An Adolescent with Episodic Rhabdomyolysis and a Nondiagnostic Acylcarnitine Profile
A 15-year-old girl presents with two episodes of dark urine and muscle pain after prolonged exercise and a febrile illness. Creatine kinase is 28,000 U/L during the episode, falling to 300 U/L at baseline. She has no weakness between episodes, normal growth, and no hepatomegaly. Fasting glucose 78 mg/dL, urine ketones negative during the episode, and serum bicarbonate 20 mmol/L. Plasma acylcarnitine profile obtained during the acute episode is reported as 'nondiagnostic, possible mild elevation of C14:1.' Urine organic acids show dicarboxylic acids. A fasting study was not performed. The family is anxious for a diagnosis and asks about a 'muscle biopsy.'
1. How do you interpret the acylcarnitine result and the dicarboxylic aciduria, and what is the most informative next test?
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Interpretation: A mild C14:1 elevation with dicarboxylic aciduria during an acute crisis is suggestive of, but not diagnostic of, a very-long-chain acyl-CoA dehydrogenase (VLCAD) or other long-chain fatty acid oxidation defect. Critically, acylcarnitine profiles are unreliable during acute illness and after fasting; they can be normal or misleadingly abnormal. The absence of ketones with hypoglycemia would be more concerning, but her glucose is normal. Dicarboxylic acids are a nonspecific marker of fatty acid oxidation stress and can occur in many conditions.
Next test: The most informative single test is a fasting study (or a controlled fasting challenge) performed when well, with serial glucose, ketones, free fatty acids, and acylcarnitines, ideally in a monitored setting. This can unmask a fatty acid oxidation defect that is silent when fed. In parallel, obtain a repeat acylcarnitine profile when well and after a standardized fast, and consider molecular testing of the fatty acid oxidation genes (ACADVL first, then others) as a noninvasive alternative. A muscle biopsy is not the first-line test for a suspected fatty acid oxidation defect; it is reserved for cases where molecular and biochemical testing are uninformative and a myopathy is suspected.
Practical point: Avoid prolonged fasting and strenuous exercise until the diagnosis is clarified; provide an emergency plan.
2. The fasting study is not feasible in your setting. How do you proceed, and how do you counsel the family about the possibility of a fatty acid oxidation disorder?
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Proceeding without a fasting study:
- Obtain a repeat acylcarnitine profile when well and at least 4-6 hours after a meal, and a repeat urine organic acid profile.
- Send molecular testing: a fatty acid oxidation gene panel or exome, prioritizing ACADVL, then CPT2, HADHA/HADHB, SLC22A5, and ETFDH. This is the most definitive noninvasive route.
- If molecular testing is uninformative and the clinical suspicion remains high, refer to a metabolic center for a controlled fasting challenge or, rarely, enzyme studies on cultured fibroblasts or muscle.
Counseling:
- Explain that a fatty acid oxidation disorder is a plausible but unconfirmed explanation for exercise- and illness-triggered rhabdomyolysis, and that the acylcarnitine result is not definitive.
- Give a safety plan regardless of diagnosis: avoid prolonged fasting (e.g., no more than 8-10 hours overnight for a teenager, with a bedtime snack), carry glucose, and seek urgent care with illness or dark urine.
- Discuss that some fatty acid oxidation disorders are treatable with dietary fat modification, carnitine, and avoidance of triggers, and that a precise diagnosis guides this.
- Be honest about uncertainty: a normal repeat test does not fully exclude the diagnosis, and a genetic result may be a variant of uncertain significance.
Key point: do not let the absence of a fasting study push you to an invasive test prematurely; use molecular testing and safety counseling.