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At a glance

Acylated coenzyme A (Acyl-CoA) dehydrogenases are a large family of mitochondrial flavoproteins that catalyze α,β-dehydrogenation of Acyl-CoA esters in the mitochondrial matrix. Fatty acids are an essential energy substrate for a number of tissues, including heart, brain, skeletal muscles, pancreas, kidney, liver, brown adipose tissue, and placenta. The different disorders are inherited as an autosomal recessive trait. Acyl-CoA dehydrogenase deficiency syndromes in general are a potentially very serious group of diseases. In one case series with a total of 154 patients, only one-third was still alive at the time of publication, one-third died within the first week and two-thirds within the first year of life. In more than 40% of affected families, there was at least one death in the sibship. Hepatic symptoms (steatosis, hypoketotic hypoglycemia, hepatomegaly, ☞Reye Syndrome-like symptoms) were observed in 73% of patients, while true hepatic failure occurred in 10% of patients. Cardiac anomalies were found in 51% of patients (67% of them with [mainly hypokinetic and hypertrophic] cardiomyopathy and 47% with arrhythmias) causing collapse, near-missed, or sudden unexpected death. Renal symptoms (tubulopathy) and transient renal failure were present in 27% of patients. It is important to recognize that although hypoglycemia is often present during metabolic decompensations, it is a late sign and neither suitable to monitor the severity of the illness nor to direct treatment. In many countries, screening for Acyl-CoA dehydrogenase deficiency syndromes is now part of the regular newborn workup and identified patients have generally remained healthy due to proactive measures when prolonged fasting is expected or intercurrent illness occurs. However, it is possible that serious symptoms already occur in the first days of life, ie, before the screening results are known.

Classification

The family of Acyl-CoA dehydrogenase deficiency syndromes contains several members. The most frequent ones are the following six:

  • Short-Chain Acyl-CoA Dehydrogenase Deficiency (SCADD; SCADH Deficiency; SCAD Deficiency; ACADS Deficiency; Lipid-Storage Myopathy Secondary to Short-Chain Acyl-CoA Dehydrogenase Deficiency)

  • Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD; ACAD1; MCADH Deficiency; ACADM Deficiency; MCAD Deficiency; Carnitine Deficiency Secondary to MCADD)

  • Long-Chain Acyl-CoA Dehydrogenase Deficiency (LCADD)

  • Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD)

  • Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD; VCLAD Deficiency)

  • Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) (Glutaric Aciduria II; Glutaric Acidemia Type II; Electron Transfer Flavoprotein (ETF) Deficiency; ETFA Deficiency; ETFB Deficiency, ETFDH Deficiency; ETF-Ubiquinone Oxidoreductase Deficiency (ETF:QO) Deficiency)

Pathophysiology

The myocardium requires fatty acids for energy supply. In contrast, the liver relies on nutrients delivered from intestinal absorption and is responsible for the short- and medium-term storage and distribution of energy gained from glycogenolysis and gluconeogenesis. During longer periods of fasting or increased energy requirements, the liver also metabolizes acetyl-CoA to ketone bodies, which are then used in the central nervous system by switching promptly from glucose to ketone body-based energy production to preserve glucose. During prolonged exercise, the skeletal muscles utilize longer-chain fatty acid oxygenation to generate energy. All Acyl-CoA dehydrogenases catalyze ...

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