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

Area of Science:

• Genetics
• Hematology
• Biochemistry

Background:

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disorder prevalent in many populations, affecting red blood cells.
• This deficiency can lead to acute hemolytic anemia upon exposure to certain triggers like fava beans or drugs, and is a risk factor for neonatal jaundice.
• The World Health Organization (WHO) recommends G6PD testing to guide the administration of 8-aminoquinolines for preventing Plasmodium vivax malaria relapse.

Approach:

• A literature review was conducted to gather G6PD activity data from 2291 males with polymorphic G6PD variants.
• Mean residual red blood cell G6PD activity was estimated for 16 common G6PD deficient variants, revealing a range from 1.9% to 33% of normal activity.
• Analysis explored the relationship between residual G6PD activity and substrate affinity (Km G6P) to understand the biochemical basis of G6PD deficiency variants.

Key Points:

• Most G6PD deficient males exhibit residual enzyme activity below 30% of normal levels, with significant variation across different G6PD variants.
• A direct correlation was observed between residual G6PD activity and substrate affinity (Km G6P), suggesting a protective mechanism against chronic non-spherocytic hemolytic anemia (CNSHA).
• Extensive overlap in G6PD activity values among individuals with different variants and a lack of mean value clustering around 10% support merging WHO G6PD deficiency classes II and III.

Conclusions:

• The study provides reliable estimates for mean residual G6PD activity in common variants, crucial for clinical management and genetic counseling.
• The findings suggest that the biochemical properties of polymorphic G6PD variants, particularly their substrate affinity, play a role in preventing severe chronic hemolytic anemia.
• Consolidating G6PD deficiency classifications based on activity overlap can simplify diagnostic and therapeutic strategies, especially in malaria-endemic regions.