Thompson & Thompson Genetics in Medicine, 8th Edition

Case 19. Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD Mutation, MIM 305900)



• Heterozygote advantage

• Pharmacogenetics

Major Phenotypic Features

• Age at onset: Neonatal

• Hemolytic anemia

• Neonatal jaundice

History and Physical Findings

L.M., a previously healthy 5-year-old boy, presented to the emergency department febrile, pale, tachycardic, tachypneic, and minimally responsive; his physical examination was otherwise normal. The morning before presentation, he had been in good health, but during the afternoon, he had abdominal pain, headache, and fever; by late evening, he was tachypneic and incoherent. He had not ingested any medications or known toxins, and results of a urine toxicology screen were negative. Results of other laboratory tests showed massive nonimmune intravascular hemolysis and hemoglobinuria. After resuscitation, L.M. was admitted to the hospital; the hemolysis resolved without further intervention. L.M. was of Greek ethnicity; his parents were unaware of a family history of hemolysis, although his mother had some cousins in Europe with a “blood problem.” Further inquiry revealed that the morning before admission, L.M. had been eating fava beans from the garden while his mother was working in the yard. The physician explained to the parents that L.M. probably was deficient for glucose-6-phosphate dehydrogenase (G6PD) and that because of this, he had become ill after eating fava beans. Subsequent measurement of L.M.'s erythrocyte G6PD activity confirmed that he had G6PD deficiency. The parents were counseled concerning L.M.'s risk for acute hemolysis after exposure to certain drugs and toxins and given a list of compounds that L.M. should avoid.


Disease Etiology and Incidence

G6PD deficiency (MIM 305900), a hereditary predisposition to hemolysis, is an X-linked disorder of antioxidant homeostasis that is caused by mutations in the G6PD gene. In areas in which malaria is endemic, G6PD deficiency has a prevalence of 5% to 25%; in nonendemic areas, it has a prevalence of less than 0.5% (Fig. C-19). Like sickle cell disease, G6PD deficiency appears to have reached a substantial frequency in some areas because it confers some resistance to malaria and thus a survival advantage to individuals heterozygous for G6PD deficiency (see Chapter 9).


FIGURE C-19 World distribution of G6PD deficiency. The frequencies of G6PD-deficient males in the various countries are also the allele frequencies because the gene is X-linked. See Sources & Acknowledgments.


G6PD is the first enzyme in the hexose monophosphate shunt, a pathway critical for generating nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is required for the regeneration of reduced glutathione. Within erythrocytes, reduced glutathione is used for the detoxification of oxidants produced by the interaction of hemoglobin and oxygen and by exogenous factors such as drugs, infection, and metabolic acidosis.

Most G6PD deficiency arises because mutations in the X-linked G6PD gene decrease the catalytic activity or the stability of G6PD, or both. When G6PD activity is sufficiently depleted or deficient, insufficient NADPH is available to regenerate reduced glutathione during times of oxidative stress. This results in the oxidation and aggregation of intracellular proteins (Heinz bodies) (see Fig. 11-8) and the formation of rigid erythrocytes that readily hemolyze.

With the more common G6PD alleles, which cause the protein to be unstable, deficiency of G6PD within erythrocytes worsens as erythrocytes age. Because erythrocytes do not have nuclei, new G6PD mRNA cannot be synthesized; thus erythrocytes are unable to replace G6PD as it is degraded. During exposure to an oxidative stress episode, therefore, hemolysis begins with the oldest erythrocytes and progressively involves younger erythrocytes, depending on the severity of the oxidative stress.

Phenotype and Natural History

As an X-linked disorder, G6PD deficiency predominantly and most severely affects males. Rare symptomatic females have a skewing of X chromosome inactivation such that the X chromosome carrying the mutant G6PD allele is the active X chromosome in erythrocyte precursors (see Chapter 6).

