A 7-year-old boy from Mumbai presents with recurrent episodes of dark urine and jaundice after strenuous play. Enzyme assay shows normal hexokinase and phosphofructokinase activity. Which finding best distinguishes his condition from phosphofructokinase deficiency?

## Clinical Comparison: Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency vs Phosphofructokinase (PFK) Deficiency ### Clinical Presentation Analysis The vignette describes a child with: - Recurrent dark urine (hemoglobinuria) - Jaundice (hemolysis) - Triggered by exertion - Normal hexokinase and PFK activity (rules out glycolytic defects) This clinical picture is **G6PD deficiency**, not a glycolytic enzyme defect. | Feature | G6PD Deficiency | PFK Deficiency (Tarui Disease) | |---------|-----------------|--------------------------------| | **Pathway affected** | Pentose phosphate pathway (oxidative branch) | Glycolysis | | **Primary mechanism** | Impaired NADPH generation → ↓ antioxidant defense | Glycolytic block → ATP depletion | | **Trigger** | Oxidative stress (infection, drugs, fava beans, exertion) | Exertion (ATP demand exceeds supply) | | **RBC involvement** | Hemolysis from oxidative damage | Hemolysis from ATP depletion | | **Muscle manifestations** | Absent or mild | Myalgia, cramps, weakness | | **Lactate levels** | Normal or low | Elevated (anaerobic metabolism) | | **Glucose-6-phosphate** | Normal (enzyme is present, just deficient) | Elevated (upstream accumulation) | | **Substrate for hemolysis** | Oxidative stress (H₂O₂, free radicals) | Energy depletion (↓ ATP) | ### Key Point: **G6PD deficiency causes hemolysis via oxidative damage**, whereas **PFK deficiency causes hemolysis via ATP depletion**. The mechanism of RBC injury is fundamentally different. ### High-Yield: G6PD deficiency is the most common enzyme deficiency worldwide (>400 million people). Hemolysis is triggered by **oxidative stressors** (infections, certain drugs like sulfonamides, aspirin, antimalarials, and fava beans), not by substrate depletion. ### Clinical Pearl: In G6PD deficiency, acute hemolytic episodes are self-limited because older RBCs (which have lower G6PD activity) are preferentially destroyed, leaving younger RBCs with higher residual enzyme activity. PFK deficiency, by contrast, affects all muscle and RBC populations equally. ### Mnemonic: **G6PD = Glucose-6-phosphate Dehydrogenase = Pentose Phosphate Pathway = Oxidative defense**; **PFK = Phosphofructokinase = Glycolysis = Energy production**. [cite:KD Tripathi 8e Ch 7; Robbins 10e Ch 7]