A 38-year-old woman with a history of recurrent muscle pain and weakness after fasting is found to have deficiency of carnitine palmitoyltransferase II (CPT-II). Regarding the pathophysiology of this condition, all of the following are true EXCEPT:

Explanation

## CPT-II Deficiency and Fatty Acid Oxidation ### Clinical Context: **Key Point:** CPT-II deficiency is a mitochondrial disorder causing recurrent myoglobinuria, muscle pain, and weakness triggered by fasting, exercise, or illness. It is one of the most common inherited disorders of fatty acid oxidation. ### Understanding the CPT System: ```mermaid flowchart LR A["Long-chain Acyl-CoA<br/>(Cytoplasm)"] -->|CPT-I| B["Acyl-Carnitine<br/>(Carnitine shuttle)"] B -->|Transport| C["Acyl-Carnitine<br/>(Mitochondrial matrix)"] C -->|CPT-II| D["Long-chain Acyl-CoA<br/>(Matrix)"] D -->|β-oxidation| E["Acetyl-CoA<br/>FADH₂, NADH"]:::action style A fill:#e8f4f8 style C fill:#e8f4f8 style D fill:#fff4e6 style E fill:#d4edda ``` **High-Yield:** - **CPT-I** (outer membrane) transfers acyl groups **onto** carnitine - **CPT-II** (inner membrane) transfers acyl groups **off** carnitine back to CoA - **Carnitine shuttle** transports long-chain acyl groups across the inner mitochondrial membrane ### Why Option 3 is WRONG: **Clinical Pearl:** Short- and medium-chain fatty acids (< 12 carbons) **do NOT require carnitine** for transport into mitochondria. They can diffuse directly across the mitochondrial membranes and be activated to CoA inside the matrix by medium-chain acyl-CoA synthetase. | Fatty Acid Chain Length | Carnitine Required? | Transport Mechanism | |-------------------------|-------------------|---------------------| | **Short-chain (< 6 C)** | NO | Direct diffusion + intramitochondrial activation | | **Medium-chain (6–12 C)** | NO | Direct diffusion + intramitochondrial activation | | **Long-chain (> 12 C)** | YES | CPT-I → carnitine shuttle → CPT-II | | **Very long-chain (> 20 C)** | YES | CPT-I → carnitine shuttle → CPT-II | Therefore, patients with CPT-II deficiency **can still oxidize short- and medium-chain fatty acids normally** because these bypass the carnitine shuttle entirely. ### Correct Statements (Options 0, 1, 2): 1. **Option 0 (Correct):** CPT-II catalyzes the transfer of the acyl group from carnitine back to CoA in the mitochondrial matrix, allowing β-oxidation to proceed. Deficiency blocks this step. 2. **Option 1 (Correct):** During fasting or exercise, the body relies heavily on long-chain fatty acid oxidation. CPT-II deficiency prevents this, forcing reliance on glucose and amino acids, leading to hypoglycemia and myoglobinuria. 3. **Option 2 (Correct):** Accumulation of carnitine esters (acyl-carnitines) in muscle and secondary loss of free carnitine contributes to the myopathy phenotype. **Mnemonic:** **Short & Medium skip the Shuttle** — only long-chain fatty acids need the carnitine shuttle (CPT-I/CPT-II). [cite:Lehninger Principles of Biochemistry 8e Ch 21]