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  1. Mitochondrial β-oxidation plays a major role in energy production during periods of fasting and physiologic stress. The pathway includes >20 individual steps. Fatty acids must first be released from stored triglycerides by the action of insulin-regulated lipases. They are then carried by albumin and specialized fatty acid carrier proteins through the blood stream to cells where they utilize specific transporters for cellular import. Medium- and short-chain fatty acids are able to enter mitochondria directly (probably as free fatty acids), while long-chain fatty acids are first activated to their acyl-CoA esters, transesterified to acylcarnitines, translocated across the mitochondrial membrane, then released again as acyl-CoA esters. In the mitochondrial matrix, a series of four enzymatic reactions known as the β-oxidation cycle occurs. Each cycle generates an acetyl-CoA molecule, an acyl-CoA ester that is two carbons shorter, and reducing equivalents that are transferred to electron transfer flavoprotein [ETF] and NAD+. Acetyl-CoA can enter the tricarboxylic acid cycle in most tissues. In liver, it can be converted to ketone bodies through an additional pathway. Each step in the cycle is catalyzed by multiple enzymes with overlapping chain-length specificities. There are also enzymes specifically required for the oxidation of unsaturated fatty acids.

  2. Inherited defects of many of the proteins directly involved in this process have been identified in humans. The defects of plasma membrane carnitine transport (MIM 212140); carnitine palmitoyltransferase (CPT) I (MIM 255120) and CPT II (MIM 255110); carnitine/acylcarnitine translocase (MIM 212138), also called the carnitine cycle, are reviewed in Chapter 101a. Disorders of enzymes in the mitochondrial matrix include deficiencies of very-long-chain, medium-chain, and short-chain acyl-CoA dehydrogenases [VLCAD; ACADVL (MIM 201475; EC, ACAD9 (MIM 611103; EC, MCAD; ACADM (MIM 201450; EC, and SCAD; ACADS (MIM 201470), respectively] and of 2,4-dienoyl-CoA reductase [DECR1 (MIM 222745; EC]. Isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD (MIM 609019)] is due to mutations in the HADHA gene (MIM 601609; EC while deficiency of all activities in the mitochondrial trifunctional protein (MIM 609015) can be caused by mutations in the HADHA or HADHB genes. The genetic and clinical nomenclature for SCHAD is somewhat confusing. The gene defective in patients with hyperinsulinism is referred to as HADHSC in the literature but is designated as HADH in GenBank. Patients are often designated as having SCHAD or M/SCHAD deficiency (MIM 231530). The final cleavage step is catalyzed by three distinct thiolase enzymes: long-chain 3-ketothiolase within TFP for long-chain substrates, medium-chain 3-ketoacyl-CoA thiolase (MKAT; MIM 604770; ACAA2; EC for medium-chain substrates and by short-chain 3-ketoacyl-CoA thiolase (SKAT; MIM 607809; ACAT1; EC for short-chain substrates. The product of this reaction is one molecule of acetyl-CoA and a two carbon-shortened fatty acyl-CoA. Multiple acyl-CoA dehydrogenase deficiency caused by a deficiency of their physiologic electron acceptor ETF or its dehydrogenase (ETF-CoQ dehydrogenase) is dealt with in Chapter 103.

  3. Fatty acid oxidation defects present with a wide variety of symptoms from catastrophic neonatal hypoglycemia and hyperammonemia to ...

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