An 8-month-old boy is evaluated for developmental delay, failure to thrive, and episodic seizures. Physical examination shows ophthalmoplegia and hypotonia. Laboratory studies reveal an elevated serum lactate level. Further histochemical studies show severely reduced pyruvate dehydrogenase enzyme activity in both freshly isolated peripheral blood lymphocytes and cultured fibroblasts. Increasing which of the following substances in his diet is most likely to help this patient generate energy without further elevating lactate levels?

Question

An 8-month-old boy is evaluated for developmental delay, failure to thrive, and episodic seizures.  Physical examination shows ophthalmoplegia and hypotonia.  Laboratory studies reveal an elevated serum lactate level.  Further histochemical studies show severely reduced pyruvate dehydrogenase enzyme activity in both freshly isolated peripheral blood lymphocytes and cultured fibroblasts.  Increasing which of the following substances in his diet is most likely to help this patient generate energy without further elevating lactate levels?

Quizplus · Accepted Answer

This patient has pyruvate dehydrogenase deficiency, an inherited inborn error of metabolism often presenting in infancy with lactic acidosis and neurologic defects. The disease results from deficient activity of the pyruvate dehydrogenase complex, a multi-enzyme complex generating acetyl-CoA from pyruvate, thereby linking glycolysis and the TCA cycle. Dietary carbohydrates are broken down into pyruvate via glycolysis; in patients with pyruvate dehydrogenase deficiency, the lack of enzymatic activity leads to a buildup of pyruvate, which is shunted to lactate via lactate dehydrogenase, generating a potentially life-threatening lactic acidosis. Disease management involves the implementation of a ketogenic diet: a high-fat, low-carbohydrate diet with moderate levels of protein. This diet forces the production of ketone bodies from fat and amino acid catabolism to fuel the body in the place of glucose. The near-absence of glucose in the diet decreases the amount of pyruvate generated, thereby decreasing lactate levels. Amino acid catabolism results in formation of intermediates that are referred to as glucogenic, ketogenic, or both. Glucogenic amino acid metabolism produces pyruvate or TCA cycle intermediates, which can be converted to glucose via gluconeogenesis. Ketogenic amino acid metabolism generates the ketone body precursor acetyl-CoA. Lysine and leucine are exclusively ketogenic amino acids; they cannot be metabolized to pyruvate and consumption will not lead to increased production of lactic acid. (Choices A and F) The non-essential glucogenic amino acids alanine and serine can be converted to pyruvate through a transamination reaction catalyzed by alanine transaminase and a deamination reaction catalyzed by serine dehydratase, respectively. (Choice B) Asparagine is catabolized to aspartate and subsequently transaminated to produce glutamate and oxaloacetate, an intermediate of the TCA cycle. Oxaloacetate by itself cannot be used to produce energy; it must first undergo condensation with acetyl-CoA to form citrate. (Choice C) The monosaccharide galactose is metabolized in the glycolytic pathway; dietary intake will result in elevated levels of lactate in patients with pyruvate dehydrogenase deficiency. (Choice D) Glycerol is metabolized to glyceraldehyde 3-phosphate, a glycolysis intermediate. It can be used as a substrate to form pyruvate and, subsequently, lactate. Educational objective: Pyruvate dehydrogenase complex deficiency is an inherited inborn error of metabolism causing lactic acidosis and neurologic defects. Patients are unable to convert pyruvate to acetyl-CoA, resulting in a shunting of pyruvate to lactic acid. In these patients, metabolism of exclusively ketogenic amino acids (eg, lysine, leucine) can provide energy in the form of acetyl-CoA without increasing lactate production. __________ References: Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. (http://www.ncbi.nlm.nih.gov/pubmed/9409363)

An 8-Month-Old Boy Is Evaluated for Developmental Delay, Failure to Thrive