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
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.
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]).
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.