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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.
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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).
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Autosomal recessive; the gene has been mapped
to 11q13.4-q13.5.
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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).
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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.
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The clinical presentation is highly variable;
however, three distinct clinical presentations have been described.
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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 ...