Organic Acidurias

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

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