Very long-chain acyl-CoA dehydrogenase and mitochondrial trifunctional protein (including long-chain L-3-hydroxyacyl-CoA dehydrogenase) deficiencies are recessively inherited inborn errors of mitochondrial fatty acid oxidation. They have a wide range of manifestations, from clinically asymptomatic to severe hypertrophic cardiomyopathy and/or acute, life-threatening episodes of hypoketotic, hypoglycemic coma induced by fasting. In infancy, the presentation can mimic sudden infant death syndrome. Milder variants may primarily affect skeletal muscle and become manifest in adolescence or early adulthood as chronic weakness, pain, recurrent rhabdomyolysis, or acute or chronic cardiomyopathies. Insights into clinical presentation, etiology, pathophysiology, diagnostic work-up, treatment, and pregnancy are presented in this article. The authors describe novel diagnostic tools and clinical trials on potential new management strategies for these fatty oxidation disorders.
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• Mitochondrial fatty acid oxidation is the central metabolic pathway for ATP production, especially in liver, heart, and skeletal muscle.
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• Fatty acid-oxidation disorders can present with acute, life-threatening episodes of hypoketotic, hypoglycemic coma induced by fasting.
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• Milder variants become manifest in adolescence or early adulthood as chronic muscle weakness, pain, recurrent rhabdomyolysis, or acute or chronic cardiomyopathies.
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• Newborn screening has significantly reduced morbidity and mortality.
Historical note and terminology
Mitochondrial fatty acid oxidation plays a major role in energy production and homeostasis. Very long-chain acyl-CoA dehydrogenase and mitochondrial trifunctional protein (including long-chain L-3-hydroxyacyl-CoA dehydrogenase) deficiencies, are recessively inherited inborn errors of mitochondrial fatty acid oxidation resulting in overlapping clinical pathology.
Very long-chain acyl-CoA dehydrogenase deficiency was first identified independently by 2 groups (06; 11). All of the patients initially described with long-chain acyl-CoA dehydrogenase deficiency (49) appear in retrospect to have had defects in very long-chain acyl-CoA dehydrogenase (144). Two disorders of the mitochondrial trifunctional protein complex associated with the inner mitochondrial membrane have been described: long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency (43) and a deficiency of all 3 enzymatic components (mitochondrial trifunctional protein deficiency) (62).
The long-chain fatty acid oxidation disorders are best detected by analysis of urinary or, preferably, dried blood spots or best plasma acylcarnitine profiles utilizing tandem mass spectrometry. Distinguishing elevated metabolic markers (acylcarnitines) for very long-chain acyl-CoA dehydrogenase deficiency are C14 and C14:1 species, and for trifunctional protein deficiencies, increased hydroxy forms of C16:0H and C18:1 species. Urinary analysis may show elevated dicarboxylic acids.