Long-chain fatty acid oxidation defects

Marina A Morath MD (Dr. Morath of University Children's Hospital in Heidelberg, Germany, has no relevant financial relationships to disclose.)
Georg F Hoffmann MD (Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.)
Tyler Reimschisel MD, editor. (Dr. Reimschisel of Vanderbilt University has received contracted research grants from Shire and Vtesse.)
Originally released November 7, 2004; last updated May 17, 2017; expires May 17, 2020

This article includes discussion of long-chain fatty acid oxidation defects, LCHAD deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency, mitochondrial trifunctional protein deficiency, trifunctional protein deficiency, MTP deficiency, very long chain acyl-CoA dehydrogenase deficiency, and VLCAD deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

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 in clinical presentation, etiology, pathophysiology, diagnostic work-up, treatment, and pregnancy are presented in this article. The authors describe novel pathophysiological aspects, a potential treatment strategy for very long-chain acyl-CoA dehydrogenase deficiency, and report surprising results concerning the use of medium-chain fatty acids for the treatment of very long-chain acyl-CoA dehydrogenase deficiency.

Key points

 

• Mitochondrial fatty acid oxidation is the central metabolic pathway for ATP production, especially in liver, heart, and skeletal muscle.

 

• Fatty acid-oxidation disorders can present with acute, life-threatening episodes of hypoketotic, hypoglycemic coma induced by fasting.

 

• Milder variants become manifest in adolescence or early adulthood as chronic muscle weakness, pain, recurrent rhabdomyolysis, or acute or chronic cardiomyopathies.

 

• 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 deficiencies, which includes long-chain L-3-hydroxyacyl-CoA dehydrogenase, 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 (Aoyama et al 1993; Bertrand et al 1993). All of the patients initially described with long-chain acyl-CoA dehydrogenase deficiency (Hale et al 1985) appear in retrospect to have had defects in very long-chain acyl-CoA dehydrogenase (Vianey-Saban et al 1998). 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 (Glasgow et al 1983) and a deficiency of all 3 enzymatic components (mitochondrial trifunctional protein deficiency) (Jackson et al 1992).

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.

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