Case control study Cases: 168 Caucasian children 148 (84.5%) males 26 (5.5%) females Controls: 5389 Caucasians
73.8% autism, 26.3% PDD diagnosed by neurologist, psychiatrist, or neuropsychologist. DSM IV criteria used for diagnosis
Frequency of MTHFR alleles 677CT 1298AC in cases and controls
Significantly increased () frequencies of homozygous mutation 677CT allele (23% in cases versus 11% in controls) and heterozygous 677CT allele (56% in cases versus 41% in controls). Overall increased risk of ASD associated with common mutations affecting the folate/methylation cycle.
Case control study Cases: 80 Caucasian children from autism clinics 89% males 11% females Mean age yrs. Controls: 73 unrelated healthy Caucasian from a metabolic study Mean age: yrs.
Autism diagnoses: by independent specialists DSM IV or ADOS or CARS criteria
Plasma methionine and SAM/SAH ratio was significantly lower in autistic cases as compared to age matched controls (an indicator of lower methylation capacity). Antioxidant capacity as indicated by plasma levels of cysteine and glutathione was significantly decreased in cases. Significant increase in odds ratio, allele frequency, and genotype distribution among autistic cases were found for RFC-1 80A>G, TCN2 776C>G, and COMT 472G>A genes. An increase in frequency of MTHFR 667C>T reached border line significance in autistic cases. Increased vulnerability to oxidative stress related to folate metabolism may contribute to development of autism.
There was no significant difference in serum folate levels between autistic cases and controls. The mean CSF level of MTHF was significantly lower than controls (27.3 nmol/L compared to 82.0 nmol/L). Autistic cases with low CSF MTFR had autoantibodies of blocking type against human FR. The reduced CSF folate in autistic cases was associated with FR autoantibodies blocking the folate binding site.
CHARGE population based case control study Cases: 284 autistic and 141 children with ASD between ages 2–5 years Controls: 278 children with typical development
Consumption of prenatal multivitamins, nutrient specific vitamins at any time during the period of 3 months before conception through pregnancy Maternal, paternal, and child samples were genotyped for MTHFR 667C>T MTHFR A1298C COMT 472G>A MTRR A66G TCN2
Use of prenatal vitamins during 3 months before and first month of pregnancy was associated with reduced risk of autism. (OR = 0.62, 95%. C.I. = 0.42–0.93). No association observed for vitamins intake during months 2 through 9 of pregnancy. Significant interactions were observed for autism between lack of perinatal maternal prenatal vitamin intake and both maternal MTFHR 667TT and CBSrs 234715GT+TT genotypes. With combined OR = 4.5, C.I. = 1.4–14.6 and 2.6 (1.2–5.4), respectively.
CHARGE case control study Cases: 429 children with ASD Controls: 278 children with typical development. Cases and controls were frequency matched to age and catchment area distribution of autism cases with a 4 : 1 male-to-female ratio
The diagnoses of autism cases were confirmed by the Autism Diagnostic Interview-Revised (ADI-R) and by ADOS. The two initially identified subgroups, ASD and Autism, were later collapsed and results presented for combined ASD groups
Maternal folic acid intake was calculated from data on intake of multivitamins and prenatal vitamin including folic acid specific vitamins, cereal, and supplements during the index period (3 months before and throughout pregnancy) Maternal and cases MTHFR 667C>T was genotyped
The mean (SEM) folic acid intake was significantly greater for typical development children than for mothers of children with ASD () in first month of pregnancy. A mean folic acid intake of ≥600 µg versus <600 µg was associated with reduced risk of ASD (AOR = 0.62, 95% C.I. = 0.42–0.92) The association between folic acid and reduced ASD risk was strongest for mothers and children with MTHR 667C>T variant genotype. Periconceptional folic acid may reduce ASD risk in those with inefficient folate metabolism.
Population based prospective study The study sample of 85,175 children born in 2002–2008 was derived from Primary Norwegian Mother and Child Cohort study (MoBa), with the mean age of 6.4 years Exposure of interest was use of folic acid from 4 weeks before to 8 weeks after the start of pregnancy
Cases of ASD confirmed by linkages to the Norwegian Patient registry, capturing data for all children diagnosed with ASD by Norwegian health services
Specialist confirmed diagnoses of ASD
270 children who were in the study sample were diagnosed with ASD at the end of the study. In children whose mother took folic acid, 0.10% had ASD as compared to 0.21% in those unexposed to folic acid. The AOR for autistic children of folic acid users was 0.61, 95% C.I. = 0.41–0.90 as compared to folic acid nonusers. There was no association with Asperger syndrome or PDD-NOs, but power was limited. Use of prenatal folic acid supplements around the time of conception was associated with a significantly lower risk of ASD in the MoBa cohort.
Enzymes and their alleles: MTHFR: 5,10-methylenetetrahydrofolate reductase COMT: catechol-O-methyltransferase MTR: methyltetrahydrofolate homocysteine methyl transferase TCN2: transcobalamin II CBS: cystathionine -synthase.
