MCAD deficiency is the most common inborn error of β-oxidation. Hypoketotic hypoglycemia is a common manifestation, as is Reye syndrome–like illness with hypoglycemia and elevated liver enzymes. Fatty infiltration of the liver also occurs. True hepatic failure is rare. Episodes may be recurrent in the patient or the family. Sudden infant death syndrome is reported in infants with MCAD deficiency, perhaps related to hypoglycemia. Treatment requires avoidance of fasting and provision of calories with fever or other metabolic stress. Medium-chain triglycerides must be avoided.
VLCAD deficiency and LCHAD (trifunctional protein) deficiency result in significant myopathy and cardiomyopathy. LCHAD deficiency is accompanied by a retinopathy in later childhood. In all of the disorders of β-oxidation, carnitine depletion can occur through excessive urinary excretion of carnitine esters of the incompletely oxidized fatty acids. Measurement of plasma carnitine is helpful in monitoring for this deficiency, which results in weakness and muscle pain, along with myoglobinuria in some people.
Hydroxymethylglutaryl-CoA lyase deficiency, although not a disorder of β-oxidation, interferes profoundly with hepatic adaptation to fasting by impairing ketogenesis (see Fig. 55-1). The clinical manifestations are those of MCAD deficiency, except that carnitine depletion is less prominent.
The diagnosis of disorders involving a deficiency of β-oxidation is suggested by the clinical picture and by hypoketotic hypoglycemia. The diagnosis is confirmed by analysis of urinary organic acid and acylglycine profiles, along with plasma acylcarnitine and free fatty acid profiles. Enzyme measurements and DNA testing complete the confirmatory testing. The profile of acylcarnitines in cultured skin fibroblasts may be helpful if other testing is not conclusive. In MCAD deficiency, a single mutation 985 A→G accounts for a significant percentage of cases. Treatment includes avoidance of fasting, as well as fluid and calorie supplementation during periods of metabolic stress, such as fever. In MCAD deficiency, medium-chain triglycerides must be avoided. In the long-chain fatty acid metabolic disorders, provision of medium-chain fatty acids improves muscle energy metabolism.
Glutaric aciduria type II (multiple acyl-CoA dehydrogenase deficiency) is a clinical disease produced by a defect in the transfer of electrons from flavine adenine nucleotides to the electron transport chain (electron transfer flavoprotein [ETF], or ETF dehydrogenase); this defect results in a deficiency of multiple fatty acyl CoA dehydrogenases (see Fig. 55-1).
medium-chain fatty acyl-CoA dehydrogenase, short-chain fatty acyl-CoA dehydrogenase, β-ketothiolase, (6) β-hydroxy-β-methylglutaryl-CoA synthase, (7) β-hydroxy-β-methylglutaryl-CoA lyase, (8) β-hydroxybutyrate dehydrogenase. CoA, Coenzyme A.