Defective MTRR causes HMAE

Defects in MTRR cause methylcobalamin deficiency type E (cblE; methionine synthase reductase deficiency; MIM:236270). Patients with cblE exhibit megaloblastic anemia and hyperhomocysteinemia. SAM is used as a methyl donor in many biological reactions and demethylation of SAM produces S-adenosylhomocysteine, which is deadenosylated to form homocysteine. Homocysteine remethylation is carried out by MTR, which requires MTRR to maintain enzyme-bound cobalamin (Cbl) in its active form; but in cblE patients, MTR becomes inactivated and thus homocysteine accumulates.

Summary from Reactome (R-HSA-3359467), read 2026-09-23.