Molecular genetics of methylenetetrahydrofolate reductase deficiency

In severe MTHFR deficiency with neonatal or adolescent onset, 9 rare mutations have been identified. In mild MTHFR deficiency with thermolabile enzyme, a single common mutation (an alanine-to-valine substitution) is involved, but a genetic-nutrient interactive effect is required to produce mild hyperhomocysteinaemia. This interactive effect has been proposed to be a risk factor for arteriosclerosis and for neural-tube defects. Large-scale studies are required for confirmation of the role of MTHFR in these multifactorial processes as well as to assess its role in other folate-dependent disorders.