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dc.contributor.authorBarbera, Gabrielleen_US
dc.date.accessioned2018-01-31T19:34:17Z
dc.date.available2018-01-31T19:34:17Z
dc.date.issued2017
dc.identifier.urihttps://hdl.handle.net/2144/26514
dc.description.abstractMedium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) is the most common inborn error of metabolism affecting the fatty acid oxidation pathway. The deficiency is caused by a defect in the medium-chain acyl-CoA dehydrogenase enzyme which catalyzes the first step in the oxidation of medium-chain fatty acids. Long-chain fatty acids, after being transported into the mitochondria and activated into long-chain acyl-CoAs, are sequentially broken down until they become medium-chain acyl-CoAs. Medium-chain acyl-CoAs are then broken down until they become short-chain acyl-CoAs. Short-chain acyl-CoAs are broken down until only acetyl-CoA remains. The block in the oxidation of fatty acids in those with MCADD happens once the long-chain acyl-CoAs have been oxidized to medium-chain acyl-CoAs. The medium-chain acyl-CoAs cannot be further oxidized and build up. Without the breakdown of fatty acids, individuals with MCADD cannot produce enough energy during times of increased metabolic demand. Thus, prolonged exercise, fasting, or fever can precipitate clinical symptoms once the body enters a hypoketotic hypoglycemic state. Those with MCADD typically present in the early months of life with fasting intolerance, vomiting, lethargy, and, in more serious cases, seizures. Adult presentation is rare, but should not be ruled out of a differential diagnosis, because early detection and intervention can prevent permanent brain damage and death. Because early detection can prevent the serious effects of metabolic decompensation, MCADD was added to the Newborn Screen and is tested through measuring levels of medium-chain acylcarnitines in dried blood smears by tandem mass spectrometry. Metabolic decompensation is manifested clinically through dehydration, vomiting, and acidosis. In serious cases, metabolic decompensation can progress to seizures, coma, and death. Introduction of the Newborn Screen has reduced the morbidity of the deficiency, but has not eliminated it. Those with MCADD need to be closely monitored and emergency glucose needs to be available to them in case of a hypoglycemic emergency. The Newborn Screen has been effective in finding mutations in the ACADM gene that produce a mild phenotype of MCADD. Before the Newborn Screen, the most common variant, K329E, was detected in clinically diagnosed patients. However, the screen has shown that there are about 150 variants leading to MCADD. The most common variant of the MCAD protein, K329E, has been studied and characterized in order to further understand the pathogenesis of MCADD. This mutation substitutes a lysine for a glutamic acid, introducing hindrance and the inability of the protein to form its fully functional tetrameric form. The mutant protein also has an increased sensitivity to heat denaturation. Currently, there are no pharmacological treatments for MCADD. The idea of pharmacological chaperones is explored by using the example of tetrahydrobiopterin and phenylketonuria. Future studies will need be done to find a treatment for MCADD that is curative rather than treating the symptoms of the deficiency; however, curative therapies which target the mutant enzyme may be problematic since there is a wide array of mutations that result in a defective enzyme in affected individuals.en_US
dc.language.isoen_US
dc.subjectBiochemistryen_US
dc.subjectMCADDen_US
dc.subjectMetabolismen_US
dc.subjectAcyl-CoA dehydrogenaseen_US
dc.subjectInborn error of metabolismen_US
dc.titleMedium-chain Acyl-CoA dehydrogenase deficiency: a characterization of the most common variant and current and future therapeuticsen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2017-11-01T22:11:47Z
etd.degree.nameMaster of Scienceen_US
etd.degree.levelmastersen_US
etd.degree.disciplineMedical Sciencesen_US
etd.degree.grantorBoston Universityen_US


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