A 28-year-old woman from Delhi presents to the emergency department with acute-onset severe myalgia, dark urine, and malaise 4 hours after intense gym training. Serum creatinine is 2.1 mg/dL (baseline 0.8), urine myoglobin is positive, and serum CK is 45,000 U/L. Arterial blood gas shows pH 7.28 with HCO₃⁻ 16 mmol/L. Serum potassium is 6.8 mmol/L. Which glycolytic enzyme deficiency would most likely predispose to this acute rhabdomyolysis during exercise?

Explanation

## Clinical Diagnosis: Exercise-Induced Rhabdomyolysis in PFK-M Deficiency This patient presents with **Tarui disease** (muscle phosphofructokinase deficiency), the second most common glycogen storage disease affecting skeletal muscle. ### Acute Presentation Explained **High-Yield:** PFK-M catalyzes the rate-limiting step of glycolysis: $$\text{Fructose-6-phosphate} + \text{ATP} \xrightarrow{\text{PFK}} \text{Fructose-1,6-bisphosphate} + \text{ADP}$$ Without functional PFK-M, muscle cannot generate ATP from glucose during exercise, leading to: 1. **Energy crisis** → muscle fiber necrosis → rhabdomyolysis 2. **Myoglobinuria** → dark urine (as seen in this patient) 3. **Acute kidney injury** from myoglobin precipitation in renal tubules (Cr 2.1) 4. **Hyperkalemia** (K⁺ 6.8) from muscle cell lysis 5. **Metabolic acidosis** (pH 7.28) from anaerobic metabolism and myoglobin-induced renal failure ### Pathophysiology of Tarui Disease | Glycolytic Block | Consequence | |------------------|-------------| | PFK-M deficiency | Glucose cannot be phosphorylated beyond F6P | | Glucose-6-phosphate accumulates | Shunted to glycogen synthesis → muscle glycogen accumulation | | No ATP from glycolysis during exercise | Muscle contraction fails; fiber necrosis | | Anaerobic metabolism blocked | Lactate cannot be produced (paradoxically, lactate is LOW or absent) | | Fructose-1,6-bisphosphate unavailable | Glycolytic ATP generation impossible | **Key Point:** Unlike other glycogen storage diseases, Tarui disease patients have **normal or low blood lactate during exercise** because glycolysis is blocked before lactate formation. This is a diagnostic clue. ### Clinical Features of PFK-M Deficiency - **Exercise intolerance** with myalgia, cramps, and weakness ("second wind" phenomenon: symptoms improve after 10 min as alternative fuels activate) - **Recurrent rhabdomyolysis** with exertion, especially in heat or with infection - **Myoglobinuria** → dark urine, acute kidney injury - **Hemolysis** (PFK-M is also expressed in RBCs) → mild anemia, elevated indirect bilirubin - **Hyperuricemia** → gout risk (from purine degradation of necrotic muscle) - **Normal fasting glucose** (unlike other GSDs) - **Muscle glycogen accumulation** on biopsy (vacuolar myopathy) ### Diagnostic Clues **Mnemonic: TARUI = Transient ATP Reduction in Unexercised Individuals** - Ischemic forearm exercise test: **no lactate rise** (pathognomonic) - Serum CK markedly elevated (45,000 U/L in this case) - Urine myoglobin positive - RBC PFK activity reduced (diagnostic tissue) - Genetic testing: PFKM gene mutations **Clinical Pearl:** The "second wind" phenomenon (symptom improvement after 10–15 min of exercise) is unique to Tarui disease. As glycogen is depleted, alternative fuels (fatty acids, ketones) activate, bypassing the glycolytic block.