Genetic Modulation of One-Carbon Metabolism in Autism Spectrum Disorder: An MTHFR-Based Cross-Sectional Study with...

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition in which disruptions in one-carbon metabolism, regulated by methylenetetrahydrofolate reductase (MTHFR), may contribute to phenotypic variability. This study investigated MTHFR C677T and A1298C polymorphisms and their association with serum vitamin B12, folate, and ASD risk in children.

One hundred children with ASD and 100 age-matched neurotypical controls were enrolled. MTHFR genotyping was performed by allele-specific real-time PCR. Serum vitamin B12 and folate by enzyme-linked immunosorbent assay. Associations were assessed using logistic regression under dominant, additive, and recessive genetic models. Discrimination was evaluated by receiver operating characteristic analysis.

The C677T TT genotype was overrepresented in ASD cases (57% vs. 43% controls), with significant Hardy-Weinberg deviation (χ² = 21.812, p <0.0001). Mutant A1298C genotypes were observed in 79% of cases. Vitamin B12 declined with increasing C677T T-allele dosage (p <0.001) and folate with A1298C C-allele burden (p = 0.003). Higher vitamin B12 independently associated with reduced ASD odds (OR 0.36, 95% CI 0.17-0.76, p = 0.008). C677T TT homozygosity was significantly associated with increased ASD odds under the recessive model (OR 1.76, 95% CI 1.00-3.08, p = 0.049). A1298C was non-significant across all models, indicating modest discrimination suitable for exploratory purposes only.

Children with ASD showed a high burden of functional MTHFR variants with genotype-linked metabolic variation. TT homozygosity was associated with ASD risk under recessive model, supporting a threshold-dependent genetic effect on one-carbon metabolism. These findings warrant prospective validation in larger independent cohorts.