Infection Infection is the most common precipitating factor of hemolysis in G6PD deficiency. The inflammatory response to infection results in the generation of free radicals in macrophages. The radicals can diffuse into the RBC and cause oxidative damage.
C. Variant G6PD properties
Almost all G6PD variants are caused by point mutations (see p. 449) in the gene for G6PD. Some mutations do not affect enzymic activity. However, other mutations result in decreased catalytic activity, decreased stability, or an alteration of binding affinity for NADP+ or glucose 6-phosphate. [Note: Active G6PD exists as a homodimer or tetramer. Mutations at the interface between subunits can affect stability.] The severity of the disease usually correlates with the amount of residual enzyme activity in the patient’s RBC. For example, variants can be classified as shown in Figure 13.12. G6PD A– is the prototype of the moderate (class III) form of the disease. The RBC contain an unstable but kinetically normal G6PD, with most of the enzyme activity present in the reticulocytes and younger RBC (Fig. 13.13). Therefore, the oldest RBC have the lowest level of enzyme activity and are preferentially removed in a hemolytic episode. Because hemolysis does not affect younger cells, the episodes are self-limiting. G6PD Mediterranean is the prototype of a more severe (class II) deficiency. Class I mutations (rare) are the most severe and are associated with chronic nonspherocytic hemolytic anemia, which occurs even in the absence of oxidative stress.
D. G6PD molecular biology
The cloning of the gene for G6PD and the sequencing of its DNA (see Chapter 34) have permitted the identification of mutations that cause G6PD deficiency. More than 400 G6PD variants have been identified, a finding that explains the numerous biochemical and clinical phenotypes that have been described. Most mutations that result in enzymic deficiency are missense mutations (see p. 449) in the coding region. Both G6PD A− and G6PD Mediterranean represent mutant enzymes that differ from the respective normal variants by a single amino acid. Large deletions or frameshift mutations have not been identified, suggesting that complete absence of G6PD activity is likely lethal.
VI. CHAPTER SUMMARY