Isovaleric Acidemia

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 600 mg/kg/day. Administration of carnitine with or without glycine also decreases isovaleric acidemia, but the data are still too limited to evaluate the optimal combination for long-term management. Chronic pancreatitis may occur.

Obtain full history of progression of the disease: frequency of acute crisis, nature of treatment, psychomotor development. Obtain arterial blood gases (correct metabolic acidosis preoperatively if possible); hematologic examination: pancytopenia may be significant, requiring platelets, red cells, and eventually granulocyte transfusions (consult with hematologist if necessary); pancytopenia is more frequent during infancy. Consult with competent authorities regarding leucine-restricted diet and glycine and carnitine supplements. During acute episodes, glucose infusion helps to provide calories and reduce endogenous protein catabolism.

Stress of surgery may precipitate acute acidosis and neurologic deterioration. In the perioperative period, the goal is maintaining adequate hydration and sufficient calorific intake to prevent catabolism. Acid-base status should be monitored during long procedures. In the presence of significant metabolic acidosis, bicarbonate infusion and mechanical ventilatory support may be necessary, including the postoperative period. Until corrected, thrombocytopenia precludes regional anesthesia. If pancytopenia is documented, platelets and red blood cells should be available before the patient enters the operating room for any type of invasive procedure.

Salicylic acid, derived from aspirin, is a substrate for glycine N-acylase and could interfere with synthesis of isovalerylglycine, preventing the beneficial effects of glycine. Therefore it is contraindicated in isovaleric acidemia. Patients with carnitine deficiency may have a lower threshold for bupivacaine-induced cardiotoxicity, so this local anesthetic is best avoided in affected patients with carnitine deficiency.

Carnitine Deficiency: Disorder caused by decreased carnitine concentrations in plasma and tissues preventing mitochondria from adequate beta oxidation. Primary and secondary defects have been described. The manifestations are cardiomyopathy, encephalopathy, and myopathy.

Methylmalonic Acidemia (MMA): Heterogeneous inborn error of metabolism affecting the amino acid metabolism, leading to metabolic acidosis and accumulation of methylmalonic acid and its by-products.

Propionic Acidemia: Inborn error of metabolism of branched-chain organic acids (defective propionyl-coenzyme A carboxylase) resulting in accumulation of propionic acid in the body and several toxic metabolites. Patients present with vomiting, seizures, choreoathetoid movements, lethargy, hypotonia, and encephalopathy. Autosomal recessive transmission.