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25 Cards in this Set
- Front
- Back
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Go to question 3
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Go to question 3
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Go to question 3
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Go to question 3
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What is the most common inborn error of B12 (cobalamin)? (Hint: what is observed biochemically?)
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methylmalonic aciduria and homocysteinuria
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What chromosome, locus, and gene related to methymalonoic aciduria and homocysteinuria?
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1p34, cb1C, MMACHC
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How was the gene located?
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homozygosity mapping and haplotype analysis
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Which mutations in MMACHC accounts for most diseased alleles and early onset?
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271dupA and 331C
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besides homocysteine metabolism (methionine synthase) , where else is cobalamin an important cofactor?
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Methylmalonyl CoA -- Succinyl CoA... (In BCAA and fatty acid catabolism)
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Which mitochondrial enzyme and reaction is the cobalamin dervative (AdoCbl) require for?
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methylmalonyl CoA mutase… converts methylmalonyl CoA to succinyl CoA
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What are the 6 major steps in the cobalamin pathway in cells, which are the potential source of inherited cobalamin transport and metabolism disorders? (Hint: what's the breakdown, why are they getting their B12?)
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receptor mediated transport, endocytosis, TC II degradation in lysosome, release of Cbl into the cytoplasm, enzyme reduction of cobalt atom, cytosolic methylation (MeCbl) or mitochondrial adenylation to form AdoCbl.
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What is the role of methylcobalamin (MeCbl… in the cytosol)?
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it is a cofactor of methyltransferase in the conversion of Homocysteine to methionine
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What is the role of adenosylcobalamin (AdoCbl in the mitochondria)?
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it is a cofactor of mutase in the conversion of L-Methylmalonyl-CoA to Succinyl-CoA
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What is TC II?
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It is the tranport protein of cobalamin that enters cells via receptor mediated transport.
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What is the methylmalonyl-CoA to Succinyl-CoA (Krebs) an entry port for? (hint: diet/protein breakdown… name amino acids, etc.)
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cholesterol, odd-chain fatty acids, leucine, threonine
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What are the 6 biochemical features of Cobalamin C disease? Which of the 6 is the definitive feature of the disease?
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a) 1. megablastic anemia, 2. homocyteinuria, 3. hyperhomocysteinemia, 4. methylmalonic aciduria, 5. normal serum folate and B12… b) and 6 and the definitive feature: hypomethioninemia
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Besides failure to thrive, feeding difficulties, dev and behavioral abnormalities, what are the clinical manifestations of Cobalamin C disease in early onset?
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seizures, hypotonia, opthalmologic findings, renal impairment, marfanoid habitus
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What are the clinical features of late onset cobalamin C?
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acute neurologic decompensation, myelopathy, dementia or psychosis-like symptoms
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What is the treatment of Cobalamin C disease?
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hydroxycobalamin… there are others such as betaine, carnithine and folic acid supplementation but they are of little consequence
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What is the inheritance pattern of Cobalamin C disease?
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autosomal recessive
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What are 2 prenatal diagnosis techniques of Cobalamin C disease?
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1. Check for elevated levels of methylmalonic acid in amnionic fluid… 2. Appropriate uptake of both labelled propionate and methyl-FH4 by amniocytes
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How would you treat the inherited metabolic diseases associated with the following? BCKA, homocysteinuria, familial rickets
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BCKA -thiamin (B1)… Homocysteinuria-pyridoxine (B6) and Folic acid… Familial Rickets-Vit D
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How was the cblC locus mapped to the 1p chromosome?
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linkage analysis
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How was the gene location pinpointed?
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homozygosity mapping and haplotype analysis
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What happened to the phenotype of cultured cells after the transduction of wild type MMACHC?
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They functioned properly
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Is MMACHC well conserved?
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yes, bacterial cells have similar motiffs… ( TonB)
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What are the uses for mutational analysis of MMACHC?
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carrier identification and prenatal diagnosis
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