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At a glance

Most common human enzyme deficiency in the world. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive enzymopathy responsible for acute hemolysis following exposure to oxidative stress. Clinically characterized by an acute red cell hemolysis resulting from intake of oxidative agents. Glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals are more resistant to Plasmodium falciparum (malaria-causing parasite).

Synonyms

Baghdad Anemia; Broad Bean Syndrome; Favism (usually in persons of Mediterranean area descent).

Nature

Genetic enzyme deficiency (>400 variant alleles, or different forms of the same gene). Favism has been known to exist since antiquity; Pythagoras had warned his disciples against the dangers of eating fava beans.

Incidence

Most of the affected individuals reside in Africa, the Middle East, tropical, subtropical Asia, areas around the Mediterranean’s sea, Papua New Guinea, and Southeast Asia (areas where malaria is common). It is estimated that about 400 million people are affected by this deficiency.

Genetic inheritance

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive enzymopathy. It is a predominantly a male syndrome. Most of the variants arise from a single point mutation (amino acid substitution) in the structural gene encoding for G6PD, which is located at the Xq28 region on the tip of the long arm of the X chromosome.

Pathophysiology

G6PD catalyzes the first step in the hexose monophosphate pathway, producing nicotinamide adenine dinucleotide phosphate (NADPH). This pathway is the only source of NADPH in the erythrocyte. NADPH is required to reduce oxidized glutathione. Reduced glutathione is the substrate for peroxide removal from the red blood cells. When G6PD-deficient patients are given drugs that form peroxides in contact with oxyhemoglobin, the lack of glutathione peroxide removal leads to hemolysis and formation of Heinz bodies. There exist at least five variants of this syndrome: the rare class 1, or hereditary nonspherocytic hemolytic anemia (associated with chronic hemolysis); class 2, or severe deficiency (<10%); class 3, or moderate-to-mild deficiency; class 4, or very mild-to-no enzyme deficiency (60%); and class 5, an increase in enzyme activity. The degree of hemolysis also may be related to other non–G6PD-related issues, such as acetylator status (ie, a rapid acetylator will metabolize drug quicker than a slow or nonacetylator, and the lack of drug accumulation prevents hemolysis).

Diagnosis

A variety of laboratory tests are available for patients who have not hemolyzed, including the dye reduction test and the fluorescent spot test. Oxidant stress causes hemoglobin denaturation and the formation of Heinz bodies. For patients who have hemolyzed, the most powerful diagnostic technique is genomic DNA analysis.

Clinical aspects

There are three classes of G6PD that consists of:

  • Class 1: Chronic hemolysis without exposure to “classic” trigger ...

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