A 28-year-old male from Mumbai presents with severe muscle cramps and dark urine after strenuous exercise. Laboratory investigations reveal elevated creatine kinase, myoglobinuria, and hemolytic anemia. Genetic testing confirms a homozygous loss-of-function mutation in the gene encoding the enzyme marked **B** in the glycolysis pathway diagram. Which of the following best explains the pathophysiology of this patient's condition?

Explanation

## Why option 1 is correct The enzyme marked **B** is phosphofructokinase-1 (PFK-1), the rate-limiting enzyme of glycolysis. PFK-1 catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate — the committed step of glycolysis. Deficiency of PFK-1 (Tarui disease or GSD type VII) severely impairs ATP generation from glucose, particularly during muscle contraction when ATP demand is high. This energy deficit causes muscle necrosis (rhabdomyolysis) with myoglobinuria and hemolytic anemia due to impaired erythrocyte ATP production. The clinical presentation of exercise intolerance, myoglobinuria, and hemolytic anemia is pathognomonic for PFK-1 deficiency (Harper 32e, Ch 18). ## Why each distractor is wrong - **Option 2**: While glucose-6-phosphate may accumulate upstream of the PFK-1 block, this is a consequence, not the primary pathophysiologic mechanism. The critical problem is ATP depletion, not G6P accumulation. Moreover, G6P accumulation does not directly explain rhabdomyolysis or hemolysis. - **Option 3**: Pyruvate kinase (marked **C**) catalyzes the pyruvate-to-lactate conversion; PFK-1 deficiency does not impair this step. Lactic acidosis is not a feature of Tarui disease. This describes a different glycolytic enzyme defect. - **Option 4**: Hexokinase/glucokinase (marked **A**) catalyzes glucose phosphorylation to glucose-6-phosphate. PFK-1 acts downstream of this step. Deficiency of **A** would prevent glucose entry; deficiency of **B** allows glucose entry but blocks the committed step, leading to ATP depletion. **High-Yield:** PFK-1 is the rate-limiting enzyme and the most regulated step of glycolysis; its deficiency (Tarui disease) causes exercise intolerance, myoglobinuria, and hemolytic anemia due to ATP depletion in muscle and RBCs. [cite: Harper 32e, Ch 18 — Glycolysis and Gluconeogenesis]