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17 Cards in this Set
- Front
- Back
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Tyrosine metabolism |
Phe -phe hydroxyxlase-> Tyr Tyr -> PHPP PHPP -PHPP dioxygenase- Homogentrisic acid Homogentrisic acid -> Methylacetoacetate Methylacetoacetate <-> Succinylacetone <-> Fumarylacetoacetate Fumarylacetoacetate -FAA hydrolase-> Fumarate + Acetoacetate |
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Causes of hypertyrosinemia |
Immaturity of PHPP dioxygenase Liver disease Inborn errors of tyrosine metabolism Other - vitamin C deficiency, scurvy, postprandial state |
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Tyrosinemia type 1 - Hepatorenal Tyrosinemia |
Deficiency in fumarylacetoacetate hydrolase Infants present with liver disease; older people with growth failure and rickets because of loss of phosphate. Boiled cabbage urine. Elevated succinylacetone inhibits delta-aminolevulinate dehydratase causing porphyria like abdominal pain and peripheral neuropathy. Liver damage causes elevations in methionine, phenylalanine and tyrosine. Treat with nitisinone (NTBC) to inhibit PHPP dioxygenase, lowering succinylacetone and causing tyrosinemia type 3. |
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Nonketotic hyperglycinemia |
Defect in glycine cleavage enzyme (P, H, T, L) with 70% mutations in P-protein and none in L-protein. Neonatal presentation - 85% severe with lethargy, intractable seizures, poor tone, apnea, and profound MR. Non-acidotic, no ketones, normal ammonia. Elevated blood, urine, and CSF glycine. No effective treatment. |
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Methionine metabolism |
Met -> Hcy Hcy -methyl cobalamin-> Met Hcy -cystathionine-beta-synthase (CBS)-> cystathione cystathione->cysteine |
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Classical homocystinuria |
Defect in CBS causing elevation of Hcy and Met. 50% are pyridoxine responsive (pyridoxine is CBS cofactor). Marfan phenocopy - ectopia lentis, myopia, osteoporosis, thrombosis, developmental delay. Treat with betaine, artifical substrate that pushes pathway towards Met, and low Met diet. |
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Disorders of organic acid metabolism
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Organic acids are low MW, contain carboxy and other functional groups, and soluble. General features: vomiting, seizures, FTT, hypotonia, lethargy, unusual odor, metabolic acidosis, hyperammonemia. Evaluate with urine organic acid analysis by gas chromatography. |
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Branched Chain Amino Acid Metabolism |
Leu/Ile/Val + alpha-kg -transaminase pyridoxine-> glutamate + alpha ketoacid (REVERSIBLE)
alpha keto acid -branched chain ketoacid dehydrogenase (BCKD)/thiamine-> acetoacetate+acetyl coA / acetyl coA + succinyl coA / succinyl coA (IRREVERSIBLE)
Leucine is ketogenic. |
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Maple Syrup Urine Disease |
Deficiency in E1alpha, E1beta, E2, or E3 branched chain ketoacid dehydrogenase (BCKD). Lethargy, coma, MR. Increase in branched chain alpha ketoacids and amino acids (transaminase is reversible). Alloisoleucine is diagnostic. Diagnose with leucine in blood spots. Forms: Classic (severe), intermediate, intermittent, thiamine responsive (E2 mutations), and E3 deficient. Treat: restrict Leu (encephalopathy), Ile, Val |
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Propionyl coA pathway |
Valine/Methionine/Isoleucine/Threonine/Odd-chain fatty acids/Cholesterol -> Propionyl coA
Propionyl coA -prop coA carboxylase/biotin-> methylmalonyl coA -methylmalonyl coA mutase/adenosylcobalamin B12-> succinyl coA
Propionyl coA -> propionic acid Methylmalonyl coA -> methylmalonic acid |
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Propionic acidemia |
Deficiency in alpha or beta propionyl coA carboxylase (isolated) or biotin deficiency Biotin associates with alpha subunit. Clinical - vomiting, poor feeding, seizures, and poor tone. Cardiomyopathy. Metabolic acidosis (propionic acid), ketonuria (FA oxidation), hypoglycemia. Secondary hyperammonemia. Elevated plasma glycine. |
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Methylmalonic acidemia |
Defect in methyl malonyl coA mutase Mut0 - no detectable enzyme (Crm-). Severe, early onset and not Cb responsive. Mut- - enzyme with reduced affinity for cofactor. Somewhat Cb responsive. CblA/B - milder, Cb responsive. |
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Production of adenosylcobalamin |
Dietary Cbl -CblC/D/E-> Cobalamin Cobalamin -CblA/B-> Adenosylcobalamin Cobalamin -> methylcobalamin (cofactor for Met synthase) |
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CblC defect |
Causes increase in methylmalonic acid, increase in Hcy, and decrease in methionine. Leads to methylmalonic acidemia and homocystinuria. |
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Secondary effects of proponic and methyl malonic acidemia |
1. Hyperglycinemia: inhibition of glycine cleavage enzyme 2. Hypoglycemia: inhibition of pyruvate carboxylase 3. Hyperammonemia: inhibition of n-acetylglutamine synthetase 4. Hyperlacticacademia: inhibition of PDH complex |
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Biotin (Vit B7) metabolism |
Biotin + apocarboxylase -holocarboxylase synthetase-> holocarboxylase holocarboxylase -biotinidase-> Lysine + Biotin Biotin is used for: pyruvate carboxylase (gluconeogenesis), acetyl coA carboxylase (fatty acid synthesis), propionyl coA carboxylase (valine, Ile metabolism), methylcrotonyl coA carboxylase (leu metabolism) |
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Late-onset multiple carboxylase deficiency |
AR deficiency of biotinase Late onset because takes 8-10 months for infants to exhaust maternal store of biotinidase (holocarboxylase deficiency presents immediately). Alopecia, ketoacidosis, aciduria, seizures, skin rash. <10% profound, 10-30% partial deficiency Treat with biotin supplementation |
