Association of methylenetetrahydrofolate reductase genetic polymorphisms with atlantoaxial dislocation

OBJECT: Genetic mechanisms of atlantoaxial dislocation (AAD) have not previously been elucidated. The authors studied association of polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, which encodes enzymes of the folate pathway (implicated in causation of neural tube defects [NTDs]), in patients with AAD. METHODS: Molecular analysis of MTHFR polymorphisms (677C-->T, cytosine to thymine and, 1298A-->C, adenine to cytosine, substitutions) was carried out using polymerase chain reaction and restriction enzyme digestion in 75 consecutive patients with AAD and in their reducible (nine patients, 12%) and irreducible (66 patients, 88%) subgroups. Controls were 60 age- and sex-matched patients of the same ethnicity. Comparisons of genotype and allele frequencies were performed using a chi-square test (with significance at p < 0.05). RESULTS: The CT genotype frequency of MTHFR 677C-->T polymorphism was significantly increased in the full group of patients with AAD (odds ratio [OR] 3.00, 95% confidence interval [CI] 1.28-7.14, p = 0.005) as well as in the irreducible subgroup (OR 2.81, 95% CI 1.17-6.86, p = 0.01). The frequency of T alleles was also higher in the AAD group (25.3%) than in controls (15%). The comparison of the combined frequency of CT and TT genotypes with the frequency of the CC genotype again showed significant association in AAD (OR 2.63, 95% CI 1.98-5.90, p = 0.009) and the irreducible (OR 2.5, 95% CI 1.1-5.74, p = 0.016) subgroup. There was, however, no significant association of MTHFR 1298A-->C polymorphism with AAD. CONCLUSIONS: Both MTHFR 677C-->T polymorphism and higher T allele frequency have significant associations with AAD, especially the irreducible variety. Perhaps adequate supplementation of periconceptional folic acid to circumvent effects of this missense mutation (as is done for prevention of NTDs) would reduce the incidence of AAD.