A 28-year-old woman with a history of recurrent episodes of muscle pain and myoglobinuria during prolonged fasting or intense exercise is admitted with acute rhabdomyolysis. Serum creatine kinase is 8,500 U/L. Muscle biopsy shows lipid accumulation. Genetic testing confirms a mutation in the CPT II gene. During the acute episode, which of the following metabolic changes would you expect in her blood?

Explanation

## CPT II Deficiency: Metabolic Consequences During Acute Crisis **Key Point:** CPT II deficiency impairs the re-entry of long-chain fatty acyl-CoA into mitochondria for β-oxidation. During metabolic stress (fasting, exercise), the block causes accumulation of free fatty acids in blood, inability to generate ketones and ATP, and secondary hypoglycemia. ### Carnitine Palmitoyltransferase II (CPT II) Function CPT II catalyzes the re-esterification of long-chain acyl-carnitine back to acyl-CoA on the inner mitochondrial membrane: $$\text{Acyl-carnitine} + \text{CoA} \xrightarrow{\text{CPT II}} \text{Acyl-CoA} + \text{Carnitine}$$ Without functional CPT II: - Acyl-carnitine accumulates in the mitochondrial matrix - Acyl-CoA cannot be generated for β-oxidation - Long-chain fatty acids cannot enter the mitochondrial oxidative pathway ### Metabolic Changes During Acute Metabolic Stress | Parameter | CPT II Deficiency | Normal Response to Fasting | |-----------|-------------------|---------------------------| | **Free Fatty Acids** | ↑↑ (cannot be oxidized; accumulate in blood) | ↑ (mobilized and oxidized) | | **Ketone Bodies** | ↓ (no acetyl-CoA from FAO) | ↑↑ (abundant from FAO) | | **Blood Glucose** | ↓ (impaired gluconeogenesis; ATP depletion) | Normal to slightly ↓ | | **Muscle ATP** | ↓↓ (cannot oxidize FAA; glycogen depleted) | Maintained | | **Lipid in Muscle** | ↑↑ (accumulation due to impaired oxidation) | Normal | ### Why This Patient Presents with Rhabdomyolysis 1. **Energy crisis in muscle:** During exercise or fasting, muscles normally rely on fatty acid oxidation for ATP. CPT II deficiency blocks this pathway. 2. **ATP depletion** → muscle cell necrosis → myoglobinuria and elevated CK 3. **Lipid accumulation** → toxic metabolite buildup (acyl-carnitine, acyl-CoA) → further cellular damage 4. **Hypoglycemia** → additional metabolic stress on muscle **High-Yield:** CPT II deficiency is **autosomal recessive** and presents in three forms: - **Infantile form** (severe, neonatal): hepatic encephalopathy, hypoketotic hypoglycemia - **Myopathic form** (adult-onset):** recurrent myoglobinuria with exercise/fasting (this patient's phenotype) - **Neonatal form:** fulminant presentation ### Clinical Pearl: The Paradox of Elevated Free Fatty Acids with Low Ketones In normal fasting, elevated FFA correlates with elevated ketones (both increase together). In CPT II deficiency, FFA are elevated but ketones are low — this **discordance** is a diagnostic clue. The reason: FFA are mobilized from adipose tissue but cannot enter mitochondria for oxidation, so they accumulate in blood without being converted to ketones. **Mnemonic: "CPT II blocks the door"** — Free fatty acids line up at the mitochondrial door (as carnitine esters) but cannot enter (no CPT II). They back up in the bloodstream, while ketone production (which requires acetyl-CoA from FAO) is blocked. ### Why Glucose Is Low During fasting, gluconeogenesis requires ATP and NADH, both of which are normally generated by fatty acid oxidation. In CPT II deficiency: - No acetyl-CoA from FAO → impaired TCA cycle → reduced NADH and ATP - Glycogen depletion during exercise - Result: hypoglycemia, especially if fasting is prolonged **Warning:** Do not confuse CPT II deficiency (myopathic form) with CPT I deficiency. CPT I deficiency also presents with hypoketotic hypoglycemia and hepatomegaly but is typically neonatal/infantile and does NOT cause recurrent myoglobinuria with exercise.