Propionic aciduria

Methylmalonic aciduria Propionic aciduria Isovaleric aciduria... 

Propionic aciduria Pyridoxine-responsive seizures Adapted from Walter and Wraith [19]... 

Touati G, et al. Methylmalonic and propionic acidurias management without or with a few supplements of specific amino acid mixture. J Inherit Metab Dis. 2006 29(2-3) 288-98. 

Romano S, et al. Cardiomyopathies in propionic aciduria are reversible after liver transplantation. J Pediatr. 2010 156(l) 128-34. 

Gebhardt B, et al. N-carbamylgJutamate protects patients with decompensated propionic aciduria from hyperammonaemia. J Inherit Metab Dis. 2005 28(2) 241-4. 

Glycerol kinase deficiency HMG-CoA lyase deficiency Methylmalonic aciduria Mitochondrial disorders 2-oxoadipic aciduria Propionic aciduria Additional causes Bacterial production MCT containing formulas Riboflavin deficiency (acquired)... 

Niederwieser, A., Matasovic, A., Steinmann, B., Baerlocher, K. and Kempken, B. (1976), Hydantoin-5-propionic aciduria in folic acid non-dependent formiminoglutamic aciduria observed in two siblings. Pediatr. Res., 10,215. 

Nevertheless, malonyl-CoA is a major metabolite. It is an intermediate in fatty acid synthesis (see Fig. 17-12) and is formed in the peroxisomal P oxidation of odd chain-length dicarboxylic acids.703 Excess malonyl-CoA is decarboxylated in peroxisomes, and lack of the decarboxylase enzyme in mammals causes the lethal malonic aciduria.703 Some propionyl-CoA may also be metabolized by this pathway. The modified P oxidation sequence indicated on the left side of Fig. 17-3 is used in green plants and in many microorganisms. 3-Hydroxypropionyl-CoA is hydrolyzed to free P-hydroxypropionate, which is then oxidized to malonic semialdehyde and converted to acetyl-CoA by reactions that have not been completely described. Another possible pathway of propionate metabolism is the direct conversion to pyruvate via a oxidation into lactate, a mechanism that may be employed by some bacteria. Another route to lactate is through addition of water to acrylyl-CoA, the product of step a of Fig. 17-3. Tire water molecule adds in the "wrong way," the OH ion going to the a carbon instead of the P (Eq. 17-8). An enzyme with an active site similar to that of histidine ammonia-lyase (Eq. 14-48) could... 

A closely related disease is caused by a deficiency of propionyl-CoA carboxylase.3 This may be a result of a defective structural gene for one of the two subunits of the enzyme, of a defect in the enzyme that attaches biotin to carboxylases, or of biotinitase, the enzyme that hydrolytically releases biotin from linkage with lysine (Chapter 14). The latter two defects lead to a multiple carboxylase deficiency and to methylmalonyl aciduria as well as ketoacidosis and propionic acidemia. ... 

Methylmalonic aciduria, Types I, III Methylmalonic, 2-methylcitric, propionic... 

An important aspect of metabolite profiles is the study of known inborn errors where the qualitative and quantitative interrelationship of the affected metabolites can be studied. A recent example of this is the comparative study of three diseases, )8-methylcrotonylglycinuria, propionic acidemia and methylmalonic aciduria [362]. The advantage of considering a complete class of compounds in a single experiment is that biochemical markers for a disorder can be detected in the context of any variations in other components. This is particularly important in monitor-... 

Lactic acidosis occurs in two clinical settings (1) type A (hypoxic), associated with decreased tissue oxygenation, such as shock, hypovolemia, and left ventricular failure and (2) type B (metabolic), associated with disease (e.g., diabetes melUtus, neoplasia, liver disease), drugs and/or toxins (e.g., ethanol, methanol, and salicylates), or inborn errors of metabolism (e.g., methylmalonic aciduria, propionic acidemia, and fatty acid oxidation defects). Lactic acidosis is not uncommon and occurs in approximately 1% of hospital admissions. It has a mortality rate greater than 60%, which approaches 100% if hypotension is also present. Type A is much more common. 

