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

Alessandra Frustaci, Monica Neri, Alfredo Cesario, James Adams, Enrico Domenici, Bernardo Dalla Bernardina, Stefano Bonassi

Research output: Contribution to journalReview articlepeer-review

262 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2128-2141
Number of pages14
JournalFree Radical Biology and Medicine
Issue number10
StatePublished - May 15 2012


  • Amino acids
  • Antioxidants
  • Autistic disorder
  • Biological markers
  • Case-control studies
  • Free radicals
  • Genetic polymorphisms
  • Glutathione
  • Oxidative stress
  • Oxidoreductases
  • Vitamins

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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