A 28-year-old woman from Delhi presents with progressive muscle weakness, myalgia, and dark urine after a 48-hour viral illness with fever and vomiting. On examination, she has proximal muscle tenderness and mild hepatomegaly. Laboratory findings: CK 8,500 U/L (normal <200), myoglobin in urine (3+), serum carnitine 18 μmol/L (normal 40–60), and acylcarnitine profile shows elevated long-chain acylcarnitines (C16, C18). Fasting serum glucose is 72 mg/dL. A diagnosis of carnitine palmitoyltransferase II (CPT II) deficiency is considered. Which of the following best explains why this patient developed rhabdomyolysis despite normal blood glucose?

Explanation

## Pathophysiology of Rhabdomyolysis in CPT II Deficiency ### Role of CPT II in Fatty Acid Oxidation CPT II (carnitine palmitoyltransferase II) catalyzes the reconversion of long-chain acylcarnitines back to acyl-CoA on the inner mitochondrial membrane: $$\text{Long-chain acylcarnitine} + \text{CoA} \xrightarrow{\text{CPT II}} \text{Acyl-CoA} + \text{Carnitine}$$ This is the **rate-limiting step** for long-chain fatty acid β-oxidation in muscle. ### Mechanism of Myonecrosis in CPT II Deficiency | Feature | Normal | CPT II Deficiency | |---------|--------|-------------------| | **Long-chain acyl-CoA levels** | Low (rapidly oxidized) | **Markedly elevated** | | **Carnitine availability** | Sufficient | Depleted (trapped as acylcarnitine) | | **Mitochondrial β-oxidation** | Normal | **Severely impaired** | | **Cellular energy (ATP)** | Maintained | **Depleted during fasting/stress** | | **Toxic metabolite** | None | **Acyl-CoA** | ### Why Rhabdomyolysis Occurs Despite Normal Glucose 1. **Accumulated long-chain acyl-CoA is lipotoxic:** - Acyl-CoA activates caspase-dependent apoptosis pathways - Triggers endoplasmic reticulum stress and unfolded protein response - Causes mitochondrial dysfunction and calcium dysregulation 2. **Muscle energy crisis during viral illness:** - Fever and infection increase metabolic demand - Fasting (from vomiting) forces reliance on fatty acid oxidation - CPT II deficiency blocks this pathway → ATP depletion - Myocyte necrosis ensues 3. **Why glucose is normal:** - Hepatic glucose production is **not** impaired in CPT II deficiency (unlike MCAD) - The block is in muscle fatty acid oxidation, not hepatic gluconeogenesis - Glucose levels reflect hepatic function, not muscle energy status ### Why Other Options Are Incorrect **Option 1 (Carnitine depletion):** Carnitine is not depleted; it is sequestered as acylcarnitine. The problem is that acylcarnitine cannot be converted back to acyl-CoA for oxidation. **Option 3 (Impaired ketone utilization):** CPT II deficiency does NOT affect ketone metabolism. Muscles can use ketones normally; the problem is that ketone production may be reduced due to muscle's inability to provide acetyl-CoA precursors. **Option 4 (ETC inhibition):** Acylcarnitines do not directly inhibit the electron transport chain. The problem is that acyl-CoA accumulates *upstream* of oxidation, preventing ATP generation. ### Clinical Pearl: Muscle vs. Liver CPT II Deficiency ```mermaid flowchart TD A[CPT II Deficiency]:::outcome --> B{Which tissue?}:::decision B -->|Muscle isoform| C[Rhabdomyolysis<br/>Myalgia<br/>Normal glucose]:::action B -->|Liver isoform| D[Hypoketotic hypoglycemia<br/>Hepatomegaly<br/>Encephalopathy]:::urgent C --> E[Acyl-CoA accumulation<br/>Lipotoxicity<br/>Myonecrosis]:::outcome D --> F[Impaired hepatic<br/>fatty acid oxidation<br/>Energy crisis]:::outcome ``` **High-Yield:** CPT II deficiency is the most common carnitine cycle disorder. The **muscle form** (most common) presents with exercise-induced or illness-triggered rhabdomyolysis and **normal fasting glucose**. The **hepatic form** (rare) presents like MCAD: hypoketotic hypoglycemia and hepatomegaly. **Mnemonic: ACYL-CoA TOXICITY** — Accumulated **A**cyl-**C**oA **Y**ields **L**ipotoxicity, **C**aspase activation, **O**xidative stress, **A** ATP depletion. [cite:Lehninger Principles of Biochemistry 8e Ch 21; Harrison 21e Ch 401]