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Hepatic biosynthesis of ketone bodies involves the condensation of acetyl-CoA and acetoacetyl-CoA to hydroxymethylglutaryl-CoA (HMG-CoA) by HMG-CoA synthetase, followed by hydrolysis of HMG-CoA to acetyl-CoA and acetoacetic acid (AcAc) by HMG-CoA lyase. AcAc is reduced to 3-hydroxybutyric acid (3HB), and extrahepatic tissues use the two ketone bodies as energy sources during fasting (ketolysis). Recessively inherited defects of HMG-CoA synthetase and HMG-CoA lyase cause hypoketotic hypoglycemia during fasting, and defects of ketolysis cause episodic ketoacidosis.

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Deficiency of HMG-CoA synthetase causes hypoketotic hypoglycemia, often after prolonged diarrhea and vomiting. Serum free fatty acids are elevated, urine organic acid analysis shows severe dicarboxylic aciduria with unsaturated and 3-hydroxy derivatives, and serum acylcarnitines are normal. When the deficiency is suspected, mutation analysis can confirm the diagnosis. Treatment involves avoiding fasting and administering glucose during episodes of hypoglycemia.1

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Deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase can present in the newborn with severe hypoketotic hypoglycemia, metabolic acidosis, and hyperammonemia, or with episodes of hypoglycemia, hepatomegaly, and encephalopathy following intercurrent infection. The latter form of the disease is often mistaken for Reye syndrome. If not promptly treated, cerebral atrophy, neurological effects, and mental retardation may follow.

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Diagnosis

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Urine organic acid analysis shows increased 3-hydroxy-3-methylglutaric, 3-methylglutaconic, and 3-methylglutaric acids, and MS-MS shows increased 3-hydroxy-3-methylglutarylcarnitine. Liver function tests may be abnormal at times of acute illness. The enzyme defect is apparent in many tissues, including fibroblasts and peripheral leukocytes, and fetal disease can be diagnosed by enzyme assay on cultured amniocytes or chorionic villus samples, or by demonstrating the characteristic organic acids in amniotic fluid.

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Treatment

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Acute management requires intravenous fluids, electrolytes, and glucose, and long-term management is directed to avoiding fasting and the resulting hypoglycemia. The possible life-threatening consequences of fasting make it imperative that parents bring the child to the hospital as soon as possible when oral intake is compromised.2

1. Zschocke J, Penzien JM, Bielen M, et al. The diagnosis of mitochondrial HMG-synthase deficiency. J Pediatr. 2002;140:778.  [PubMed: 12072887]
2. Bakker HD, Wanders RJA, Schutgens RBH, et al. 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency: absence of clinical symptoms due to a self-imposed dietary fat and protein restriction. J Inherited Metab Dis. 1993;16:1061.  [PubMed: 8127066]

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