An Inherited Disorder of Isoleucine Catabolism Causing Accumulation of α-Methylacetoacetate and α-Methyl-β-hydroxybutyrate, and Intermittent Metabolic Acidosis
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Keywords:
Catabolism
Isoleucine
Ketosis
Lethargy
Thiolase
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency and mitochondrial acetoacetyl-CoA thiolase (beta-ketothiolase or T2) deficiency are classified as autosomal recessive disorders of ketone body utilization characterized by intermittent ketoacidosis. Patients with mutations retaining no residual activity on analysis of expression of mutant cDNA are designated as severe genotype, and patients with at least one mutation retaining significant residual activity, as mild genotype. Permanent ketosis is a pathognomonic characteristic of SCOT-deficient patients with severe genotype. Patients with mild genotype, however, may not have permanent ketosis, although they may develop severe ketoacidotic episodes similar to patients with severe genotype. Permanent ketosis has not been reported in T2 deficiency. In T2-deficient patients with severe genotype, biochemical diagnosis is done on urinary organic acid analysis and blood acylcarnitine analysis to observe characteristic findings during both ketoacidosis and non-episodic conditions. In Japan, however, it was found that T2-deficient patients with mild genotype are common, and typical profiles were not identified on these analyses. Based on a clinical study of ketone body utilization disorders both in Japan and worldwide, we have developed guidelines for disease diagnosis and treatment. These diseases are treatable by avoiding fasting and by providing early infusion of glucose, which enable the patients to grow without sequelae.
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Isoleucine
Decarboxylation
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Ketoacidosis
Catabolism
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From the description of 2 unrelated patients with succinyl-CoA transferase (3-OAT) deficiency and 1 patient with acetoacetyl-CoA thiolase (AAT) deficiency, we have attempted to draw the clinical and metabolic consequences of such defects. The association of recurrent attacks of severe ketoacidosis with blood glucose levels generally high or normal, low lactacidemia and low ammonemia is the most common presentation of these disorders. In 3-OAT deficiency, a potentially fatal disorder, there is a permanent ketosis with the only excretion of 3-hydroxybutyrate, acetoacetate and 3-hydroxyisovalerate. AAT patients usually excrete, in addition to the usual ketone bodies, 2-methyl-3-hydroxybutyrate and tiglylglycine; 2-methyl-acetoacetate may also be present. Both conditions can be identified by enzymatic analysis in cultured fibroblast. These disorders can mimic diabetic ketoacidosis or salicylism and can easily be missed. The knowledge of these ketolytic defects must severely question the complacent diagnosis of 'fasting ketoacidosis' or 'idiopathic ketotic hypoglycemia', mainly when severe metabolic acidosis is present.
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Metabolic disorder
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Sunflower ( Helianthus annus L) cotyledons have two thiolase activities that have been identified previously. Thiolase II (acetoacetyl CoA thiolase) has specificity for the four‐carbon acetoacetyl CoA, resulting in the production of two Acetyl CoA molecules. Thiolase I (oxoacyl CoA thiolase) is active towards short, medium and long chain acyl CoAs. Crystal structures of thiolase from other organisms have identified conserved cysteines and a histidine present in the active site of the enzyme indicating that these residues probably play a key role in the reaction mechanism and other residues have been implicated in the stabilization of the enolate intermediate in the synthetic reaction. Site‐directed mutagenesis of the various amino acid residues was done and the effect of these mutations on the catalytic activity was measured. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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The etiology of 3-ketothiolase deficiency has been attributed to a defect of mitochondrial acetoacetyl-CoA thiolase because the acetoacetyl-CoA thiolase activity in related materials is not activated by K+, a property characteristic for this enzyme. We studied the enzyme protein and the biosynthesis of mitochondrial acetoacetyl-CoA thiolase, using cultured skin fibroblasts from a 5-yr-old boy with 3-ketothiolase deficiency. The following results were obtained. (a) Activation of acetoacetyl-CoA thiolase activity by K+ was nil; (b) The enzyme activity was not affected by treatment with the antibody against mitochondrial acetoacetyl-CoA thiolase; (c) A signal for mitochondrial acetoacetyl-CoA thiolase protein was not detected in the immunoblot analysis; and (d) Pulse-chase experiments of skin fibroblasts, using [35S]methionine, revealed no incorporation of radioactivity into this enzyme. Therefore, fibroblasts from this patient lacked mitochondrial acetoacetyl-CoA thiolase protein due to a defect in its biosynthesis.
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Anion gap metabolic acidosis is a common disorder seen in the emergency department. The differential can include toxicological, renal, endocrine, infectious, and cardiogenic disorders. Ketosis, however, is one of the rarer causes of metabolic acidosis seen by the emergency physician in developed nations.A 53-year-old female presented after starting a low-carbohydrate ketogenic diet for weight loss. She reported xerostomia, nausea with abdominal pain and a 17-pound weight loss over the previous 22 days. Labs revealed an anion-gap metabolic acidosis with ketosis. She was treated with 5% dextrose in normal saline and a sliding scale insulin coverage. Her anion gap corrected during her hospital course and was discharged on hospital day three.The ketogenic diet typically consists of a high-fat, adequate protein and low carbohydrate diet that has previously been thought to be relatively safe for weight loss. However, when carbohydrates are completely removed from the diet an overproduction of ketones bodies results in ketoacidosis. Treatment should be aimed at halting the ketogenic process and patient education.Although rarely included in the differential for metabolic acidosis, diet-induced ketosis should be included by the emergency physician when faced with a patient who recently changed their eating patterns.
Diabetic ketoacidosis
Ketoacidosis
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Sunflower ( Helianthus annus L) cotyledons have two thiolase activities that have been identified previously. Thiolase II (acetoacetyl CoA thiolase) has specificity for the four‐carbon acetoacetyl CoA, resulting in the production of two Acetyl CoA molecules. Thiolase I (oxoacyl CoA thiolase) is active towards short, medium and long chain acyl CoAs. Crystal structures of thiolase from other organisms have identified conserved cysteines and a histidine present in the active site of the enzyme indicating that these residues probably play a key role in the reaction mechanism and other residues have been implicated in the stabilization of the enolate intermediate in the synthetic reaction. Site‐directed mutagenesis of the various amino acid residues was done and the effect of these mutations on the catalytic activity was measured.
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Thiolase
Peroxisomal disorder
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Isoleucine
Organic acid
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