A 28-year-old woman from Delhi presents to the emergency department with acute-onset severe muscle pain, dark urine, and malaise following intense gym exercise. Serum creatine kinase is 8,500 U/L, myoglobin is elevated, and urine dipstick shows blood without RBCs (myoglobinuria). Serum potassium is 6.2 mmol/L. Arterial blood gas shows pH 7.28 with HCO₃⁻ 16 mmol/L. Which glycolytic enzyme deficiency is most consistent with exertional rhabdomyolysis triggered by intense exercise?

Explanation

## Exertional Rhabdomyolysis in Glycolytic Enzyme Deficiency **Key Point:** Muscle phosphofructokinase (PFK-M) deficiency causes exertional rhabdomyolysis because muscle cannot generate ATP during intense exercise, leading to myocyte necrosis and myoglobinuria. ### Pathophysiology of PFK-M Deficiency Phosphofructokinase catalyzes the committed step of glycolysis: $$\text{Glucose-6-phosphate} \xrightarrow{\text{PFK}} \text{Fructose-1,6-bisphosphate} + \text{ADP}$$ This is the rate-limiting and most highly regulated step of glycolysis. ### Why Muscle Is Affected 1. **Energy crisis during exercise:** Muscle relies on glycolysis for rapid ATP generation during high-intensity exercise. - PFK deficiency blocks glycolysis → no ATP production from glucose - Muscle cannot sustain contraction → myocyte necrosis - Rhabdomyolysis occurs with exertion (not at rest) 2. **Metabolic consequences:** - Glucose-6-phosphate accumulates → shunted into glycogen synthesis - Fructose-1,6-bisphosphate is not generated → no pyruvate, no lactate - Paradoxically, **no lactic acidosis** (unlike PK deficiency) - Severe hyperkalaemia from myocyte breakdown (K⁺ release) - Myoglobinuria from muscle necrosis 3. **Why only with exercise:** At rest, muscle can use other fuels (fatty acids, ketones, amino acids) and has lower ATP demand. Intense exercise forces reliance on glycolysis. ### Clinical Features of PFK-M Deficiency (Tarui Disease) | Feature | Present? | Mechanism | |---|---|---| | Exertional rhabdomyolysis | Yes | ATP failure during glycolysis block | | Myoglobinuria | Yes | Muscle necrosis | | Elevated CK | Yes | Myocyte breakdown | | Hyperkalaemia | Yes | K⁺ release from necrotic muscle | | Lactic acidosis | No | Pyruvate not generated | | Hepatomegaly | Yes (mild) | G6P → glycogen accumulation | | Haemolytic anaemia | Yes | RBC PFK deficiency | | Second wind phenomenon | Yes | Adenosine → purine salvage pathway activates | **High-Yield:** The **absence of lactic acidosis** despite rhabdomyolysis is a key discriminator for PFK-M deficiency. In contrast, phosphoglycerate kinase deficiency causes lactic acidosis. **Clinical Pearl:** The "second wind phenomenon" is pathognomonic: after 1–2 minutes of exercise-induced pain, patients experience relief and can continue exercising. This occurs because adenosine from ATP breakdown activates purine salvage pathways, providing alternative ATP sources. ### Why Not Phosphoglycerate Kinase Deficiency? Phosphoglycerate kinase (PGK) catalyzes: $$\text{1,3-bisphosphoglycerate} \xrightarrow{\text{PGK}} \text{3-phosphoglycerate} + \text{ATP}$$ PGK deficiency DOES cause exertional rhabdomyolysis, BUT: - It causes **lactic acidosis** (pyruvate is still generated) - It is X-linked recessive (affects males predominantly) - Haemolytic anaemia is more severe - Neurological symptoms (developmental delay) are common In this case, the **absence of lactic acidosis** (pH 7.28 with HCO₃⁻ 16 = metabolic acidosis from myoglobin/K⁺, not lactate) points to **PFK-M deficiency**. ### Differential Diagnosis: Glycolytic Enzyme Defects Causing Rhabdomyolysis ```mermaid flowchart TD A[Exertional Rhabdomyolysis]:::outcome --> B{Lactic Acidosis?}:::decision B -->|Yes| C[Phosphoglycerate Kinase Deficiency]:::outcome B -->|No| D{Haemolytic Anaemia?}:::decision D -->|Yes| E[Muscle Phosphofructokinase Deficiency]:::outcome D -->|No| F[Rare glycolytic defects]:::outcome C --> G[X-linked, neurological symptoms]:::action E --> H[Autosomal recessive, Second wind phenomenon]:::action ```