Inborn errors of metabolism may be due to propionyl-CoA carboxylase deficiency, defects in biotin transport or metabolism, methylmalonyl-CoA mutase deficiency, or defects in adenosylcobalamin synthesis. The former two defects result in propionic acidemia, the latter two in methylmalonic acidemia. All cause metabolic acidosis and developmental retardation. Organic acidemias often exhibit hyperammonemia, mimicking ureagenesis disorders, because they inhibit the formation of N-acetylglutamate, an obligatory cofactor for carbamoyl phosphate synthase (Chapter 17). Some of these disorders can be partly corrected by administration of pharmacological doses of the vitamin involved (Chapter 38). Dietary protein restriction is therapeutically useful (since propionate is primarily derived from amino acids). Propionic and methylmalonyl acidemia (and aciduria) results from vitamin B12 deficiency (e.g., pernicious anemia Chapter 38). 

The answer is d. (Murray, pp 238-249. Scriver, pp 2165-2194. Sack, pp 121-144. Wilson, pp 287-324.) Propionic acidemia (232000) results from a block in propionyl CoA carboxylase (PCC), which converts propionic to methylmalonic acid. Excess propionic acid in the blood produces metabolic acidosis with a decreased bicarbonate and increased anion gap (the serum cations sodium plus potassium minus the serum anions chloride plus bicarbonate). The usual values of sodium (-HO meq/L) plus potassium ( 4 meq/T) minus those for chloride (-105 meq/L) plus bicarbonate (—20 meq/L) thus yield a normal anion gap of -20 meq/L. A low bicarbonate of 6 to 8 meq/L yields an elevated gap of 32 to 34 meq/L, a gap of negative charge that is supplied by the hidden anion (propionate in propionic acidemia). Biotin is a cofactor for PCC and its deficiency causes some types of propionic acidemia. Vitamin B deficiency can cause methylmalonic aciduria because vitamin Bn is a cofactor for methylmalonyl coenzyme A mutase. Glycine is secondarily elevated in propionic acidemia, but no defect of glycine catabolism is present. 

Because persons may be bom with defects in almost any gene, a variety of other problems leading to accumulation of organic acids are also known. Methylmalonic aciduria and propionic acidemia are discussed in Box 17-B. Lactic acidemia (Box... 

In propionic and methylmalonic aciduria, metronidazole, given orally, inhibits the production of propionic acid by gut bacteria. In isovaleric aciduria and methylcrotonyl-CoA carboxylase deficiency, glycine accompanied by carnitine supplementation inCTeases the elimination of toxic metabolites. In many severe conditions, empiric administration of substances that act as cofactors proves to be helpful, and this treatment option should not be neglected (Table 5.3) [19]. 

FiUppi L, et al. N-carbamylgluteunate in emergency management of hyperammonemia in neonatal acute onset propionic and methylmalonic aciduria. Neonatology. 2010 97(3) 286-90. 

As was already pointed out, methylmalonic aciduria occurs in children as a hereditary disease. Some patients are responsive to large doses of vitamin Bi2-The biochemical pathogenesis of the disease has been clarified at least in part. Cultures of fibroblasts obtained from such patients oxidize propionate and methylmalonic acid to CO2 much more slowly than do fibroblasts obtained from normal cells. But if large amounts of hydroxycobalamin are added to the culture medium, methylmalonate and propionic acid oxidation is restored to normal, thus excluding a defect in the methylmalonate mutase levels. Assays for deoxyadenosylcobalamin in fibroblasts obtained from methylmalonic aciduria patients and normal individuals revealed that the concentration of coenzyme is in the mutant only 10% of that in the normal fibroblast. Inasmuch as the mechanism of vitamin B12 conversion to the deoxyadenosylcobalamin coenzyme is not known, except for the fact that several enzymic steps are involved, the exact nature of the defect in methylmalonic aciduria cannot be ascertained. 

Methylc rotonylglycinur ia 3-Methylglutaconic aciduria, other types Biotinidase def 3-Oxothiolase def Methylmalonic acidemia Propionic acidemia L-2-Hydroxyglutaric aciduria Urea cycle disorders... 

Methylmalonic acidemia Propionic acidemia Carbamyl phosphate synthetase def. Lysinuric protein intolerance Hereditary orotic aciduria Wilson disease... 

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