A 28-year-old woman from Delhi presents with progressive muscle weakness, myalgia, and dark urine after a 36-hour fasting period. She has a history of similar episodes triggered by prolonged exercise or illness. Serum creatine kinase is 8,500 U/L (normal < 200). Urine myoglobin is positive. Plasma free carnitine is 35 µmol/L (normal 40–50). During fasting, serum glucose is 68 mg/dL with inappropriately low serum ketones (0.3 mmol/L; expected > 2 mmol/L). Muscle biopsy shows lipid accumulation. Which enzyme defect best explains this clinical presentation?

Explanation

## Clinical Diagnosis: CPT II Deficiency (Muscular Form) ### Pathophysiology This patient has **CPT II deficiency**, specifically the adult-onset muscular form. CPT II catalyzes the reconversion of acyl-carnitine to acyl-CoA on the inner mitochondrial membrane, the final step before β-oxidation. Loss of CPT II activity causes: 1. Accumulation of long-chain acyl-carnitine in muscle 2. Impaired fatty acid oxidation → energy crisis in muscle 3. Rhabdomyolysis with myoglobinuria 4. Hypoketotic hypoglycemia (fasting cannot mobilize fat) ### Diagnostic Features of CPT II Deficiency | Feature | CPT II Deficiency | MCAD | LCHAD | SLC22A5 | |---------|-------------------|------|-------|----------| | **Primary symptom** | Muscle pain/weakness | Encephalopathy | Cardiomyopathy | Encephalopathy | | **Rhabdomyolysis** | Yes (hallmark) | No | Rare | No | | **CK elevation** | Marked (> 5,000) | Mild | Mild–moderate | Mild | | **Myoglobinuria** | Yes | No | No | No | | **Plasma carnitine** | Normal/low-normal | Normal | Low | Markedly ↓ | | **Hypoketotic hypoglycemia** | Yes (fasting) | Yes (illness) | Yes (pregnancy) | Yes | | **Lipid in muscle** | Yes | No | Yes | Yes | **High-Yield:** The combination of **rhabdomyolysis with myoglobinuria + hypoketotic hypoglycemia + lipid accumulation in muscle** is pathognomonic for CPT II deficiency. The normal plasma carnitine rules out primary carnitine deficiency. ### Biochemical Mechanism ```mermaid flowchart TD A["Long-chain fatty acid"]:::outcome --> B["Activation to acyl-CoA<br/>in cytoplasm"]:::action B --> C["CPT I transfers to<br/>acyl-carnitine"]:::action C --> D["Carnitine shuttle<br/>across inner membrane"]:::action D --> E{"CPT II present?"}:::decision E -->|"Yes (Normal)"| F["Reconversion to acyl-CoA<br/>in matrix"]:::action E -->|"No (Deficiency)"| G["Acyl-carnitine accumulates<br/>in matrix"]:::urgent F --> H["β-oxidation proceeds"]:::action G --> I["Impaired oxidation<br/>Lipid accumulation"]:::urgent H --> J["Acetyl-CoA → Energy"]:::outcome I --> K["Muscle energy crisis<br/>Rhabdomyolysis"]:::urgent ``` **Clinical Pearl:** CPT II deficiency has three phenotypes: - **Infantile cardiomuscular** (severe, neonatal) - **Adult muscular** (myalgia/rhabdomyolysis triggered by fasting/exercise) — **this patient** - **Neonatal hypoketotic hypoglycemia** (rare) This patient fits the adult muscular form: triggered by prolonged fasting, presents with myalgia and rhabdomyolysis, normal plasma carnitine. ### Why Hypoketotic Hypoglycemia Occurs During fasting, the body normally shifts to fatty acid oxidation for energy and ketone production. In CPT II deficiency: - Fatty acids cannot be oxidized (CPT II block) - Glucose is rapidly depleted (no fat-derived acetyl-CoA for gluconeogenesis) - Ketone production fails (no acetyl-CoA substrate) - Result: **hypoketotic hypoglycemia** (low glucose + inappropriately low ketones) **Mnemonic: CPT II = "Carnitine Palmitoyltransferase II" = "Can't Process inside (matrix) — Trapped outside (carnitine shuttle)"** [cite:KD Tripathi 8e Ch 18; Harrison 21e Ch 398]