A 28-year-old woman with a history of recurrent muscle pain, myoglobinuria after exercise, and normal fasting glucose presents to the metabolic clinic. Serum CK is markedly elevated (8500 U/L). Suspicion is raised for pyruvate kinase (PK) deficiency. Which investigation is most appropriate to confirm the diagnosis?

Explanation

## Diagnosis of Pyruvate Kinase Deficiency ### Why Erythrocyte PK Activity Assay is Correct **Key Point:** Pyruvate kinase (PK) catalyzes the final irreversible step of glycolysis, converting phosphoenolpyruvate (PEP) to pyruvate. PK deficiency is an autosomal recessive disorder affecting multiple tissues, particularly RBCs and skeletal muscle. **High-Yield:** PK deficiency presents with: - Hemolytic anemia (RBCs are energy-dependent; ATP depletion → membrane instability) - Myopathy with exercise-induced rhabdomyolysis and myoglobinuria - Elevated serum CK and myoglobin - Normal or mildly elevated lactate at rest (the block is at the final glycolytic step) **Clinical Pearl:** Unlike proximal glycolytic blocks (e.g., PFK deficiency), PK deficiency does NOT cause severe lactic acidosis at rest because pyruvate accumulation is modest. However, during intense exercise, myoglobin release and CK elevation are prominent due to muscle ATP depletion. **Mnemonic:** FINAL STEP BLOCK → ATP DEPLETION → RBC + MUSCLE DAMAGE. Direct enzyme assay in RBCs confirms the diagnosis. ### Why Other Investigations Are Less Specific | Investigation | Limitation | |---|---| | Muscle biopsy + EM | Shows non-specific myopathic changes; does NOT identify the enzymatic defect | | ABG + lactate during stress | Lactate may be only mildly elevated; non-specific for PK deficiency | | MRI of lower limbs | Detects muscle edema/rhabdomyolysis but does NOT confirm the underlying metabolic cause | [cite:Harrison 21e Ch 297]