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Pathway Description
Congenital Lactic Acidosis
Homo sapiens
Disease Pathway
Congenital lactic acidosis, also known as CLA, is an inherited inborn error of metabolism (IEM) characterized by the build-up of lactic acid in the body (lactic acidosis). The incidence of congenital lactic acidosis is unknown. One estimate places the incidence at 250-300 live births per year in the United States. CLA is typically caused by a mutation in the genes encoding the pyruvate dehydrogenase complex (PDC) leading to deficiencies in the function and efficiency of pyruvate dehydrogenase complex proteins, which are located in the mitochondria. Collectively the PDC converts pyruvate, NAD+, coenzyme A into acetyl-CoA, CO2, and NADH. While CLA-associated defects have been identified in all 3 enzymes of the PDC complex, the E1-alpha subunit is the most commonly mutated form. Defects in the citric acid cycle due to PDC deficiency deprives the body of energy and leads to an abnormal build-up of lactic acid in tissues and biofluids. CLA has either an autosomal recessive or X-linked mode of inheritance. There are two forms of CLA: severe and mild. Severe cases of CLA manifest in the neonatal period while milder cases may not manifest until early adulthood. Symptoms may be persistent or brought on by an event causing stress, such as an asthma attack, seizure, or infection. Symptoms in the neonatal form of CLA include hypotonia, lethargy, vomiting, and tachypnea. As the disease progresses, it can cause developmental delays, cognitive disabilities, abnormal development of the face and head, and organ failure. Treatments for CLA that are occasionally used include the ketogenic diet and dichloroacetate.
References
Congenital Lactic Acidosis References
[Metagen: CONGENITAL LACTIC ACIDOSIS](http://metagene.de/program/d.prg?id_d=100)
[OMIM: 245400](http://omim.org/entry/245400})
Kuroda Y, Naito E, Takeda E, Yokota I, Miyao M: Congenital lactic acidosis. Enzyme. 1987;38(1-4):108-14.
Pubmed: 3440441
Citric Acid Cycle References
Lehninger, A.L. Lehninger principles of biochemistry (4th ed.) (2005). New York: W.H Freeman.
Salway, J.G. Metabolism at a glance (3rd ed.) (2004). Alden, Mass.: Blackwell Pub.
Krebs HA, Johnson WA: Metabolism of ketonic acids in animal tissues. Biochem J. 1937 Apr;31(4):645-60. doi: 10.1042/bj0310645.
Pubmed: 16746382
Johnson JD, Mehus JG, Tews K, Milavetz BI, Lambeth DO: Genetic evidence for the expression of ATP- and GTP-specific succinyl-CoA synthetases in multicellular eucaryotes. J Biol Chem. 1998 Oct 16;273(42):27580-6. doi: 10.1074/jbc.273.42.27580.
Pubmed: 9765291
Mullins EA, Francois JA, Kappock TJ: A specialized citric acid cycle requiring succinyl-coenzyme A (CoA):acetate CoA-transferase (AarC) confers acetic acid resistance on the acidophile Acetobacter aceti. J Bacteriol. 2008 Jul;190(14):4933-40. doi: 10.1128/JB.00405-08. Epub 2008 May 23.
Pubmed: 18502856
Corthesy-Theulaz IE, Bergonzelli GE, Henry H, Bachmann D, Schorderet DF, Blum AL, Ornston LN: Cloning and characterization of Helicobacter pylori succinyl CoA:acetoacetate CoA-transferase, a novel prokaryotic member of the CoA-transferase family. J Biol Chem. 1997 Oct 10;272(41):25659-67. doi: 10.1074/jbc.272.41.25659.
Pubmed: 9325289
Denton RM, Randle PJ, Bridges BJ, Cooper RH, Kerbey AL, Pask HT, Severson DL, Stansbie D, Whitehouse S: Regulation of mammalian pyruvate dehydrogenase. Mol Cell Biochem. 1975 Oct 31;9(1):27-53.
Pubmed: 171557
Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, Cox JE, Cardon CM, Van Vranken JG, Dephoure N, Redin C, Boudina S, Gygi SP, Brivet M, Thummel CS, Rutter J: A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science. 2012 Jul 6;337(6090):96-100. doi: 10.1126/science.1218099. Epub 2012 May 24.
Pubmed: 22628558
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