Hereditary methemoglobinemia- recessive

Synonyms

2

Overview

Autosomal recessive congenital methemoglobinemia is an inherited condition that affects the normal function of hemoglobulin (Hemoglobin carries oxygen to cells and tissues throughout the body). Methemoglobinemia, occurs when red blood cells (RBCs) contain methemoglobin at levels higher than 1%. Methemoglobin results from the presence of iron in the ferric form instead of the usual ferrous form. This results in a decreased availability of oxygen to the tissues, leading to a bluish appearance of the skin, lips, and nails (cyanosis).

There are four types of hereditary methemoglobinemias that are secondary to deficiency of NADH cytochrome b5 reductase, which is encoded by the CYB5R3gene. All of them are autosomal recessive disorders. Heterozygotes have 50% enzyme activity and no cyanosis; homozygotes that have elevated methemoglobin levels above 1.5% have clinical cyanosis. The four types are as follows:

  • Type I – This is the most common variant, and the enzyme deficiency is limited to the erythrocytes causing cyanosis; cyanosis usually, but not always, develops during infancy
  • Type II – Widespread deficiency of the enzyme occurs in various tissues, including erythrocytes, liver, fibroblasts, and brain; it is associated with severe CNS symptoms, including encephalopathy, microcephaly, hypertonia, athetosis, opisthotonos, strabismus, mental retardation, and growth retardation; cyanosis is evident at an early age
  • Type III – Although the hematopoietic system (platelets, RBCs, and white blood cells [WBCs]) is involved, the only clinical consequence is cyanosis
  • Type IV – Like type I, this type has isolated involvement of the erythrocytes but results in chronic cyanosis

Symptoms

The list of signs and symptoms mentioned in various sources for Hereditary methemoglobinemia, recessive includes the symptoms listed below:

  • Slate-gray cyanosis
  • Asymptomatic
  • Fatigability after exercise
  • Breathing difficulty after exercise

Causes

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Deficiency of NADPH-flavin reductase can also cause methemoglobinemia.

Prevention

Genetic counseling is recommended for couples with a family history of methemoglobinemia who are considering having children.

Diagnosis

Arterial blood with elevated methemoglobin levels has a characteristic chocolate-brown color as compared to normal bright red oxygen-containing arterial blood. If methemoglobinemia is suspected, an arterial blood gas and co-oximetry panel should be obtained.

Prognosis

The clinical course of hereditary forms of methemoglobinemia is generally benign. Patients are usually asymptomatic, except for the presence of chronic cyanosis. However, individuals with type IIb5 cytochrome reductase deficiency have a markedly shortened life expectancy, primarily because of multiple neurologic complications.

Treatment

Methylene blue is the primary emergency treatment for (hereditary and acquired) methemoglobinemia and exists in a 0.5% and 1% solution for IV injection.

Methylene blue restores the iron in hemoglobin to its normal oxygen-carrying state. This is achieved by providing an artificial electron acceptor (such as methylene blue or flavin) for NADPH methemoglobin reducetase (RBCs usually don't have one; the presence of methylene blue allows the enzyme to function at 5× normal levels). 

Genetically induced chronic low-level methemoglobinemia may be treated with oral methylene blue daily. Also, vitamin C can occasionally reduce cyanosis associated with chronic methemoglobinemia.