Carnitine deficiency occurs because isovaleric acid combines readily with carnitine, forming a compound that is excreted in the urine. Hyperglycinemia is mild because glycine combines with isovaleric acid to form isovalerylglycine, which is rapidly cleared in the urine. Treatment of isovaleric acidemia consists of correction of hypoglycemia, acidosis, and other metabolic abnormalities. Glycine 250 mg/kg per day should be used to promote the formation of isovalerylglycine.

Glutaric acidemia type II
Glutaric acidemia type II is a disorder of the mitochondrial electron transfer flavoprotein system. Known problems in the mitochondrial electron transfer flavin system causing Glutaric acidemia type II are (1) deficiency of the electron transfer flavoprotein (ETF), and (2) deficiency of the electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO).
Failure of the mitochondrial electron transfer flavoprotein system leads to dysfunction of several distint acyl CoA dehydrogenases.The most important concequences are mitochondrial fatty acid beta-oxidation dysfunction and amino acids defects (Figure 75.1 D).

Figure 75.1.— 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 (not all the chemical reactions involved are shown); E: multiple carboxylase deficiency; F: HMG-CoA lyase deficiency.

Glutaric acidemia type II should be suspected in neonates with dysmorphism (unusual facies, macrocephaly, abdominal wall defects, enlarged polycystic kidney, hepatomegaly and hypospadias), hypotonia, or encephalopathy. A sweaty feet odor may be present. The metabolic clues to the diagnosis of Glutaric acidemia type II are hypoketotic hypoglycemia, metabolic acidosis and hyperammonemia. Urine organic acid revealed a pattern in keeping with the metabolic disarrangement produced by the deficiency of the mitochondrial flavin-containing acyl-CoA dehydrogenases. Carnitine is usually low because it is used as an alternative pathway by the products that accumulate as the result of the blocks in their main pathways. There is no satisfactory treatment in neonates. Riboflavin and carnitine may be used.

Beta-methylcrotonyl-CoA carboxylase deficiency
A block in the leucine pathway due to beta-methylcrotonyl-CoA carboxylase deficiency occurs in multiple carboxylase deficiency (Figure 75.2 E). The block in the leucine pathway leads to accumulation of many metabolites (Figure 75.2).

Figure 75.2.— 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.

Multiple carboxylase deficiency
The metabolic profile of multiple carboxylase deficiency is characterized by the accumulation of metabolites that reflect the block in the leucine pathway (Figure 75.2 E), and in other nonleucine pathways (Figure 75.1 E). These nonleucine pathway involvements produce: (1) lactic acidosis with an increased lactate-to-pyruvate ratio due to a defect in pyruvate metabolism, (2) propionic acidemia due to a defect in propionic metabolism, and (3) decreased fatty acid formation due to a defect in acetyl-CoA metabolism. Multiple carboxylase deficiency may be due to holocarboxylase deficiency (normal serum biotinidase level but low enzyme activity in leukocytes or cultured fibroblasts) or biotinidase deficiency (low serum biotinidase level). Treatment of these disorders consists of correction of metabolic abnormalities and large doses of biotin.

Hydroxymethylglutaryl-CoA (HMG-CoA) lyase deficiency
A block in the leucine pathway due to a defect of hydroxymethylglutaryl-CoA (HMG-CoA) lyase occurs in HMG-CoA lyase deficiency (Figure 75.1 F). The metabolic profile is characterized by the accumulation of the metabolites prior to the leucine pathway block (Figure 75.2 F), and hypoglycemia and hypoketonemia due to a defect in fatty acid metabolism (Figure 75.1 F).