Genetic disorder affecting the branched-chain organic
acids, the most frequent of the leucine metabolism disorders. This inborn
error of metabolism leads to body accumulation of isovaleric acid (and its
metabolites) resulting in vomiting, dehydration, severe metabolic acidosis,
and neurologic manifestations.
Isovaleric Acid CoA Dehydrogenase Deficiency.
Uncertain (lack of general population screening); more
than 60 cases have been reported since the first description in 1966.
Autosomal recessive; chromosome 15q14-q15.
Isovaleryl-CoA dehydrogenase catalyzes the first
step of branched-chain organic acid metabolism of leucine. The deficiency of
isovaleryl-CoA dehydrogenase activity results in accumulation of abnormal
metabolites (isovaleric acid, isovalerylglycine, hydroxyisovaleric acid,
isovalerylglucuronide, isovalerylglutamic acid). The build-up of these
metabolites is responsible for the disease. The precise mechanism of
isovaleric acid toxicity is not well known, but it is an inhibitor of
succinate CoA ligase in the Krebs cycle and inhibits liver mitochondrial
oxygen consumption with glutamic, 2-oxoglutaric, and succinic acids. The
neutropenia often seen in the disease may be attributed to inhibition of
granulopoietic progenitor cell proliferation by isovaleric acid.
Clinical course; occasionally foul odor of “sweaty
feet” caused by isovaleric acid in body fluids; metabolic acidosis with
mild-to-moderate ketonuria and lactic acidemia; hyperammonemia.
Thrombocytopenia, neutropenia, and pancytopenia may be present, as well as
hypocalcemia. The “sweaty feet” odor is suggestive of, but not specific
for, isovaleric acidemia because it may be present in other organic
acidurias (e.g., “maple syrup” urine disease, glutaric aciduria type II).
Urine analysis for nonvolatile organic acids reveals marked elevation of
isovalerylglycine acid with lesser elevation of hydroxyvaleric acid and
smaller, but still significant, amounts of the other abnormal metabolites.
Confirmation of the diagnosis of isovaleric acidemia comes from assays on
patients' fibroblasts showing deficiency of isovaleryl-CoA dehydrogenase
(improved tritium release assay or fluorometric assay). Prenatal diagnosis
can be made by amniocentesis by stable isotope dilution analysis of elevated
isovalerylglycine in amniotic fluid or by fluorometric assay of
isovaleryl-CoA dehydrogenase activity.
Two clinical categories: half of the patients
present with an acute neonatal illness with poor feeding, dehydration,
hypothermia, and coma, and if untreated, death secondary to severe metabolic
acidosis, cerebral edema, cerebral hemorrhage, or infection. The other half
of patients either are survivors of the acute neonatal episode or later
developed symptoms and suffer from a chronic intermittent form with similar
episodes. The majority of patients have normal psychomotor development, but
some present with various degrees of developmental delay. The recurrent
episodes often follow upper respiratory infection or intake of protein-rich
food to which patients frequently develop aversion. Most diagnoses of the
disease are made during the first episode. Acute episodes are treated
symptomatically (protein restriction, hydration, correction of acid-base
disturbances, glucose infusion). Along with symptomatic treatment are more
specific therapeutic approaches, such as glycine and carnitine
administration. Under stable conditions of a leucine-restricted diet, the
optimal regimen is 150 mg/kg/day of glycine per os or per nasogastric tube.
During acute crisis, increase glycine supplements to ...