The gene that encodes the G6PD enzyme is located on the X chromosome and is highly polymorphic, with over 180 genetic variants identified that result in enzyme deficiency. Greater than 90% of variants are single-base substitutions in the coding region that produce amino acid changes, which result in unstable proteins with reduced enzyme activity. As with most X-linked traits, males with one reference X chromosome and females with two reference X chromosomes will have equivalent “normal” G6PD activity. Similarly, hemizygous-deficient males (with a deficient copy of the G6PD gene on their single X chromosome) and homozygous-deficient females (with two deficient copies) express reduced activity phenotypes (Table 5–1). However, for heterozygous females (with one deficient allele and one normal allele), genotype-to-phenotype predictions are less reliable due to the X-chromosome mosaicism, ie, where one X chromosome in each female cell is randomly inactivated, leading to G6PD activity that may range from fully functional to severely deficient. G6PD enzyme activity phenotype estimations for heterozygous females therefore may be improved with complementary G6PD activity testing.
G6PD enzyme deficiency affects over 400 million people worldwide, and the World Health Organization has categorized G6PD activity into five classes (Table 5–3). The majority of polymorphic G6PD-deficient genotypes are associated with class II for severe deficiency (< 10% enzyme activity) and class III for moderate deficiency (10–60% enzyme activity). Most individuals with reduced function alleles of G6PD have ancestries in geographical areas of the world corresponding to areas with high malaria prevalence. Polymorphic alleles gained in frequency over time as they offered some benefit against death from malaria. The estimated frequency of G6PD deficiency is approximately 8% in malaria endemic countries, with the milder G6PD-A(–) allele prevalent in Africa, and the more severe G6PD-Mediterranean allele widespread across western Asia (Saudi Arabia and Turkey to India). There is a much more heterogeneous distribution of variant alleles in East Asia and Asia Pacific, which complicates G6PD risk predictions; however, the most frequently identified forms in Asia include the more severe class II alleles, eg, Mediterranean, Kaiping, and Canton, as well as some class III alleles, eg, Mahidol, Chinese-5, and Gaohe (Table 5–1).
Example: Rasburicase, a recombinant urate-oxidase enzyme, is indicated for the initial management of high uric acid levels in cancer patients receiving chemotherapy. Rasburicase alleviates the uric acid burden that often accompanies tumor-lysing treatments by converting uric acid into allantoin, a more soluble and easily excreted molecule. During the enzymatic conversion of uric acid to allantoin, hydrogen peroxide, a highly reactive oxidant, is formed. Hydrogen peroxide must be reduced by glutathione to prevent free radical formation and oxidative damage. Individuals with G6PD deficiency receiving rasburicase therapy are at greatly increased risk for severe hemolytic anemia and methemoglobinemia. The manufacturer recommends that patients at high risk (individuals of African or Mediterranean ancestry) be screened prior to the initiation of therapy and that rasburicase not be used in patients with G6PD deficiency (Table 5–2).