NADH cytochrome B5 reductase deficiency




Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency (recessive congenital methemoglobinemia, RCM) is an autosomal recessive disorder characterized clinically by decreased oxygen carrying capacity of the blood, with resultant cyanosis and hypoxia.

There are 2 types of RCM. In type I, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type II, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes, and all body tissues. Type II methemoglobinemia is associated with mental deficiency and other neurologic symptoms. The neurologic symptoms may be related to the major role played by the cytochrome b5 system in the desaturation of fatty acids. 


Erythrocytes from affected individuals with methemoglobinemia are unable to reduce methemoglobin that is formed continuously at a normal rate under physiologic conditions. Increased circulating levels of methemoglobin, which is brown, give the skin a bluish colour, which appears as cyanosis. Cyanosis is present from birth. In the normal state, about 1% of hemoglobin exists as methemoglobin; individuals become symptomatic when methemoglobin levels rise above 25%. Vascular collapse, coma, and death can occur when methemoglobin approaches 70% of total hemoglobin.

Type I, with deficiency demonstrable only in the erythrocytes, presents as uncomplicated, benign methemoglobinemia. The only symptom is well-tolerated cyanosis that causes mild complaints of headaches, fatigue and shortness of breath upon exertion.

Type II, generalized cytochrome B5 deficiency demonstrable in all of the tissues that have been examined, is accompanied by severe, lethal, progressive neurological disability, in addition to methemoglobinemia. Developmental delay starts to manifest at around 4 months. Children exhibit substantial secondary microcephaly, profound cognitive impairment, strabismus, and failure to thrive. The clinical course of type II disease is devastating. Severe impairment of brain development has been confirmed by magnetic resonance imaging scans indicating cortical and subcortical atrophy. The fully expressed neurological syndrome is characterized by severe mental retardation, retarded growth, opisthotonus and generalized hypertonia. 


The NADH-cytochrome B5 reductase deficiency is recessively inherited and can be present in the homozygous or doubly heterozygous form. It is caused by various mutations in the CYB5R3 gene. More than 40 mutations of this gene have been described. 


Once the diagnosis has been established by the measurement of enzyme activity is it important for patients with type I of RCM to know the molecular defect in order to provide future genetic counselling advice to carriers of the disorder.


For individuals who present with cyanosis of an unknown origin, the analysis of blood by a co-oximeter, as opposed to a pulse oximeter, allows the detection of methaemoglobin.

To establish a diagnosis of RCM, it is important to demonstrate enzyme deficiency of cb5r and this is usually done using a spectrophotometric method. RCM type I patients manifest a deficiency of cb5r in erythrocytes only whereas type II patients harbour the deficiency in both erythrocytes and leucocytes.

Specific mutations in the CYB5R3 gene can be detected using methods of molecular genetics.

Prenatal diagnosis is possible, as shown by Kaftory et al. (1986) who demonstrated an almost complete deficiency of cytochrome b5 reductase activity in cultured amniotic fluid cells.


NADH cytochrome B5 reductase deficiency is an inborn error of metabolism and, hence, a lifelong condition. Type I has a normal life expectancy. Patients with the more severe Type II usually die before reaching the age of 10. 


Generally, most patients with Type I tolerate their condition well even when the methemoglobin levels rise to 40%. In cases of severe methemoglobinemia the treatment of choice is methylene blue (100-300 mg orally per day) singly or in combination with ascorbic acid (500 mg a day). In milder cases ascorbic acid is sufficient alone to alleviate the cyanosis.

In Type II, severe methemoglobinemia can be treated successfully by daily doses of 200–500 mg of ascorbic acid. There is no effective treatment for the neurological symptoms, which are thought to arise from defective fatty acid synthesis because cb5r would be required to provide oleic acid for the synthesis of myelin phospholipids.


[1] Percy, M. J., Lappin, T. R. Recessive congenital methaemoglobinaemia: cytochrome b5 reductase deficiency. Brit. J. Haemat. 141: 298-308, 2008.


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[7] Shirabe, K., Landi, M. T., Takeshita, M., Uziel, G., Fedrizzi, E., Borgese, N. A novel point mutation in a 3-prime splice site of the NADH-cytochrome b5 reductase gene results in immunologically undetectable enzyme and impaired NADH-dependent ascorbate regeneration in cultured fibroblasts of a patient with type II hereditary methemoglobinemia. Am. J. Hum. Genet. 57: 302-310, 1995.

[8] Aalfs, C. M., Salieb-Beugelaar, G. B., Wanders, R. J. A., Mannens, M. M. A. M., Wijburg, F. A. A case of methemoglobinemia type II due to NADH-cytochrome b5 reductase deficiency: determination of the molecular basis. Hum. Mutat. 16: 18-22, 2000.

[9] Waller, H. D. Inherited methemoglobinemia (enzyme deficiencies). Humangenetik 9: 217-218, 1970.