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Hepatic biosynthesis of ketone bodies involves the condensation of acetyl-coenzyme A (CoA) and acetoacetyl-CoA to hydroxymethylglutaryl-CoA (HMG-CoA) by HMG-CoA synthase, followed by hydrolysis of HMG-CoA to acetyl-CoA and acetoacetic acid (AcAc) by HMG-CoA lyase as the final step in leucine degradation. AcAc is reduced to 3-hydroxybutyric acid (3HB), and extrahepatic tissues use the 2 ketone bodies as energy sources during fasting (ketolysis). Recessively inherited defects of HMG-CoA synthase (HMGCS2) and HMG-CoA lyase (HMGCL) cause hypoketotic hypoglycemia during fasting, and defects of ketolysis cause persistent or episodic ketoacidosis.


Deficiency of HMG-CoA synthase (MIM no. 605911) causes hypoketotic hypoglycemia, typically during intercurrent illnesses, along with encephalopathy and hepatomegaly. Serum free fatty acids are very elevated, urine and serum ketones are inappropriately low or absent, transaminases 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, along with bedtime carbohydrates such as uncooked cornstarch.


Deficiency of 3-hydroxy-3-methylglutaryl-CoA lyase (MIM no. 246450) can present in the newborn period with severe hypoketotic hypoglycemia, elevated transaminases, metabolic acidosis, and hyperammonemia, or later 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, neurologic effects, and developmental disabilities may follow. Adolescent-and adult-onset patients have been described and may also have a leukoencephalopathy. It is a common organic aciduria in the Saudi population but is otherwise rare.


Urine organic acid analysis shows increased 3-hydroxy-3-methylglutaric, 3-methylglutaconic, and 3-methylglutaric acids, and tandem mass spectrometry (MS/MS) shows increased 3-hydroxy-3-methylglutarylcarnitine. The disorder can also be identified by MS/MS on newborn screening blood spots with elevations typically reported as “C5-hydroxyacylcarntine,” a designation shared by several other isobaric metabolites. Due to the possibility of a catastrophic presentation, rapid additional diagnostic testing by urine organic acids is necessary. Liver function tests may be abnormal at times of acute illness. The enzyme defect is apparent in many tissues, including fibroblasts and peripheral leukocytes, but is usually not necessary to measure due to the availability of DNA testing. Fetal disease can be diagnosed by enzyme assay on cultured amniocytes or chorionic villus samples, by demonstrating the characteristic organic acids in amniotic fluid, or by DNA analysis if a familial mutation is known.


Acute management requires intravenous fluids, electrolytes, and glucose. Long-term management is directed at avoiding fasting and the resulting hypoglycemia, and bedtime carbohydrates may be warranted. 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.


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