Chicago Center for Jewish Genetics Disorders - Sephardi Disorders: Glucose-6-Phosphate Dehydrogenase Deficiency

Sephardi Disorders

Glucose-6-Phosphate Dehydrogenase Deficiency

Gene: Glucose-6-phosphate dehydrogenase deficiency is caused by a mutation in the glucose-6-phophate dehydrogenase (G6PD) gene, which is located at Xq28. It encodes for the G6PD protein, which is involved in the hexose monophosphate pathway.

Mutations and testing: More than 400 mutations have been identified, the majority being missense mutations and transition mutations involving a C -> T change within a CpG dinucleotide. A few of the mutations may cause chronic hemolysis but most are conditional and cause symptoms only under conditions of oxidative stress.

Traits: G6PD is in the hexose monophosphate pathway and it is the only NADPH-generating process in mature red cells. It oxidizes glucose-6-phosphate to 6-phosphogluconolactone, reducing NADP to NADPH. NADPH protects the cell against oxidative damage by regenerating reduced glutathione from its oxidized form, which leads to the removal of peroxide from the erythrocyte. In G6PD deficiency, oxidant medications deplete the cell of reduced glutathione and consequent oxidative damage leads to hemolysis. This hemolysis can lead to anemia, jaundice, and splenomegaly. Cholelithiasis (presence of gallstones in the gallbladder), and cholecystitis (acute or chronic inflammation of the gallbladder) can also occur. In neonates, significant hyperbilirubinemia requiring phototherapy may occur. The symptoms of G6PD are self-limiting because of two reasons. First, mutated G6PD protein is unstable and is degraded quickly, resulting in diminished activity. Second, young red blood cells still have their nuclei and are able to produce new G6PD to replace what is degraded. However, mature red blood cells have lost their nuclei and thus once the G6PD is degraded in these cells, it cannot be replaced. In cells subjected to oxidizing stress, this leads to hemolysis.

Treatment: During an acute hemolytic crisis, blood transfusions may be necessary. The best course is avoidance of precipitating factors.

G6PD and medications: Anti-malarials, analgesics, sulfonamides, and antipyrectics are oxidizing drugs, which result in diminshed glutathione levels. Glutathione acts as a scavenger for dangerous oxidative metabolites in the cell by converting damaging hydrogen peroxide into water. Without this protection and in the presence of oxidative drugs, hemolysis occurs in a person with G6PD deficiency.

G6PD and Favism: Some individuals with G6PD deficiency react to oxidizing substances in fava beans, resulting in hemolysis and the symptoms listed previously. This is called Favism.

G6PD and malaria: G6PD may provide a selective advantage in endemic areas such as sub-Saharan Africa, southern Asia, and the Middle East by providing some protection against malaria. This is due to the lifecycle of falciparum malaria. The immature falciparum malaria generates hydrogen peroxide, which weakens the cell membrane. This causes potassium to leak out of the cell and kills both the cell and the parasite living inside it before the parasite reaches maturity.

Reviewed by Dr. Joel Charrow, Children's Memorial Hospital.
1/03

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This page last updated on January 10, 2003.