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Mitochondrial disease impairing synthetic pathways and leading to hypoglycemia and severe lactic acidosis. Clinically characterized by seizures, neuromuscular incoordination, abnormal eye movements, and poor response to visual stimuli. Other clinical features include lethargy, vomiting, and poor feeding. Apnea, dyspnea and/or respiratory depression complete the presentation.

Approximately 1:250,000 newborns. In North America, a high incidence has been found in the linguistic group of Algonquian-speaking Native Americans (Manitoba, Saskatchewan, and Nova Scotia, Canada).

Autosomal recessive; the gene has been mapped to 11q13.4-q13.5.

Pyruvate carboxylase (PC) is a biotin-dependent mitochondrial enzyme that converts pyruvate and CO2 to oxaloacetate, one of two essential substrates (beside acetyl-CoA) in the production of citrate. As a result of this enzyme defect, the citric acid cycle cannot start because its first substrate (oxaloacetate) is missing or available only in low concentrations. The accumulation of pyruvate, the metabolite proximal to the enzyme defect, results in activation of alternate pyruvate pathways with increased production of lactic acid and acetyl-CoA, which then is converted into ketones because the tricarboxylic acid cycle pathway is closed. Glucose production is affected because the now lacking oxaloacetate is also involved in gluconeogenesis, which puts patients at risk for hypoglycemia during fasting periods. Because the tricarboxylic acid cycle is not available, energy delivery is entirely dependent on glycolysis. Compared to the tricarboxylic acid cycle, however, glycolysis is highly inefficient and results in the depletion of glucose. Oxaloacetate is also involved in the generation of aspartate, which is required for the synthesis of argininosuccinate, an intermediate metabolite in the urea cycle. This results in decreased urea production and hyperammonemia. Furthermore, oxaloacetate also participates in the malate-aspartate shuttle, which represents the principal mechanism for the transport of reducing equivalents from the cytoplasm into the mitochondria. The reduction of oxaloacetate to malate by cytoplasmic malate dehydrogenase also results in oxidation of the reduced form of nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotidase (NAD+). Malate (carrying the electrons) then enters the mitochondria, where mitochondrial malate dehydrogenase reverses the previous action, resulting in conversion of malate to mitochondrial oxaloacetate. During oxidative phosphorylation in the mitochondria, these electrons of NADH get coupled to the ATP production. PC is also involved in lipogenesis and the formation of some nonessential amino acids (aspartate, glutamate).

To be considered in any infant presenting with severe lactic acidosis with increased blood lactate/pyruvate ratio, ketosis, hyperammonemia, and neurologic anomalies. Lactic acidosis improves following ingestion of carbohydrate. The measurement of amino acids and organic acids in the urine has been used for screening. The deficiency in PC can be confirmed by measuring the enzyme activity in fibroblasts or other tissues.

The clinical presentation is highly variable; however, three distinct clinical presentations have been described.

Severe neonatal (“French”) type: Total absence of PC activity leads to severe, progressive, lactic acidosis and ketosis, hypoglycemia, hepatomegaly with steatosis, and neurologic dysfunction (seizures, coma, abnormal muscle tone). The ...

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