Congenital methemoglobinemia methemoglobin reductase deficiency.

Shortly after the first white settlers crossed through the Cumberland Gap into the western foothills of the Appalachians there arose in one kinship several particu­ larly swarthy offspring characterized by deep bluish skin coloration. These folks — the Blue Fugates — apparently suffered no ill effects of this condition and indeed numerous off-spring were bom some of which also had this peculiar cyanotic ap­ pearance. The tale of an Indian princess being an ancestor in this family tree is more likely due to the resemblance of the skin color to the Shawnees of the “dark and bloody ground,” i.e., Kentucky. In time the condition yielded to the ad­ vances of biomedical science and the exact biochemical lesion associated with these dark-skinned folks was determined. While being much more accurate and precise such knowledge is not nearly so exciting. The deep color in these people has been shown to be due to methemoglobin (M eH b). W hen the ferrous (+ 2 ) atom of the hemoglobin molecule is converted (oxidized) to the ferric ( +3) state by the addition of the OH group the resulting molecule is called MeHb. This process of MeHb production is occurring continually. Reducing enzymes continually convert methemoglobin to the physiologically use­ ful hemoglobin which is capable of trans­ porting oxygen and carbon dioxide. These two counter mechanisms result in a steady state of blood MeHb of about one percent or less of the total hemoglobin concen­ tration. In general two large classes of methemo­ globinemia are known i.e. the congenital and acquired varieties. The acquired va­ riety is caused by the ingestion, inhalation or absorption through the skin of a great variety of drugs and chemicals. Chemicals include inorganic as well as organic com­ pounds. The nitrites and nitrates are causal particularly in infants. Congenital or familial methemoglobi­ nemia is due to an insufficiency or decom­ pensation of the normal biochemical process (an rbc enzyme function) which ordinarily keep methemoglobin levels at very low levels. This is a function of the red cell enzyme, methemoglobin reductase, at times called diaphorase. It is an NADH dependent enzyme. A deficiency of this enzyme results in a build-up of methemo­ globin in the affected individual. Recently Bloom and Zarkowsky have in­ vestigated several unrelated patients with methemoglobin reductase deficiency.1 Three distinct and different types of enzyme de­ ficiency were reported. These included a complete absence of detectable enzyme,