Chapter 179

## Abstract

Abstract  Quod aliis cibus est, aliis fuat acre venenum What is food to some men may be fierce poison to others Lucretius Caro De Rerum Natura 4641, 65 BC

Abstract  Glucose-6-phosphate dehydrogenase (G6PD) is a cytoplasmic enzyme that is distributed in all cells. G6PD catalyzes the first step in the hexose monophosphate pathway, and it produces NADPH, which is required for reactions of various biosynthetic pathways as well as for the stability of catalase and the preservation and regeneration of the reduced form of glutathione (GSH). Because catalase and glutathione (via glutathione peroxidase) are essential for the detoxification of hydrogen peroxide, the defense of cells against this compound depends ultimately and heavily on G6PD. This is especially true in red cells, which are exquisitely sensitive to oxidative damage and in which other NADPH-producing enzymes are lacking.

Abstract  G6PD in its active enzyme form is made up of either two or four identical subunits, each having a molecular mass of about 59 kDa. The primary sequence of 515 amino acids has been determined from the cDNA sequence, and it shows more than 90 percent identity with the protein sequence of rat liver G6PD. The gene encoding G6PD maps to band Xq28 on the long arm of the X chromosome (just over 1 Mb from the telomere, between the GD1 mental retardation locus and the dyskeratosis congenita locus). Therefore, one of the two G6PD alleles is subject to inactivation in females. As determined from overlapping genomic phage clones, the gene spans 18 kb and consists of 13 exons (the first of which is noncoding). The sequence of the DNA region upstream from the major transcription initiation site has features similar to those found in other housekeeping gene promoters.

Abstract  G6PD deficiency is the most common known enzymopathy; it is estimated to affect 400 million people worldwide. The highest prevalence rates (with gene frequencies in the range of 5 to 25 percent) are found in tropical Africa, in the Middle East, in tropical and subtropical Asia, in some areas of the Mediterranean, and in Papua New Guinea. The most common clinical manifestations are neonatal jaundice and acute hemolytic anemia. In some cases, the neonatal jaundice is severe enough to cause death or permanent neurologic damage. The acute hemolytic anemia can be triggered by a number of drugs, by infections, or by the ingestion of fava beans. These manifestations may be life threatening, especially favism in children. The detailed mechanism of hemolysis is not fully known, but it results undoubtedly from the inability of G6PD-deficient red cells to withstand the oxidative damage produced, directly or indirectly, by the triggering agents mentioned above. Red cell destruction in these acute hemolytic events is largely intravascular and therefore is associated with hemoglobinuria. Fortunately, apart from these episodes of hemolytic anemia, most G6PD-deficient individuals are entirely asymptomatic. However, a rare subset of G6PD-deficient patients has, instead, a chronic hemolytic disorder, which may be severe.

Abstract  G6PD deficiency is genetically heterogeneous. About 400 different variants have been reported on the basis of diverse biochemical characteristics; this diversity suggests that these variants result from many allelic mutations in the G6PD gene. In addition, several structural mutants without enzyme deficiency have been characterized. Molecular analysis has confirmed that the basis for G6PD deficiency is widely heterogeneous. In some cases, variants that had been assigned different names turned out to be identical; conversely, however, some variants that had been thought to be homogeneous have turned out to be heterogeneous on the molecular level. Thus far, some 130 different point mutations have been identified, but only five in-frame deletions of one to eight codons and no larger deletions have been observed. Different mutants, each one having a polymorphic frequency, underlie G6PD deficiency in the various parts of the world where this abnormality is prevalent. Genetic heterogeneity also explains to a large extent the diversity of clinical manifestations. Different mutations are responsible for the less common patients who have chronic hemolytic anemia and for the frequent patients who are only at risk of developing episodic hemolysis.

Abstract  The remarkable geographic correlation between the prevalence of G6PD deficiency and the past and present endemicity of Plasmodium falciparum malaria strongly suggests that the former confers resistance against the latter. The high prevalence in malaria-endemic areas of G6PD mutants that have arisen independently corroborates this notion; indeed, it constitutes an example of convergent evolution through balanced polymorphism. Clinical data further support this notion, although it is not certain whether malaria resistance is a feature of heterozygous females only, or also of hemizygous males. In vitro culture studies have shown that the growth of malaria parasites is impaired in G6PD-deficient red cells, and that G6PD-deficient parasitized red cells are phagocytosed by macrophages more effectively than G6PD normal parasitized red cells.

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