A 32-year-old woman presents to the clinic with complaints of recurrent episodes of abdominal pain, nausea, and vomiting over the past year. These episodes are often triggered by prolonged fasting or intercurrent illness. She reports muscle weakness and occasional palpitations during these episodes. Her medical history is unremarkable, and she takes no medications. Her vital signs are within the normal range. Physical examination is unremarkable. Laboratory studies performed during an episode reveal blood glucose of 45 mg/dL (70–100 mg/dL), low ketone levels, and elevated serum free fatty acids. A fasting study confirms hypoketotic hypoglycemia.
A deficiency in which of the following enzymes is most likely responsible for this patient’s condition?
D) Medium-chain acyl-CoA dehydrogenase
This patient’s presentation of recurrent hypoglycemia, low ketone levels, and elevated free fatty acids during fasting strongly suggests a fatty acid oxidation disorder, specifically medium-chain acyl-CoA dehydrogenase deficiency. MCAD deficiency impairs the beta-oxidation of medium-chain fatty acids in mitochondria, leading to reduced ketone production and energy failure during fasting, resulting in hypoketotic hypoglycemia. The accumulation of fatty acids causes elevated serum free fatty acids, and symptoms like abdominal pain, nausea, vomiting, and muscle weakness are common during metabolic crises.
Answer choice A: Fructose-1,6-bisphosphatase, is incorrect. Fructose-1,6-bisphosphatase deficiency impairs gluconeogenesis, leading to hypoglycemia, lactic acidosis, and ketosis during fasting. The presence of normal or elevated ketones distinguishes it from MCAD deficiency, where hypoketosis is a key feature.
Answer choice B: Glucose-6-phosphatase, is incorrect. Glucose-6-phosphatase deficiency (von Gierke disease) causes glycogen storage disease type I, characterized by hypoglycemia, lactic acidosis, hyperlipidemia, and hepatomegaly. Ketone levels are typically elevated during fasting due to increased fatty acid oxidation, unlike the hypoketosis seen in this patient.
Answer choice D: Glycogen phosphorylase, is incorrect. Glycogen phosphorylase deficiency (McArdle disease) causes glycogen storage disease type V, presenting with exercise-induced muscle cramps and rhabdomyolysis. Hypoglycemia is not a feature, as glycogenolysis is impaired in muscle, not liver, and ketone production is typically normal.
Answer choice E: Pyruvate carboxylase, is incorrect. Pyruvate carboxylase deficiency impairs gluconeogenesis by reducing the conversion of pyruvate to oxaloacetate, leading to lactic acidosis, hypoglycemia, and developmental delay. Ketone levels are typically normal or elevated, and free fatty acid accumulation is not a hallmark feature.
Key Learning Point
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency disrupts fatty acid beta-oxidation, leading to hypoketotic hypoglycemia, elevated free fatty acids, and metabolic crises triggered by fasting or illness. Diagnosis is confirmed by acylcarnitine profile or genetic testing, and management includes avoiding prolonged fasting and providing glucose during illness.
