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.
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
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
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.
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.
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
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.
(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).