Glucose-6-phosphate dehydrogenase deficiency

Summary

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, being present in more than 400 million people worldwide. The global distribution of this disorder is remarkably similar to that of malaria, lending support to the so-called malaria protection hypothesis. G6PD deficiency is an X-linked, hereditary genetic defect due to mutations in the G6PD gene, which cause functional variants with many biochemical and clinical phenotypes. About 140 mutations have been described: most are single base changes, leading to aminoacid substitutions. The most frequent clinical manifestations of G6PD deficiency are neonatal jaundice, and acute haemolytic anaemia, which is usually triggered by an exogenous agent. Some G6PD variants cause chronic haemolysis, leading to congenital non-spherocytic haemolytic anaemia. The most effective management of G6PD deficiency is to prevent haemolysis by avoiding oxidative stress. Screening programmes for the disorder are undertaken, depending on the prevalence of G6PD deficiency in a particular community.

Introduction

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme that catalyses the first reaction in the pentose phosphate pathway, providing reducing power to all cells in the form of NADPH (reduced form of nicotinamide adenine dinucleotide phosphate). NADPH enables cells to counterbalance oxidative stress that can be triggered by several oxidant agents, and to preserve the reduced form of glutathione (figure 1). Since red blood cells do not contain mitochondria, the pentose phosphate pathway is their only source of NADPH; therefore, defence against oxidative damage is dependent on G6PD.¹

G6PD deficiency is an X-linked, hereditary genetic defect caused by mutations in the G6PD gene, resulting in protein variants with different levels of enzyme activity, that are associated with a wide range of biochemical and clinical phenotypes. The most common clinical manifestations are neonatal jaundice and acute haemolytic anaemia, which in most patients is triggered by an exogenous agent.¹ The striking similarity between the areas where G6PD deficiency is common and Plasmodium falciparum malaria is endemic provides circumstantial evidence that G6PD deficiency confers resistance against malaria.² The highest frequencies are detected in Africa, Asia, the Mediterranean region, and in the middle east; owing to recent migrations, however, the disorder is also found in North and South America and in northern European countries.³

A pathological disorder linked to ingestion of fava beans (Vicia faba), later identified as G6PD deficiency, has been recognised for centuries. The Greek philosopher and mathematician, Pythagoras, forbade his followers from eating fava beans, possibly because of their pathological effects.⁴ At the beginning of the 20th century, several doctors in southern Italy and Sardinia drew a clinical picture of so-called favism.⁵ However, because the response to fava bean ingestion is inconsistent, popular theories on the pathogenesis of favism were related to toxic effects or allergy.6, 7 In 1956, Carson and colleagues discovered that individuals developing haemolytic anaemia caused by the antimalarial drug primaquine had a very low level of G6PD activity in their red blood cells.8, 9 After a trip to Sardinia, Crosby noted a similarity between the severe haemolytic anaemia associated with ingestion of fava beans, or even inhalation of the plant's pollen, and the haemolytic anaemia induced by primaquine.¹⁰ A low activity of G6PD in people with a history of favism was subsequently reported in Italy and Germany.11, 12 We now know that G6PD deficiency is the most common human enzyme defect, present in more than 400 million people worldwide.13, 14 Panel 1 summarises the history of our understanding of G6PD deficiency.