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Abstract

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  1. The ketone bodies acetoacetate (AcAc) and R-3-hydroxybutyrate (3HB) are important vectors of energy transport from hepatocyte mitochondria to extrahepatic tissues during fasting and other lipolytic stress. AcAc is the product of ketogenesis and the substrate for ketolysis. 3HB is derived from AcAc. A third compound, acetone, arises from decarboxylation of AcAc and accounts for the distinct odor of ketotic individuals.

  2. Ketogenesis is fueled by fatty acids or ketogenic amino acids, principally leucine. Two mitochondrial enzymes mediate ketogenesis from fatty acids: mitochondrial HMG-CoA synthase (mHS) and HMG-CoA lyase (HL). Circulating levels of ketone bodies fluctuate greatly with age, nutrition, lipolytic stress, and other factors.

  3. Ketolysis occurs in mitochondria of extrahepatic tissues, particularly heart, kidney, and brain, via reversible reactions catalyzed by succinyl-CoA: 3-ketoacid CoA transferase (SCOT) and mitochondrial AcAc-CoA thiolase (T2). Ketolytic rate is determined by the circulating concentration of ketone bodies. The ketolytic capacity of tissues is proportional to their level of SCOT activity.

  4. Inborn errors of ketogenesis (mHS or HL deficiencies) cause episodes of hypoketotic hypoglycemia, often with coma. Ketolytic (T2 or SCOT) deficiencies cause episodes of ketoacidosis. All four disorders are autosomal recessive. Infancy is the period of highest risk for decompensation. Death or neurologic complications can occur, but with early diagnosis and treatment, many patients are clinically normal. The mainstay of treatment in these disorders is suppression of ketogenesis. Enzyme and molecular diagnosis is possible for each of these conditions.

  5. mHS undergoes intricate transcriptional and posttranscriptional regulation to control the rate of ketogenesis. In mHS deficiency, the urinary organic acid pattern is not diagnostic. Diagnosis depends upon enzyme assay in liver and/or molecular studies.

  6. HL is located in mitochondria and peroxisomes of all tissues studied to date. HL deficiency is characterized by high levels of 3-hydroxy-3-methylglutaric acid (HMG) and related leucine metabolites in urine. Enzymatic confirmation is recommended, since rare patients excrete these compounds but have normal HL activity. Mental retardation, epilepsy, and white matter changes may occur following hypoglycemic episodes.

  7. SCOT is extrahepatic in distribution. The ketolytic capacity of tissues is proportional to their levels of SCOT activity. In SCOT deficiency, ketoacidosis develops rapidly on fasting and ketonuria is often present in the fed state. Urine organic acids show only a nonspecific increase of AcAc and 3HB.

  8. T2 functions in both ketolysis and ketogenesis. T2 deficiency presents as infantile ketoacidosis. Coma and basal ganglia abnormalities may occur. A diagnostic metabolite profile including 2-methyl-3HB, 2-methylAcAc and tiglylglycine is present in most patients.

  9. 3HB dehydrogenase (3HBD) catalyzes the reversible reduction of AcAc to 3HB, functioning in both ketogenesis and ketolysis. 3HBD deficiency has not been described.

  10. A distinct cytoplasmic AcAc-CoA thiolase (CT) functions in lipogenesis and cholesterol synthesis. It was reportedly deficient in two girls with progressive mental retardation. Enzyme and molecular diagnosis is possible.

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Introduction

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The presence of ketone bodies has been used for 140 years as a sign of uncontrolled diabetes and as a tool for assessing the severity of dehydration. ...

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