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Isovaleric-CoA dehydrogenase deficiency
A block in the leucine pathway due to isovaleric-CoA dehydrogenase deficiency occurs in isovaleric acidemia (Figure 74.1 C) and multiple acyl-CoA dehydrogenase deficiency. Multiple acyl-CoA dehydrogenase deficiency is also called glutaric acidemia type II (Figure 74.1 D). Clinical findings that may suggest these disorders in a neonate are: (1) an offensive sweat odor in the urine, (2) mild facial dysmorphism, and (3) rocket-bottom feet. Neonates with multiple acyl-CoA dehydrogenase deficiency may have anterior muscular abdominal wall defects and abnormal genitalia.

Figure 74.1. Leucine pathway showing different enzymatic blocks and the amino acids that increase as a result of the block. A: maple syrup urine disease; B: dihydrolipoyl dehydrogenase deficiency; C: isovaleric acidemia; D: glutaric acidemia type II; E: multiple carboxylase deficiency; F: HMG-CoA lyase deficiency.

The metabolic profiles of isovaleric acidemia and glutaric acidemia type II are different even though the enzyme block in the leucine pathway is the same (Figure 74.1 [C,D]).

Isovaleric acidemia
The metabolic profile of isovaleric acidemia is more complex than would be expected from a single pathway-specific enzyme deficiency (Figure 74.2 C). This complex profile occurs because high levels of isovaleric acid produce carnitine deficiency and disruption of: (1) pyruvate dehydrogenase complex, producing lactic acidosis; (2) glycine cleavage system, producing hyperglycemia; and (3)carbamyl phosphate synthetase, producing hyperammonemia.

Figure 74.2. Metabolic pathways involved in branched chain amino acid disorders. A: maple syrup urine disease; B: dihydrolipoyl dehydrogenase deficiency; C: isovaleric acidemia; D: glutaric acidemia type II; E: multiple carboxylase deficiency; F: HMG-CoA lyase deficiency.

 

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HMG-CoA lyase deficiency multiple carboxylase deficiency glutaric acidemia type II isovaleric acidemia dihydrolipoyl dehydrogenase deficiency maple syrup urine disease converts to alanine and lactate branced chain alpha-keto acids converts to alanine and lactate rate-limiting citric acid cycle enzyme reaction HMG-CoA lyase deficincy multiple carboxylase deficiency glutaric acidemia type II isovaleric acidemia dihydrolipoyl dehydrogenase deficiency maple syrup urine disease De Vivo, 1990 Ogier, 1990 Instructions Pause pointer over each bar or letter. Figure must be centered. Pause pointer over each bar or letter. Figure must be centered.