Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency

Methylenetetrahydrofolate reductase (MTHFR; MIM #607093; E.C. 1.5.1.20) is a cytoplasmic enzyme that catalyzes the physio- logically irreversible reduction of 5,10-methylenetetrahydrofolate (methyleneTHF) to 5-methyltetrahydrofolate (methylTHF), a re- action that requires NADPH as electron donor and FAD as cofac- tor. Severe deficiency of MTHFR, first described in 1972 [Mudd et al., 1972; Shih et al., 1972], is inherited in an autosomal-recessive manner. It remains the most common metabolic disorder of fo- late metabolism [Watkins and Rosenblatt, 2014], although the in- cidence is likely very rare, for example, two individuals were de- tected in >400,000 retrospective newborn screening (NBS) samples [Tortorelli, et al., 2010]. It is characterized by hyperhomocysteine- mia, with elevated plasma S-adenosylhomocysteine, homocystin- uria, increased plasma cystathionine, as well as low/normal plasma methionine and S-adenosylmethionine (AdoMet). These metabolic imbalances result from decreased flux through methionine synthase (EC 2.1.1.13; MIM #156570), which depends on the methylTHF generated by MTHFR to serve as methyl donor for the methylation of homocysteine to methionine. Methionine in turn is converted to AdoMet, which is the vital cellular methyl donor [Watkins and Rosenblatt, 2014] as well as an allosteric regulator of homocysteine metabolism.