Migraine with Aura and Its Association with MTHFR Gene Mutations

Migraine with aura (MA) affects one-third of people who suffer from it and is characterized by the presence of transient neurological symptoms, such as visual, sensory, or language disturbances, that precede or accompany the headache. Various studies have highlighted the relationship between migraine with aura and mutations in the MTHFR gene, which encodes the enzyme methylenetetrahydrofolate reductase, responsible for folate metabolism and the regulation of homocysteine levels. Two main mutations, C677T and A1298C, have been implicated in the risk of developing migraine with aura. The C677T mutation in the MTHFR gene can reduce enzymatic activity by up to 30% in homozygous individuals, which increases homocysteine levels, especially in those with low folate intake. Elevated homocysteine has been associated with endothelial dysfunction and inflammatory processes, both factors involved in the pathophysiology of migraine. Additionally, the A1298C mutation has also been linked to a decrease in enzymatic activity, although its impact on homocysteine levels is less significant. Genetic studies have linked these mutations to a higher susceptibility to migraine with aura. For instance, individuals with the TT genotype of the C677T mutation have a significantly higher risk of suffering from MA compared to those without the mutation. This review article discusses the pathophysiological implications of these mutations, the relationship between hyperhomocysteinemia and migraine with aura, and the possible underlying mechanisms, including oxidative stress and mitochondrial dysfunction, which may contribute to the development and severity of migraine with aura.