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Key Features

  • Typical presentation is infantile encephalopathy

  • Due to deficiency of the enzyme that catalyzes the oxidative decarboxylation of the branched-chain keto acid derivatives of leucine, isoleucine, and valine

  • Accumulated keto acids of leucine and isoleucine cause the characteristic sweet odor

  • Only leucine and its corresponding keto acid have been implicated in causing central nervous system (CNS) dysfunction

  • Many variants of this disorder have been described, including mild, intermittent, and thiamine-dependent forms

  • All are autosomal recessive traits

Clinical Findings

  • Patients are normal at birth

  • Feeding difficulties, coma, and seizures develop after about 1 week

  • Nearly normal growth and development may be achieved if treatment is begun before about age 10 days, which is facilitated by newborn screening


  • Amino acid analysis shows marked elevation of branched-chain amino acids including alloisoleucine, a diagnostic transamination product of the keto acid of isoleucine

  • Urine organic acids demonstrate the characteristic keto acids

  • The magnitude and consistency of metabolite changes are altered in mild and intermittent forms

  • Prenatal diagnosis is possible by enzyme assay in cultured amniocytes or chorionic villi, and by molecular analysis if the mutation is known

  • Unless diagnosis is made and dietary restriction of branched-chain amino acids is begun, most infants will die in the first month of life


  • Dietary leucine restriction and avoidance of catabolism are the cornerstones of treatment

  • Infant formulas deficient in branched-chain amino acids must be supplemented with normal foods to supply enough branched-chain amino acids to permit normal growth

  • Plasma levels of branched-chain amino acids must be monitored frequently to deal with changing protein requirements

  • Acute episodes must be aggressively treated to prevent catabolism and negative nitrogen balance

  • Very high leucine levels require hemodialysis

  • Liver transplantation corrects the disorder

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