GLUCOSE‐6‐PHOSPHATE DEHYDROGENASE DEFICIENCY

In the past two decades studies on abnormal haemoglobins have made great strides possible in the understanding of human biology. in recent years, the investigations of workers all over the world have made it clear that mutations involving glucose-&phosphate dehydrogenase (G6PD) provide a similar opportunity for important insights into the biology of maninsights which were not remotely suspected when h s type of error in red-cell metabolism was discovered as an outgrowth of investigations on the pathogenesis of primaquineinduced haemolytic anaemia. The history of the discovery of G 6 P D deficiency is well known (Beutler, 1959). Some Negro volunteer subjects who were given the 8-aminoquinoline antimalarial drug, primaquine, developed acute haemolytic anaemia. Cross-transfusion studies with '' Cr-labelled cells indicated that sensitivity to haemolysis was due to an intrinsic abnormality of the red cell. The anaemia was found to be self-limited, and cohort labelling studies with s9Fe showed that only the older members of the red-cell population were destroyed. Conventional haematological studies, antiglobulin tests, osmotic and mechanical fragility, red-cell morphology, and even the then very new paper electrophoretic studies of haemoglobin were normal. But primaquine-sensitive cells were found to have a diminished content of glutathione (GSH), a sulphhydryl-containing tripeptide. Furthermore, when primaquine-sensitive cells were incubated with acetylphenylhydrazine their glutathione rapidly disappeared, while the glutathione from normal cells was unaffected. The examination of the pathways which normally maintain glutathione in a reduced form revealed that there was a severe deficiency of G6-PD activity in these red cells. Primaquine-sensitive cells were not only uniquely sensitive to the haemolytic effect of 8-aminoquinoline antimalarials, but also to many drugs commonly used in medical practice in temperate climates. Such drugs include acetanilide, nitrofurantoin, certain sulphonamides, chloramphenicol, and many others. Infection also precipitates haemolytic episodes, severe icterus may occur in G-6-PD deficient newborns and sensitivity to the haemolytic effect of fava beans is limited to individuals with th is defect. It soon became apparent that G 6 P D deficiency was a very widespread disorder, affecting perhaps IOO million individuals in the world. But the studies of Marks & Gross (1959) and of Kirkman et al(1960) soon showed that there was not just one type of G6-PD deficiency: it could be shown that the deficiency which was found in American Negroes was milder than that found among the Mediterranean subjects. Furthermore, electrophoresis of the enzyme from deficient Negro subjects showed that the mobility of a mutant enzyme was more rapid than normal, while the enzyme from deficient Mediterranean subjects moved normally (Boyer et al, 1962). Investigations of the kinetic properties of these enzymes also revealed important differences. The Mediterranean enzyme had an increased affinity for its substrates, glucose-&phosphate and NADP, and had an abnormal pH-activity curve (Kirkman et a/, 1964; Ramot et a! , 1964) while the enzyme from deficient Negroes seemed normal in these respects. When the red cells of some individuals with the clinical syndrome of non-spherocytic congenital haemolytic anaemia were assayed for G 6 P D activity, they were found to be deficient. But the biochemical characteristics of the enzyme were not the same as the character-