What causes glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Updated: Jun 25, 2020
  • Author: Lawrence C Wolfe, MD; Chief Editor: George T Griffing, MD  more...
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Answer

G6PD deficiency is an X-linked recessive enzymopathy caused by a missense mutation in the housekeeping G6PD gene. [13]  The pattern of inheritance is similar to that for hemophilia and color blindness; ie, males usually manifest the abnormality, and females are carriers. Females can be symptomatic if they are homozygous or if their normal X chromosome is inactivated.

The G6PD gene is located in the distal long arm of the X chromosome at the Xq28 locus. There have been 186 mutations documented in the G6PD gene. Most are single-base changes that result in an amino acid substitution. [3] These substitutions affect enzyme activity by decreasing intracellular stability of the protein or by affecting their catalytic activity. [14, 15, 16]

A large deletion in the G6PD gene is incompatible with life. Although small deletion mutation is rare, it has been reported and presents with severe G6PD deficiency. [16]

Specific G6PD alleles are associated with G6PD variants with different enzyme levels and, thus, different degrees of clinical disease severity. The variation in G6PD levels accounts for differences in sensitivity to oxidants.

The most common G6PD variants include G6PD A-, G6PD Mediterranean, G6PD Canton, and G6PD Union. [16]

G6PD A- occurs in high frequency in Africa, southern Europe, and North and South America. It is associated with lower enzyme levels and acute intermittent hemolysis. [4, 16, 17, 18]

G6PD Mediterranean is seen mainly in the Middle East, including Israel, and it accounts for almost all G6PD deficiency in Kurdish Jews. [4, 16, 19, 20, 21, 22, 23, 24, 25, 17, 18]  It is characterized by enzyme deficiency that is more severe than that associated with G6PD A- alleles. Hemolysis after ingestion of fava beans (favism) is most frequently associated with the Mediterranean variant of G6PD deficiency.

G6PD Canton is seen mainly in China, and G6PD Union is seen worldwide.

G6PD B is the wild type of allele (normal variant). The G6PD A+ variant is associated with high enzyme levels and, hence, no hemolysis.

Severe forms of G6PD deficiency are associated with chronic nonspherocytic hemolytic anemia. Mutations causing this anemia commonly cluster in exon 10, a region important for protein dimerization. [16, 26]


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