A 28-year-old woman from Delhi presents to the emergency department with acute onset severe muscle pain, dark urine, and malaise following an 8-hour hiking expedition in summer heat. She has a past history of similar episodes triggered by prolonged exercise or fasting. On examination, she is afebrile, heart rate 110/min, and has diffuse muscle tenderness. Laboratory findings: creatine kinase (CK) 8,500 U/L (normal <200), myoglobin in urine (3+), serum potassium 6.2 mmol/L, creatinine 1.8 mg/dL, and fasting blood glucose 72 mg/dL (normal). Serum ketones are elevated (2.1 mmol/L). Which of the following is the most likely diagnosis?

Explanation

## Clinical Presentation Analysis **Key Point:** The combination of exercise-induced rhabdomyolysis, myoglobinuria, elevated CK, normal blood glucose during fasting, and elevated ketones is classic for CPT II deficiency. ### Pathophysiology of CPT II Deficiency CPT II catalyzes the reverse carnitine-dependent transport of long-chain acyl-CoA out of the mitochondria. In CPT II deficiency: 1. **During exercise:** muscles attempt to increase β-oxidation for energy 2. **Acyl-CoA accumulates inside mitochondria** → cannot exit for re-esterification 3. **Toxic accumulation of long-chain acyl-CoA** → mitochondrial dysfunction and myotoxicity 4. **Muscle necrosis** → rhabdomyolysis, myoglobinuria, elevated CK 5. **Ketone production is preserved** (enzyme is downstream of β-oxidation) → elevated serum ketones 6. **Glucose homeostasis is normal** (gluconeogenesis is intact) → normal fasting glucose ### Clinical Presentation Comparison | Feature | CPT II | VLCAD | McArdle | Mitochondrial Myopathy | |---------|--------|-------|---------|------------------------| | **Trigger** | Exercise, fasting | Exercise, fasting | Exercise | Exercise, cold | | **Rhabdomyolysis** | Severe | Mild–moderate | Absent | Mild | | **Myoglobinuria** | Present | Rare | Absent | Absent | | **CK elevation** | Marked (>5000) | Moderate | Absent or mild | Mild–moderate | | **Fasting glucose** | Normal | Low | Normal | Normal | | **Ketones** | Elevated | Low | Elevated | Normal | | **Muscle pain** | Severe | Moderate | Absent (paradox) | Present | | **Age of onset** | Childhood–adulthood | Infancy–childhood | Childhood | Variable | | **Cardiac involvement** | Yes (cardiomyopathy) | Yes (cardiomyopathy) | No | Yes | **High-Yield:** CPT II deficiency is the most common cause of **exercise-induced rhabdomyolysis in young adults**. The preserved ketone production (normal or elevated) distinguishes it from other β-oxidation defects. ### Clinical Pearl **"Second wind" phenomenon:** Patients with CPT II deficiency (and McArdle disease) report that muscle pain and fatigue improve after 10–15 minutes of continued exercise—this is because the body switches to alternative fuel sources (glucose uptake increases, alternative pathways activate). In CPT II, this is due to increased glucose utilization and reduced reliance on fatty acid oxidation. ### Why This Patient Has CPT II and Not Other Disorders 1. **Normal fasting glucose** → rules out VLCAD (causes hypoketotic hypoglycemia) 2. **Elevated ketones** → rules out McArdle disease (which produces ketones normally but cannot mobilize muscle glycogen, so exercise is painless and CK is normal) 3. **Severe rhabdomyolysis with myoglobinuria** → rules out mitochondrial myopathy (typically causes chronic progressive weakness, not acute rhabdo) 4. **Exercise trigger + muscle pain + myoglobinuria + normal glucose + elevated ketones** → classic CPT II ### Management - **Avoid prolonged fasting and strenuous exercise** - **High-carbohydrate diet** (reduces reliance on fatty acid oxidation) - **Medium-chain triglycerides (MCTs)** (bypass CPT II, enter mitochondria directly) - **Avoid cold exposure** (increases metabolic demand) - **Aggressive fluid resuscitation** in acute rhabdomyolysis to prevent acute kidney injury [cite:Lehninger Principles of Biochemistry Ch 21; Harrison 21e Ch 356]