Methemoglobinemia hereditary

Jaffe ER, Hultquist DE Cytochrome reductase deficiency and enzymopenic hereditary methemoglobinemia. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR et al (editors). McGraw-Hill, 2001. 

Hereditary methemoglobinemia is classified into three types a red blood cell type (type I), a generalized type (type II), and a blood cell type (type HI). Enzyme deficiency of type I is limited to red blood cells, and these patients show only the diffuse, persistent, slate-gray cyanosis not associated with cardiac or pulmonary disease. In type II, the enzyme deficiency occurs in all cells, and patients of this type have a severe neurological disorder with mental retardation that predisposes them to early death. Patients with type III show symptoms similar to those of patients with type I. The precise nature of type III is not clear, but decreased enzyme activity is observed in all cells (M9). It is considered that uncomplicated hereditary methemoglobinemia without neurological involvement arises from a defect limited to the soluble cytochrome b5 reductase and that a combined deficiency of both the cytosolic and the microsomal cytochrome b5 reductase occurs in subjects with mental retardation. Up to now, three missense mutations in type I and three missense mutations, two nonsense mutations, two in-frame 3-bp deletions, and one splicing mutation in type n have been identified (M3, M8, M31). 

M8. Manabe, J., Arya, R Sumimoto, H., Yubisui, T., Bellingham, A. J Layton, D. M., and Fuku-maki, Y., Two novel mutations in the reduced nicotinamide adenine dinucleotide (NADH)-cy-tochrome b5 reductase gene of a patient with generalized type, hereditary methemoglobinemia. 

On the other hand, highly purified preparations (180-fold) obtained by Huennekens and his co-workers (H22) have been shown to be a hemo-protein with a molecular weight of approximately 185,000. With regard to these different results it is interesting that in RBC of individuals suffering from hereditary methemoglobinemia a complete lack of NAD diaphorase has been reported (S10, Sll) this would indicate the importance of an enzyme which contains FAD. The reasons for the discrepancies between the preparations obtained by two teams of investigators are not understood as yet. Perhaps they are implicated in the electron transport mechanisms or in the nature of a certain cofactor which is to be discussed now. 

Hereditary methemoglobinemia arises from a deficiency of the enzyme that catalyzes this reduction, NADH-cytochrome b reductase. 

NADH-cytochrome b5 reductase deficiency (OMIM 250800) is an autosomal recessive disorder, causing hereditary methemoglobinemia. There are three types. In type I, the enzyme is deficient only in erythrocytes. Patients are typically blue and/or gray and cyanotic, but not very sick. Type II is more severe, the enzyme being completely deficient, causing mental retardation and neurological impairment. In type III the enzyme is deficient in all blood cells. 

Hereditary methemoglobinemia is a rare condition first described in Europeans but later found in individuals of many racial backgrounds. Familial methemoglobinemia in an autosomal recessive mode of transmission is due to a deficiency in the enzyme NADH-cytochrome b5 reductase. Hb variants that stabilize the ferric iron state are associated with an autosomal dominant famUial methemoglobinemia. Methemoglobinemia is treated by the administration of ascorbic acid or methylene blue. 

A condition described as "hereditary methemoglobinemia" may result from a genetic defect (Goldstein et al. 1969). The enzyme methemoglobin reductase is absent and persons are hypersensitive to any substances such as nitrite or aniline derivatives capable of producing methemoglobinemia. The trait is inherited as an autosomal recessive allele. Thus either sex may exhibit the trait which is ordinarily detected by the presence of cyanosis at birth. Such individuals would be extremely sensitive to the effects of nitrobenzene. 

Hsieh, H.-S., and Jaffe, E. R., 1971, Electrophoretic and functional variants of NADH-methemoglobin reductase in hereditary methemoglobinemia, /. Clin. Invest. 50 196. 

Methemoglobinemia arises from poisoning with MHb-forming substances and from the hereditary deficiency of an enzyme system which either provides reduced pyridine nucleotides for MHb reduction or is involved itself in the MHb reduction mechanism (e.g., electron transport system). (See Section II of the Addendum, page 280.)... 

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