Clinical Information

Cytochrome b5 reductase (CYB5R), also called methemoglobin reductase, is the enzyme within the erythrocyte that maintains hemoglobin in the reduced (non-methemoglobin) state. A deficiency of CYB5R in erythrocytes is an autosomal recessive disorder resulting from variants in the CYB5R3 or the CYB5A genes.

Persons who are heterozygous for CYB5R genetic variants have no clinical or laboratory abnormalities, are not cyanotic, and have normal methemoglobin concentrations in their blood. However, they hold an increased risk for more severely symptomatic acute episodes of methemoglobinemia with exposure to inducing agents.

Persons who are homozygous for CYB5R genetic variants have normal arterial oxygen saturation but have varying quantities of methemoglobin in their blood, generally 15% to 20%, and are quite cyanotic. Paradoxically, homozygous individuals typically have normal blood counts; the condition only rarely causes polycythemia. The presence of methemoglobin shifts the hemoglobin-oxygen dissociation curve to the right, so although the transport of oxygen is diminished, the delivery of oxygen to tissues is normal. Because of the chronicity, the homozygous condition is usually compensated and, therefore, quite benign, but it may cause concern to parents of affected children, be a cosmetic embarrassment to the children, and alarm the attending physician. The cyanosis may be treated with methylene blue.