Mitochondrial β-oxidation plays a major role in energy production, especially during periods of fasting. The pathway is complex and includes as many as 20 individual steps: cellular uptake of fatty acids; their activation to acyl-CoA esters; transesterification to acylcarnitines; translocation across the mitochondrial membrane; re-esterification to acyl-CoA esters; and the intramitochondrial β-oxidation spiral, generating electrons that are transferred to electron transfer flavoprotein, and acetyl-CoA, which is converted to ketone bodies in the liver. Within the spiral, each step is catalyzed by enzymes with overlapping chain-length specificities. There is also a series of enzymes specifically required for the oxidation of unsaturated fatty acids.
Inherited defects of 11 proteins directly involved in this process have been identified in humans. These include defects of plasma membrane carnitine transport (MIM 212140); carnitine palmitoyltransferase (CPT) I (MIM 255120) and CPT II (MIM 255110); carnitine/acylcarnitine translocase (MIM 212138); very long-chain, medium-chain, and short-chain acyl-CoA dehydrogenases [VLCAD (MIM 201475), MCAD (MIM 201450), and SCAD (MIM 201470), respectively]; 2,4-dienoyl-CoA reductase (MIM 222745); and long- and short-chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD (MIM 143450), SCHAD (MIM 601609)]; and mitochondrial trifunctional protein (MIM 600890).
MCAD deficiency is the most common defect in the pathway and highlights many of the features that characterize patients with disorders of β-oxidation. It has been described in patients worldwide, most of whom are of northwestern European origin. MCAD deficiency is a disease primarily of hepatic fatty acid oxidation. The most frequent presentation is episodic hypoketotic hypoglycemia provoked by fasting and beginning in the first 2 years of life. Accumulation of fatty acid intermediates results in plasma and urinary metabolites, some of which are general indicators of impaired function of the β-oxidation pathway (e.g., dicarboxylic acids), while others are unique and characteristic of MCAD deficiency (e.g., octanoylcarnitine). Although the first episode may be fatal, resembling sudden infant death syndrome (SIDS), patients with MCAD deficiency are normal between episodes. Therapy includes avoidance of fasting and treatment of acute episodes with IV glucose. Diagnosis can be made by analysis of blood acylcarnitines or, in many cases, by molecular analysis because a single MCAD missense allele accounts for nearly 90 percent of the mutant MCAD genes causing this disorder.
Other disorders of the β-oxidation pathway are characterized by skeletal and/or cardiac muscle weakness. These include deficiencies of VLCAD, LCHAD, trifunctional protein, CPT II, SCAD, and carnitine/acylcarnitine translocase deficiencies, as well as a carnitine transport defect. In some of these disorders unique metabolites can be identified in blood or urine; the exceptions are CPT I deficiency and the carnitine transport defect, in which no abnormal metabolites are excreted. In addition, hypoketotic hypoglycemia with increased blood carnitine levels occurs in CPT I deficiency.
VLCAD deficiency has two distinct clinical phenotypes: hypertrophic cardiomyopathy (VLCAD-C) and a milder form manifesting recurrent hypoglycemia (VLCAD-H). They can be distinguished biochemically by different acylcarnitine profiles following incubation of fibroblasts or amniocytes with 16-2H3-palmitate.
Carnitine deficiency is a primary manifestation of the carnitine transport defect; patients with this defect respond dramatically to carnitine therapy. Carnitine deficiency is a secondary feature of all other β-oxidation disorders, except CPT I deficiency which is characterized by increased plasma carnitine levels.
Syndromes of severe maternal illness (HELLP syndrome and AFLP) have been associated with pregnancies carrying a fetus affected by LCHAD, trifunctional protein, and CPT I deficiencies. These may require emergency delivery in the last trimester. The 1528G > C mutation observed in LCHAD deficiency can often identify a mother at risk for that disease.