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.