Table 1.

Congenital methemoglobinemia: pathophysiology and classification.

Disease subtypes	Pathophysiology	Features and prognosis
Cytochrome b5 reductase deficiency (type I)	Lack of cytochrome b5 reductase activity in erythrocytes only	Cyanosis develops at 6 to 9 months of age
		Usually asymptomatic, even with levels up to 40 percent
Cytochrome b5 reductase deficiency (type II)	Altered cytochrome b5 reductase function in various tissues, notable for a decrease in oxygen supply to the central nervous system	Associated with developmental delay, failure to thrive Clinically, the most severe variant and usually fatal in the first year of life
Cytochrome b5 reductase deficiency (type III)	Decrease in functional cytochrome b5 reductase activity in all cell types	Cyanotic at birth, otherwise asymptomatic
Cytochrome b5 reductase deficiency (type IV)	Decrease in functional cytochrome b5 reductase activity in all cell types	Similar to type I
Hemoglobin M disease	Mutations of the globin gene (alpha, beta, or rarely gamma). This results in an Fe3+-phenolate complex that resists reduction.	Characterized by chronic cyanosis, otherwise asymptomatic