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  • 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 b5 reductase, a 32,000-dalton protein, and cytochrome b5, 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.

  • Enzymopenic hereditary methemoglobinemia (MIM 250800) is a rare recessively inherited disorder caused, in most cases, by deficiency of cytochrome b5 reductase only in erythrocytes (type I). Generalized cytochrome b5 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 b5 reductase deficiency limited to hematopoietic cells is also manifested by methemoglobinemia, but without neurologic effects (type III). Deficiency of cytochrome b5 may also lead to methemoglobinemia (type IV).

  • The gene regulating the synthesis of cytochrome b5 reductase has been assigned to chromosome 22. Deficiency of cytochrome b5 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 b5 reductase deficiency are asymptomatic but have an increased propensity to develop toxic methemoglobinemia induced by drugs or other chemicals.

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

  • 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.


Hereditary methemoglobinemia, an interesting albeit rare disorder (MIM 250800), has a worldwide distribution and has been known for a century and a half. In 1845, François1 described a patient with long-standing congenital cyanosis without obvious cardiac or pulmonary disease. Although altered hemoglobin pigments and drug-induced cyanosis had been reported frequently, it was 1891 before Dittrich2 established that the methemoglobinemia that developed in dogs given Blutgifte, such as nitroglycerine and acetanilide, eventually disappeared without the occurrence of anemia. He also pointed out that the methemoglobinemic cyanosis that developed in patients receiving certain medicines tended to disappear and suggested that the methemoglobin was reduced to hemoglobin within the circulating erythrocytes. Subsequently, other authors described “enterogenous cyanosis” attributed to the absorption of toxic substances from the gastrointestinal tract.3 Sulfhemoglobin present in some of these patients’ erythrocytes was differentiated from methemoglobin in 1905.4

Hitzenberger,5 in 1932, was probably the first to describe a familial incidence of idiopathic cyanosis. He suggested the possibility of congenital, familial methemoglobinemia. Between 1943 and 1945, Gibson6 and his associates7 suggested that there ...

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