*
  • Vitamins / blood


  • Biomarkers
  • Vitamins
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Glutathione