Abstract

1. The major pathway for the reduction of methemoglobin to functional hemoglobin in human erythrocytes involves a NADH-dependent methemoglobin reductase system. In addition to NADH, this system requires the presence in the cytosol of both cytochrome b ₅ reductase, a 32,000-dalton protein, and cytochrome b ₅, a 12,000-dalton protein. These proteins are presumed to arise from larger parent molecules in the erythroid precursors by proteolytic cleavage of their hydrophobic tails.

   
   

2. Enzymopenic hereditary methemoglobinemia (MIM 250800) is a rare recessively inherited disorder caused, in most cases, by deficiency of cytochrome b ₅ reductase only in erythrocytes (type I). Generalized cytochrome b ₅ reductase deficiency, demonstrable in all tissues that have been examined, occurs in 10 to 15 percent of cases and is accompanied by methemoglobinemia and severe, progressive, lethal neurologic disability (type II). Cytochrome b ₅ reductase deficiency limited to hematopoietic cells is also manifested by methemoglobinemia, but without neurologic effects (type III). Deficiency of cytochrome b ₅ may also lead to methemoglobinemia (type IV).

   
   

3. The gene regulating the synthesis of cytochrome b ₅ reductase has been assigned to chromosome 22. Deficiency of cytochrome b ₅ reductase has a worldwide distribution, and electrophoretic variants of the enzyme with normal catalytic properties may have an incidence as high as 1:100. Heterozygotes for cytochrome b ₅ reductase deficiency are asymptomatic but have an increased propensity to develop toxic methemoglobinemia induced by drugs or other chemicals.

   
   

4. The diagnosis of enzymopenic hereditary methemoglobinemia may be made by relatively simple laboratory determinations, but definition of the specific defect requires more sophisticated studies.

   
   

5. Effective treatment may be provided by the administration of methylene blue, ascorbic acid, or riboflavin but is often not indicated, except for cosmetic reasons. Such therapy, however, has had no demonstrable effect on the neurologic aberrations in the generalized type II disorder.

   
   

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