A 28-year-old woman from Delhi presents to the emergency department with acute-onset severe muscle pain, dark urine, and malaise following an intense 2-hour gym session in a non-air-conditioned facility during summer. Serum creatine kinase is 8,500 U/L (normal <200), myoglobin is markedly elevated, and urine dipstick is positive for blood but urinalysis shows no RBCs. Arterial blood gas reveals pH 7.28, HCO₃⁻ 16 mEq/L. Muscle biopsy shows normal glycogen content and normal enzyme histochemistry. Which glycolytic enzyme defect would MOST likely present with a similar acute rhabdomyolysis picture in a different clinical context?

Explanation

## Glycolytic Enzyme Defects and Rhabdomyolysis ### Clinical Context: Exercise-Induced Rhabdomyolysis The patient presented has **exertional rhabdomyolysis** (likely due to heat stress and dehydration), which is a secondary form. However, the question asks which **glycolytic enzyme defect** would cause a similar acute rhabdomyolysis picture. **High-Yield:** Phosphofructokinase (PFK) deficiency is the **glycolytic enzyme defect most commonly associated with exercise-induced rhabdomyolysis and myopathy**. ### Biochemistry of PFK Deficiency (Tarui Disease) #### Enzyme Function PFK-1 catalyzes the second committed step of glycolysis: $$\text{Fructose-6-phosphate} + \text{ATP} \rightarrow \text{Fructose-1,6-bisphosphate} + \text{ADP}$$ This is the **rate-limiting step** and is allosterically regulated by ATP, AMP, and citrate. #### Pathophysiology in Muscle 1. **Energy Crisis During Exercise:** - PFK deficiency blocks glycolysis at the rate-limiting step - Muscles cannot generate ATP from glucose during high-demand exercise - ATP depletion leads to: - Uncontrolled Ca²⁺ influx (loss of Na⁺/K⁺-ATPase function) - Proteolysis and myofibril breakdown - **Acute rhabdomyolysis** 2. **Metabolic Compensation Failure:** - Glycogen accumulates proximal to the PFK block (normal glycogen content on biopsy, but cannot be mobilized) - Muscles cannot switch to fatty acid oxidation efficiently during intense exercise - Lactate production is severely impaired → metabolic acidosis (as seen in this patient) **Mnemonic:** **PFK = "Poor Fuel for Kinetic activity"** — muscles cannot generate ATP during exercise. ### Why This Patient's Presentation Fits PFK Deficiency | Feature | This Patient | PFK Deficiency | |---------|--------------|----------------| | Acute rhabdomyolysis | Yes (heat + exertion) | Yes (exercise-induced) | | Myoglobinuria | Yes | Yes | | Metabolic acidosis | Yes (pH 7.28) | Yes (lactate cannot be produced) | | Elevated CK | Yes (8,500) | Yes (can be >10,000) | | Normal glycogen on biopsy | Yes | Yes (glycogen accumulates but cannot be used) | | Hemolytic anemia | No (not mentioned) | Yes (RBCs also depend on glycolysis) | **Clinical Pearl:** PFK deficiency is the **only glycolytic enzyme defect that causes both myopathy AND hemolytic anemia** because both skeletal muscle and RBCs rely heavily on anaerobic glycolysis for ATP. ### Pathophysiology Flowchart ```mermaid flowchart TD A[PFK Deficiency]:::outcome --> B[Glycolysis blocked at F6P → F1,6BP]:::outcome B --> C[No ATP generation from glucose]:::urgent C --> D{Intense Exercise?}:::decision D -->|Yes| E[Severe ATP depletion in muscle]:::urgent E --> F[Uncontrolled Ca2+ influx]:::urgent F --> G[Myofibril breakdown]:::urgent G --> H[Rhabdomyolysis + Myoglobinuria]:::outcome B --> I[Lactate production blocked]:::outcome I --> J[Metabolic acidosis]:::outcome B --> K[Glycogen accumulates]:::outcome ``` ### Differential: Other Glycolytic Enzyme Defects | Enzyme | Clinical Presentation | Rhabdomyolysis Risk | |--------|----------------------|---------------------| | **PFK** | Myopathy + hemolysis + exercise intolerance | **HIGH** | | Pyruvate kinase | Hemolytic anemia only | Low | | Aldolase | Hepatomegaly + hypoglycemia | Low | | GAPDH | Severe hypoglycemia + lactic acidosis | Low | | Hexokinase | Neonatal hypoglycemia (rare) | Low | | Enolase | Neurological symptoms (rare) | Low | | Phosphoglycerate mutase | Myopathy (milder than PFK) | Moderate | **Warning:** Do not confuse PFK deficiency with mitochondrial myopathies or muscular dystrophies. PFK deficiency is a **glycolytic disorder**, not a mitochondrial or structural muscle disease.