Categories of Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
G6PD deficiency is classified into five distinct categories based on enzyme activity levels and clinical manifestations, ranging from the most severe (Class I) to normal enzyme activity (Class V).
Classification System
Class I (Very Severe Deficiency): Characterized by chronic hemolytic anemia without any trigger. Enzyme activity is <10% of normal and patients present with congenital non-spherocytic hemolytic anemia 1.
Class II (Severe Deficiency): Enzyme activity is <10% of normal. Patients experience intermittent acute hemolysis when exposed to oxidative stressors but are generally asymptomatic between episodes 2, 3.
Class III (Moderate Deficiency): Enzyme activity is 10-60% of normal. Hemolysis occurs only with significant oxidative stress (e.g., certain medications or infections) 2, 3.
Class IV (Mild Deficiency/Normal Activity): Enzyme activity is 60-150% of normal. No clinical hemolysis occurs under any conditions 4, 3.
Class V (Increased Activity): Enzyme activity >150% of normal. No clinical significance 3.
Variant-Specific Considerations
African Variant (GdA-): Found in 10-15% of Black men and women, associated with milder, self-limited hemolysis (typically Class III) 5, 6.
Mediterranean Variant (Gdmed): Predominantly affects individuals from Mediterranean regions, India, and Southeast Asia. Can cause life-threatening hemolysis and is typically classified as Class II 5, 6.
Class I Variants: Examples include G6PD Santiago de Cuba (1339 G>A), which has been identified in rare cases and causes severe chronic anemia 7, 1.
Clinical Implications of Classification
Class I patients require regular monitoring for chronic hemolysis and may need supportive care including transfusions 1.
Class II and III patients should avoid known oxidant medications and foods that can trigger hemolytic crises 5, 6.
Testing recommendations: Qualitative screening is recommended for initial assessment, while quantitative testing is required to determine the specific class of deficiency and before administering certain medications like tafenoquine 5.
Molecular Basis of Classification
The severity of G6PD deficiency correlates with the location of mutations within the G6PD gene 1, 3.
Over 140 mutations have been described, most being single base changes leading to amino acid substitutions 2.
Different mutations at the same codon can result in different clinical phenotypes, as demonstrated by variants affecting codon 454 (Arg454Pro, Arg454Cys, Arg454His) 1.
Management Based on Classification
All classes: Screening is strongly recommended before starting therapy with oxidant drugs, especially in patients with predisposing racial or ethnic backgrounds 5, 6.
Class I and II: Complete avoidance of high-risk medications like dapsone and methylene blue is essential 6.
Class III: Some medications may be used with caution and monitoring, such as chloroquine/hydroxychloroquine in standard doses 6.
Family screening: First-degree relatives of patients with G6PD deficiency should be tested, particularly important for Class I and II variants 5.
Understanding the specific class of G6PD deficiency is crucial for appropriate clinical management and prevention of hemolytic episodes, especially when considering medication choices and monitoring requirements.