Genetic variants causing G6PD deficiency: Clinical and biochemical data support new WHO classification

Abstract

SummaryGlucose‐6‐phosphate dehydrogenase (G6PD) deficiency in erythrocytes causes acute haemolytic anaemia upon exposure to fava beans, drugs, or infection; and it predisposes to neonatal jaundice. The polymorphism of the X‐linked G6PD gene has been studied extensively: allele frequencies of up to 25% of different G6PD deficient variants are known in many populations; variants that cause chronic non‐spherocytic haemolytic anaemia (CNSHA) are instead all rare. WHO recommends G6PD testing to guide 8‐aminoquinolines administration to prevent relapse of Plasmodium vivax infection. From a literature review focused on polymorphic G6PD variants we have retrieved G6PD activity values of 2291 males, and for the mean residual red cell G6PD activity of 16 common variants we have obtained reliable estimates, that range from 1.9% to 33%. There is variation in different datasets: for most variants most G6PD deficient males have a G6PD activity below 30% of normal. There is a direct relationship between residual G6PD activity and substrate affinity (KmG6P), suggesting a mechanism whereby polymorphic G6PD deficient variants do not entail CNSHA. Extensive overlap in G6PD activity values of individuals with different variants, and no clustering of mean values above or below 10% support the merger of class II and class III variants.

Field assessment of the operating procedures of a semi-quantitative G6PD Biosensor to improve repeatability of routine testing

“…It affects between 400 to 500 million people worldwide and impairs the red blood cells' (RBC) ability to regulate cellular redox potential whilst ensuring their survival against oxidative stressors [11]. Males have one X-chromosome and are either hemizygous G6PD normal (the vast majority having >70% G6PD activity) or G6PD deficient (the majority having <30% G6PD activity) [12,13]. Females have two copies of the gene and can be G6PD homozygous normal, G6PD heterozygous, or G6PD homozygous deficient [14].…”

Plasmodium vivax Malaria and G6PD Testing

“…The authors make the important point that for each variant, the observed activity values span current classification thresholds. This article, together with that by Nannelli et al [14], provided much of the evidence on which the World Health Organization based their recent revision of the classification of G6PD variants that combined the former class II and class III variants into one group.…”

Uncovering an undisclosed diagnosis: a glucose‐6‐phosphate dehydrogenase deficiency diagnosis in a critically ill adult

“…G6PD deficiency is currently divided into five WHO grade classifications: WHO grade I has < 10% of normal enzyme activity and chronic hemolytic anemia, WHO grade II has < 10% of normal enzyme activity with a severe enzyme deficiency, WHO grade III exhibits 10%-60% of enzyme activity which is mild to moderate with intermittent hemolysis, WHO grade IV has 60%-100% enzyme function, and WHO grade V has twice normal increased enzyme function. This classification, however, is currently under review and the proposition of combining grades II and III has been discussed [2]. The most common variant of G6PD deficiency in the United States is the A-variant, which is present among African-Americans, and is considered WHO class III [2].…”

“…This classification, however, is currently under review and the proposition of combining grades II and III has been discussed [2]. The most common variant of G6PD deficiency in the United States is the A-variant, which is present among African-Americans, and is considered WHO class III [2]. Most people with this variant, however, do not experience severe hemolysis unless under extreme circumstances.…”