Propionic acidemia and methylmalonic acidemia result from defects in a series of reactions called the propionate pathway (Fig. 54-1). Defects in these steps produce ketosis and hyperglycinemia. Propionic acidemia and methylmalonic acidemia are identified by neonatal screening with tandem mass spectrometry methods. The clinical manifestations of both of these disorders in the neonatal period consist of tachypnea, vomiting, lethargy, coma, intermittent ketoacidosis, hyperglycinemia, neutropenia, thrombocytopenia, hyperammonemia,
Methionine Valine Threonine (?) Odd-chain fatty acids Cholesterol Pyrimidines and hypoglycemia. If these disorders are not identified by neonatal screening, intermittent episodes of metabolic acidosis occur. Crises occur during periods of catabolic stress, such as fever, vomiting, and diarrhea; they also may occur without an apparent precipitating event. During periods of neutropenia, the risk of serious bacterial infection is increased. Failure to thrive and impaired development are common.
Propionic acidemia results from deficiency in propionylCoA-carboxylase, an enzyme that has two pairs of identicalsubunits. All forms of propionic acidemia are inherited in anautosomal recessive manner and are due to mutations in one of the subunits. Methylmalonic acidemia results from deficiencyin methylmalonyl mutase; this may be caused by mutations inthe gene for the mutase protein itself or in one of the stepsof the synthesis of the cobalamin cofactors for the enzyme.A complex set of defects in cobalamin metabolism results inother forms of methylmalonic acidemia, some of which are associated with hyperhomocystinemia. Treatment with massive doses of hydroxocobalamin (the active form of vitaminB12) is helpful in some cases of methylmalonic acidemia.
For propionic acidemia and the vitamin B12–unresponsive forms of methylmalonic acidemia, management includes the restriction of dietary protein and addition of a medical food deficient in the specific amino acid precursors of propionyl-CoA (isoleucine, valine, methionine, and threonine). Carnitine supplementation is often needed because it is lost in the urine as acylcarnitines. Intestinal bacteria produce a significant quantity of propionate; thus, antibacterial treatment to reduce the population of bacteria in the gut has some beneficial effect in propionic acidemia and vitamin B12–unresponsive methylmalonic acidemia.
Isovaleric acidemia results from a block in the catabolism of leucine. Its clinical manifestations are similar to those of defects in the propionate pathway. The strong odor of isovaleric acid results in sweaty feet odor in untreated infants. Therapy involves restricting the intake of leucine, and providing glycine
Coenzyme A.
Figure 54-2 Metabolism in isovaleric acidemia. (1) Leucine catabolic pathway (transamination and decarboxylation), (2) isovaleryl-CoA dehydrogenase, (3) glycine acyltransferase. CoA, Coenzyme A.
as an alternate pathway therapy that conjugates isovaleric acid (Fig. 54-2) and is then excreted in the urine.