A 5-year-old girl is brought to the clinic due to several months of fatigue and difficulty walking. She ambulates normally at first but rapidly becomes weak and tired. The patient has not been ill recently and is usually happy and playful. She has a history of mild motor delays but is otherwise developmentally normal. Vital signs are within normal limits. Examination shows mildly decreased power in all extremities but no ataxia. Cardiac auscultation reveals a 1/6 systolic murmur and an S3 gallop. Laboratory results are as follows:
| Serum chemistry | |
| Glucose | 37 mg/dL |
| Creatine kinase | 304 U/L |
| Urinalysis | |
| Protein | none |
| Glucose | negative |
| Ketones | negative |
| Leukocyte esterase | negative |
| Nitrites | negative |
Muscle biopsy shows a very low carnitine content. This patient most likely has deficient synthesis of which of the following substances?
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This patient's myopathy (eg, elevated creatine kinase, weakness), cardiomyopathy (eg, S3 gallop), and hypoketotic hypoglycemia (eg, absence of ketones in the urine) in the setting of decreased muscle carnitine content is consistent with primary carnitine deficiency. The condition is caused by a defect in the protein responsible for carnitine transport across the mitochondrial membrane. Without sufficient carnitine, fatty acids cannot be transported from the cytoplasm into the mitochondria as acyl-carnitine (carnitine shuttle). The mitochondria therefore cannot β-oxidize the fatty acids into acetyl CoA, the carbon substrate for the citric acid cycle. As a result, cardiac and skeletal myocytes cannot generate ATP from fatty acids (leading to muscle weakness, cardiomyopathy) and the liver is unable to synthesize ketone bodies (manifests as hypoketotic hypoglycemia).
Hypoketotic hypoglycemia is also seen in other fatty acid oxidation disorders (eg, acyl CoA dehydrogenase deficiency).
(Choice B) Arachidonic acid can be ingested or synthesized from phospholipids in the cell membrane. Its eicosanoid derivatives (eg, prostanoids, leukotrienes) are important modulators of inflammation. It is not affected by carnitine levels.
(Choice C) Glutathione is a tripeptide that can be synthesized from amino acids (glutamate, cysteine, and glycine). It is an important antioxidant and plays a role in DNA synthesis and repair.
(Choice D) Homocysteine is an amino acid that is synthesized from methionine. Using vitamin cofactors, it can be converted to cysteine (pyridoxine) or recycled into methionine (cobalamin).
(Choice E) Lactate is produced from pyruvate under anaerobic conditions. Patients with carnitine deficiency synthesize lactate normally but may produce increased lactate during times of catabolic stress due to inability to utilize fatty acids for energy production.
(Choice F) Palmitate is a fatty acid that can be ingested or synthesized from carbohydrates. Palmitate synthesis occurs in the cytosol and would not be affected by carnitine deficiency.
Educational objective:
Carnitine deficiency impairs fatty acid transport from the cytoplasm into mitochondria, preventing β-oxidation of fatty acids into acetyl CoA. This leads to cardiac and skeletal myocyte injury (lack of ATP from citric acid cycle) and impaired ketone body production by the liver during fasting periods.