Folate-Responsive Homocystinuria and Schizophrenia: A Defect in Methylation Due to Deficient 5,10-Methylenetetrahydrofolate Reductase Activity

Homocystinuria and homocystinemia without hypermethioninemia, but with recurrent episodes of folate responsive schizophrenic-like behavior, was documented in a mildly retarded adolescent girl who lacked the habitus associated with cystathionine synthase deficiency. Enzymes involved in homocysteine-methionine metabolism were demonstrated to be normal. A defect in the ability to reduce N-5–10-methylenetetrahydrofolate to 5-methyltetrahydrofolate was demonstrated. Methylenetetrahydrofolate reductase was 18 per cent of control values. Methyltetrahydrofolate is used for the methylation of homocysteine to methionine, and a deficiency of this compound could explain the homocystinemia and homocystinuria. (N Engl J Med 292: 491–496, 1975), THE most frequently encountered cause of homocystinuria, an aminoaciduria described in 1962,^1,2 has been deficient activity of cystathionine-β-synthase (E.C.4.2.1.22), the enzyme that catalyzes the condensation of homocysteine with serine.³ However, homocystinuria has also been described as a consequence of defects in the methylation of homocysteine to methionine^4,5 and of the administration of 6-azauridine triacetate.⁶ The case reported below concerns a girl with a previously unrecognized cause of homocystinuria: a deficient activity of 5,10-methylenetetrahydrofolate reductase (E.C.1.1.1.68). This enzyme is necessary for the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a compound that serves as the methyl donor for the methylation of homocysteine to.