Pyruvate carboxylase deficiency

Most patients with pyruvate-carboxylase deficiency present with failure to thrive, developmental delay, recurrent seizures and metabolic acidosis. Lactate, pyruvate, alanine, [3-hydroxybutyrate and acetoacetate concentrations are elevated in blood and urine. Hypoglycemia is not a consistent finding despite the fact that pyruvate carboxylase is the first rate-limiting step in gluconeogenesis. 

Pyruvate carboxylase (also called PC) is an enzyme that converts pyruvate to oxaloacetate (shown as oxaloacetic acid in the citric acid cycle diagram). Pyruvate carboxylase deficiency is a genetic disorder that is characterized by insufficient quantities of pyruvate carboxylate in the body. How do you think this disorder affects the citric acid cycle Use print and electronic resources to research pyruvate carboxylase deficiency. Find out what its symptoms are, and how it affects the body at the molecular level. Also find out what percent of the population is affected, and how the deficiency can be relieved. Present your findings as an informative pamphlet. If possible, conduct an e-mail interview with an expert on the disorder. 

Pyruvate carboxylase deficiency is a rare disease that causes mental retardation and has led to death by age 5 In all known cases. 

The answer is B. While all of the listed conditions are consistent with lethargy and developmental defects, the lactic acidosis rules out pyruvate kinase deficiency. Thiamine and niacin deficiencies are unlikely due to the lack of effect of vitamin supplementation. Excess pyruvate is the source of the elevated alanine in the serum. The clinical findings are thus consistent with pyruvate carboxylase deficiency, which is associated with severe hypoglycemia due to fasting due to impaired gluconeogenesis. 

The answer is C. Pyruvate kinase deficiency is ruled out by the elevated serum lactate levels. The coma is associated with a fasting hypoglycemia, which is indicative of pyruvate carboxylase deficiency. The elevated citrulline and lysine in the serum are due to a reduction of aspartic acid levels, which are caused by the reduced levels of oxaloacetate, the product of the pymvate carboxylase reaction. 

ASA-lyase deficiency Pyruvate carboxylase deficiency LPI Pyrroline-5-carboxylate synthase deficiency... 

Acetazolamide can produce severe lactic acidosis, with an increased lactaterpyruvate ratio, ketosis with a low beta-hydroxybutyrateracetoacetate ratio, and a urinary organic acid profile consistent with pyruvate carboxylase deficiency. The acquired enzymatic injury that results from inhibition of mitochondrial carbonic anhydrase V, which provides bicarbonate to pyruvate carboxylase, can damage the tricarboxylic acid cycle. 

Sutton, F., Butler, E.T. Ill Smith, E.T. (1986). Isolation of the structural gene encoding a mutant form of E. coli phos-phoeno/pyruvate carboxylase deficient in regulation by fructose 1,6-bisphosphate. Journal of Biological Chemistry 261, 16078-81. 

Biotin is a cofactor of various carboxylases, but its effectiveness in pyruvate carboxylase deficiency is unproven. However, it has been used effectively in cases of biotinidase deficiency, a vary rare cause of congenital lactic acidosis. 

Thiamine deficiency causes decreased pyruvate oxidation, leading to accumulation of pyruvate and lactate, particularly in the blood and brain, and is accompanied by impairment of the cardiovascular, nervous, and gastrointestinal systems (Chapter 38). Inherited deficiency of pyruvate dehydrogenase complex is accompanied by lactic acidemia and abnormalities of the nervous system (e.g., ataxia and psychomotor retardation). Pyruvate carboxylase deficiency causes similar abnormalities (Chapter 15). Both inherited disorders of pyruvate utilization are autosomal recessive. 

Nervous system abnormalities may be attributed in part to diminished synthesis of neurotransmitters rather than to inadequate synthesis of ATP. In pyruvate dehydrogenase complex deficiency, diminished levels of acetyl-CoA cause decreased production of acetylcholine in pyruvate carboxylase deficiency, decreased production of... 

Pyruvate carboxylase deficiency is a usually fatal disease caused by a missing or defective enzyme that converts pyruvate to oxaloacetate. It is characterized by varying degrees of mental retardation and disturbances in several metabolic QUESTION 9.6... 

This reaction is important because it provides oxaloacetate for the citric acid cycle when the supplies have run low because of the demands of biosynthesis. It is also the enzyme that catalyzes the first step in gluconeogenesis, the pathway that provides the body with needed glucose in times of starvation or periods of exercise that deplete glycogen stores. But somehow these descriptions don t fill us with a sense of the importance of this enzyme and its jobs. It is not until we investigate a case study of a child born with pyruvate carboxylase deficiency that we see the full impact of this enzyme. 

Pyruvate carboxylase deficiency is one of the genetic diseases grouped together under the clinical manifestations of Leigh s disease (subacute necrotizing encephalopathy). In the mild form, the patient presents early in life with delayed development and a mild-to-moderate lactic acidemia. Patients who survive are severely mentally retarded, and there is a loss of cerebral neurons. In the brain, pyruvate carboxylase is present in the astrocytes, which use TCA cycle intermediates to synthesize glutamine. This pathway is essential for neuronal survival. The major cause of the lactic acidemia is that cells dependent on pyruvate carboxylase for an anaplerotic supply of oxaloacetate cannot oxidize pyruvate in the TCA cycle (because of low oxaloacetate levels), and the liver cannot convert pyruvate to glucose (because the pyruvate carboxylase reaction is required for this pathway to occur), so the excess pyruvate is converted to lactate. 

A high Ala level in combination with a high Cit suggests pyruvate carboxylase deficiency (Robinson et al., 1984). 

Rapid p-oxidation of fatty acids in perfused liver (DeBeer et a/., 1974) and in isolated mitochondria (Lopes-Cardozo and Van den Bergh, 1972) has been shown to suppress the operation of citric acid cycle apparently from the elevation of mitochondrial NADH/NAD ratio which restricts oxaloaceta-te availability for citrate synthase and simultaneously inhibits isocitrate oxidation (Lenartowicz et a/., 1976). Considerable support for an earlier postulate that oxaloacetate availability normally determines the rate of citrate synthesis has become available. Thus, because of marked protein binding, the concentration of free, as opposed to total, oxaloacetate in matrix of liver mitochondria is now estimated to be near the of citrate synthase (Siess et al., 1976 Brocks eta ., 1980). The antiketogenic effect of alanine (Nosadini et a/., 1980) and of 3-mercaptopicolinate, an inhibitor of phosphoenolpy-ruvate carboxykinase (Blackshear et a/., 1975), is believed to be exerted, at least in part, from their ability to raise hepatic oxaloacetate concentration. And, in pyruvate carboxylase deficiency, expected to impair oxaloacetate supply, concentration of ketone bodies is elevated (Saudubray et a/., 1976). 

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