We retrospectively examined the laboratory data of 168 children sequentially referred to our facility with a confirmed diagnosis of autism or pervasive developmental disabilities (PDD).
Since folate and methylation (single carbon metabolism) are vital in neurological development, we routinely screened children for the common mutations of the methylenetetrahydrofolate reductase gene (MTHFR), which regulates this pathway.
All children had… DNA evaluation to determine the frequency of the 677 and 1298 common polymorphisms in the MTHFR gene.
We observed a significantly increased frequency of the homozygous mutation 677CT allele (TT): 23% in the autistic children compared to 11% in the control population.
Overall, the data show an increased risk of autism spectrum disorder (ASD) associated with common mutations affecting the folate/methylation cycle. These associations by themselves may provide a partial explanation for a subgroup of children genomically at risk for ASD disorders.
Clinically available testing for methylenetetrahydrofolate reductase (MTHFR) gene mutations (polymorphisms) has recently become available and had been incorporated into our evaluation process for developmentally delayed children. The MTHFR gene codes for an essential enzyme in folate metabolism.
Common polymorphisms in the MTHFR gene have been associated with reduced enzyme activity.
The heterozygous 677CT genotype ranges from 13% in Africans to 51% in Italians and 44% in North American Caucasians. The homozygous 677TT rate in the last group is 12%.
The 677C>T allele is characterized by a mutation of a cytosine to a thymine giving rise to an amino acid replacement of valine for alanine in the catalytic domain of the enzyme. Homozygosity for the mutant T allele is associated with a 60% reduction in enzyme activity.
Compound heterozygosity for both the 677CT and 1298AC is associated with a decrease of approximately 50%-60% in MTHFR activity.
Heterzygosity for both the 677CT and 1298AC was identified in 25% of the ASD children, but only 15% of the controls.
The data demonstrate that 677C>T polymorphisms, whether homozygous or heterozygous, are significantly associated with ASD. The homozygous (TT) individuals are reported to have an approximately 50% decrease in MTHFR enzyme activity, and the heterozygous (CT) a 30% decrease in enzyme activity.
Notably, only 2% of children with ASD in our study presented without at least one polymorphism in the MTHFR gene.
It is unlikely that any single polymorphism accounts for the majority of autistic risk factors.
Given the rising prevalence of ASD, it may indicate emergence of a new environmental risk factor that exposes this genomic vulnerability commonly present in the folate pathway.
This study does not take into account the numerous potential influencing cofactors, which may be additive to the MTHFR observations, e.g… environmental exposures, or heavy-metal exposure. It is likely some combination of these influences the phenotypic expression (ASD symptoms) of the genomic risk factors (MTHFR polymorphisms).