Enhanced Genetic Vulnerability to Amyotrophic Lateral Sclerosis: Insights from a Case–Control Study on the MTHFR C677T Variant in a Brazilian Population

Background/Objectives: Amyotrophic Lateral Sclerosis (ALS) is a rare, neurodegenerative disease with complex genetic and environmental determinants. The MTHFR C677T (rs1801133) variant, known for reducing enzymatic activity in the folate cycle, has been implicated in ALS risk, though findings remain inconsistent across diverse populations. Methods: A population-based case–control study was conducted in 248 age-matched individuals to investigate the MTHFR C677T (rs1801133) and ALS susceptibility. Molecular analysis was performed using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Genetic associations were evaluated under multiple inheritance models, while survival analysis utilized the Kaplan–Meier method to assess the relationship between MTHFR genotypes and patient prognosis. Results: The C677T variant showed a significant association under the codominant and recessive models, suggesting involvement in ALS risk (OR = 4.63; p = 0.01 and OR = 3.92; p = 0.02), respectively. However, stratification by sex demonstrated an association predominantly in women (OR = 7.10, p = 0.02; OR = 5.87, p = 0.04). Additionally, Kaplan–Meier analysis revealed a numerically shorter mean survival time for the mutant genotype compared with wild-type and heterozygous carriers, without statistical significance. Conclusions: Notably, we identified a significant association between the MTHFR C677T (rs1801133) variant and ALS risk, particularly among women. These findings suggest that the mutant (T/T) genotype showed a stronger association, potentially reflecting postmenopausal hormonal influences on one-carbon metabolism and related susceptibility pathways.