MTHFR and hyperinsulinemic hypoglycemia, familial, 4: ,17 Biochemically, severe MTHFR deficiency is associated with massive accumulation of homocysteine in the blood (hyperhomocysteinemia), i.e., plasma homocysteine elevated up to 60–320 μM; reference range typically 5–15 μM) together with low or low-normal plasma methionine.18