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30 Cards in this Set
- Front
- Back
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What are the clinical features of the organic acidurias?
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Vomiting, neurological decompensation (lethargy, hypotonic, seizures), failure to thrive, unusual odors
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What are the laboratory features of organic acidurias?
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Metabolic acidosis, ketonuria, hypoglycemia, hyperammonemia, thrombocytopenia, amino aciduria, organic aciduria
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What is the cause of hypoglycemia observed in organic acidurias?
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the accumulation of metabolites inhibits the pyruvate carboxylase.
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What technique is used to diagnose organic acidurias?
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Urine organic acid analysis by gas chromotography/mass spectrometry (GS/MS). A definitive diagnosis should be established by specific enzyme assays whenever possible and followed up by molecular studies to identify specific DNA mutations.
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What OA is due to deficiency in the pathways of branched-chain amino acid metabolism?
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Maple Syrup Urine Disease (MSUD)
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Describe the metabolism of L-leucine.
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L-leucine to α-ketoisocaproate to acetoacetic acid and acetyl-CoA
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Describe the metabolism of L-isoleucine.
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Isoleucine to α-keto-β-methylvalerate to α-methylacetoacetyl-CoA to propionyl-CoA to methylmalonyl-CoA to succinyl-CoA
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Describe the metabolism of L-valine.
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Valine to α-ketoisovalerate to propionyl-CoA to methyl malonyl-CoA to succinyl-CoA.
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What are the three essential branched-chain amino acids?
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Leucine, Isoleucine, Valine
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Which enzyme is responsible for the decarboxylation of the three branched-chain amino acids and what cofactor is required?
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branched chain α-ketoacid dehydrogenase; TPP
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Approximately what percentage of patients affected with MSUD suffer from a severe classical form?
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75%
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What is the treatment for MSUD?
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Dietary restriction of branched chain amino acids.
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Is MSUD an amino acid disorder or an organic acid disorder?
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It can be classified as both.
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What about MSUD is different from other organic acidurias?
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Unlike the other organic acidurias, the amino acids will also accumulate in MSUD. Typically leucine is more elevated.
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What molecules form Propionyl acid as it is significant to MMA (methyl malonic aciduria)?
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valine, odd chain fatty acids, methionine, isoleucine, threonine, cholesterol (VOMIT-C)
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What enzyme is responsible for the conversion of propionyl-CoA to methyl malonyl CoA and what is required as a cofactor?
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propionyl carboxylase; biotin
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In the event that propionyl carboxylase is deficient, what happens to the propionyl-CoA?
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It is shuttled to the secondary pathyway to form propionic acid.
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What enzyme is required to convert methyl malonyl-CoA to succinyl-CoA and what is the required cofactor?
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methyl malonyl Co-A mutase; cobalamin (vitamin B12)
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Deficiency of what enzymes causes MMA (methylmalonic aciduria)?
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methyl malonyl-CoA mutase
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What are the secondary findings of MMA?
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hypoglycemia, hyperglycenmia, ketosis, and hyperammonemia
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What causes the hyperammonemia in MMA?
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The accumulation of methyl malonic acid inhibits NAGS (N-acetylglutamate synthetase) which is responsible for forming carbamoyl phosphate from NH4 + CO2 in the urea cycle.
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What reaction requires adenosylcobalamin as a cofactor?
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The conversion of methyl malonyl-CoA to succinyl CoA
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What reaction requires methylcobalamin as a cofactor?
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The conversion of homocysteine to methionine.
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What does OH-cobalamin become?
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adenosylcobalamin and methylcobalamin
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If you can't make adenosylcobalamin, what will it look like you have?
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MMA
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if you can't make methylcobalamin, what will it look like you have?
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homocysteinuria
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If you are unable to make OH-cobalamin, what condition(s) will you have?
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MMA and homocysteinuria
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Abnormalities in CblA and CblB result in what?
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abnormalities in adenosylCobalamin synthesis only and a biochemical defect identical to mut defects
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A defect in CblC, CblD, CblF results in?
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Impaired synthesis of both adenosyl and methylcobalamin. Biochemically, MMA plus homocystinuria.
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What is the treatment for cobalamin?
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mega doses of cobalamin; intermuscular injections of hydroxy cobalamin.
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