What is the pathophysiology of congenital (hereditary) methemoglobinemia?

Updated: Dec 09, 2018
  • Author: Mary Denshaw-Burke, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

At least two forms of congenital cytochrome b5 reductase deficiency exist. Both are inherited in an autosomal recessive pattern. In type Ib5R deficiency, the more common form, cytochrome b5 reductase is absent only in RBCs. Homozygotes appear cyanotic but usually are otherwise asymptomatic. Methemoglobin levels typically range from 10% to 35%. Life expectancy is not adversely influenced, and pregnancies are not complicated. Heterozygotes may develop acute, symptomatic methemoglobinemia after exposure to certain drugs or toxins.

The type IIb5R form is substantially less common, accounting for only 10-15% of cases of congenital cytochrome b5 reductase deficiency. In this condition, cytochrome b5 reductase is deficient in all cells, not just RBCs. It is associated with several other medical problems, including mental retardation, microcephaly, and other neurologic complications. Life expectancy is severely compromised, and patients usually die at a very young age. The exact mechanism of the neurologic complications is not known.

Methemoglobinemia may also involve the presence of abnormal hemoglobins (hemoglobin M [Hb M]). In most of these hemoglobins, tyrosine replaces the histidine residue, which binds heme to globin. This replacement displaces the heme moiety and permits oxidation of the iron to the ferric state. Consequently, Hb M is more resistant to reduction by the methemoglobin reduction enzymes (see above). This results in a functionally impaired hemoglobin with a decreased affinity for oxygen.


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