Generalised deficiency of cytochrome b₅ reductase in congenital methaemoglobinaemia with mental retardation

Abstract

RED cells from patients suffering from congenital recessive methaemoglobinaemia are deficient in a reduced nicotinamide dinucleotide (NADH) diaphorase which has a major role in the process of methaemoglobin reduction^1–3. This enzyme seems to be identical, or at least related to cytochrome b₅ reductase (EC 1.6.2.2) for the following reasons: (1) a red-cell-type NADH diaphorase has been found in several different non-erythroid cells from normal human subjects, indicating that it is a widely distributed enzyme⁴; (2) cytochrome b₅ reductase has been found in the red cells, and cytochrome b₅ seems to have a direct role in methaemoglobin reduction^5,6, (3) in patients with NADH diaphorase deficiency a concomitant deficiency of cytochrome b₅ reductase has been observed^7,8. In a small but significant proportion of the cases of congenital enzymopenic methaemoglobinaemia, the methaemoglobinaemic syndrome is associated with a progressive neurological disorder with mental retardation causing death at a young age^3,8,9. The relationship between methaemoglobinaemia and nerve system involvement has so far been poorly understood, until the finding that the leukocytes of patients with this type of disease also displayed the NADH diaphorase deficiency, whereas nearly normal enzyme levels were found in the leukocytes from methaemoglobinaemic patients without neurological symptoms^8,10. It was therefore postulated that methaemoglobinaemia with neurological involvement might result from a generalised enzyme defect^8,10.