The severity of G6PD deficiency depends not only on sex, but also on the specific G6PD mutation. In general, the mutation common in the Mediterranean basin (i.e., G6PD B or Mediterranean) tends to be more severe than those mutations common in Africa (i.e., G6PD A variants) (see Fig. C-19). In erythrocytes of patients with the Mediterranean variant, G6PD activity decreases to insufficient levels 5 to 10 days after erythrocytes appear in the circulation, whereas in the erythrocytes of patients with the G6PD A variants, G6PD activity decreases to insufficient levels 50 to 60 days after erythrocytes appear in the circulation. Therefore most erythrocytes are susceptible to hemolysis in patients with severe forms of G6PD deficiency, such as G6PD Mediterranean, but only 20% to 30% are susceptible in patients with G6PD A variants.

G6PD deficiency most commonly manifests as either neonatal jaundice or acute hemolytic anemia. The peak incidence of neonatal jaundice occurs during days 2 and 3 of life. The severity of the jaundice ranges from subclinical to levels compatible with kernicterus; the associated anemia is rarely severe. Episodes of acute hemolytic anemia usually begin within hours of an oxidative stress and end when G6PD-deficient erythrocytes have hemolyzed; therefore, the severity of the anemia associated with these acute hemolytic episodes is proportionate to the deficiency of G6PD and the oxidative stress. Viral and bacterial infections are the most common triggers, but many drugs and toxins can also precipitate hemolysis. The disorder called favism results from hemolysis secondary to the ingestion of fava beans by patients with more severe forms of G6PD deficiency, such as G6PD Mediterranean; fava beans contain β-glycosides, naturally occurring oxidants.

In addition to neonatal jaundice and acute hemolytic anemia, G6PD deficiency rarely causes congenital or chronic nonspherocytic hemolytic anemia. Patients with chronic nonspherocytic hemolytic anemia generally have a profound deficiency of G6PD that causes chronic anemia and an increased susceptibility to infection. The susceptibility to infection arises because the NADPH supply within granulocytes is inadequate to sustain the oxidative burst necessary for killing phagocytosed bacteria.


G6PD deficiency should be suspected in patients of African, Mediterranean, or Asian ancestry who present with either an acute hemolytic episode or neonatal jaundice. G6PD deficiency is diagnosed by measurement of G6PD activity in erythrocytes; this activity should be measured only when the patient has had neither a recent transfusion nor a recent hemolytic episode. (Because G6PD deficiency occurs primarily in older erythrocytes, measurement of G6PD activity in the predominantly young erythrocytes present during or immediately after a hemolytic episode often gives a false-negative result.)

The key to management of G6PD deficiency is prevention of hemolysis by prompt treatment of infections and avoidance of oxidant drugs (e.g., sulfonamides, sulfones, nitrofurans) and toxins (e.g., naphthalene). Although most patients with a hemolytic episode will not require medical intervention, those with severe anemia and hemolysis may require resuscitation and erythrocyte transfusions. Patients presenting with neonatal jaundice respond well to the same therapies as for other infants with neonatal jaundice (hydration, light therapy, and exchange transfusions).

Inheritance Risk

Each son of a mother carrying a G6PD mutation has a 50% chance of being affected, and each daughter has a 50% chance of being a carrier. Each daughter of an affected father will be a carrier, but each son will be unaffected because an affected father does not contribute an X chromosome to his sons. The risk that carrier daughters will have clinically significant symptoms is low because sufficient skewing of X chromosome inactivation is relatively uncommon.

Questions for Small Group Discussion

1. The consumption of fava beans and the occurrence of G6PD deficiency are coincident in many areas. What evolutionary advantage might the consumption of fava beans give populations with G6PD deficiency?

2. Several hundred different mutations have been described that cause G6PD deficiency. Presumably, all of these mutations have persisted because of selection. Discuss heterozygote advantage in the context of G6PD deficiency.

3. What is pharmacogenetics? How does G6PD deficiency illustrate the principles of pharmacogenetics?


Bunn HF. The triumph of good over evil: protection by the sickle gene against malaria. Blood. 2013;121:20–25.

Howes RE, Battle KE, Satyagraha AW, et al. G6PD deficiency: global distribution, genetic variants and primaquine therapy. Adv Parasitol. 2013;81:133–201.

Luzzatto L, Seneca E. G6PD deficiency: a classic example of pharmacogenetics with on-going clinical implications. Br J Haematol. 2014;164:469–480.