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The 3 essential branched chain amino acids (BCAAs), leucine, isoleucine, and valine, encompass about 25% of human protein. They are metabolized in mitochondria. The first 2 catabolic steps are common to the 3 BCAAs (Fig. 132-1). The first reaction, which occurs primarily in muscle, involves reversible transamination to 2-oxo (or keto) acids and is followed by oxidative decarboxylation to coenzyme A (CoA) derivatives by branched chain oxo (or keto) acid dehydrogenase (BCKD). BCKD is similar in structure to pyruvate dehydrogenase (and shares a common subunit), is also highly regulated by a kinase/phosphatase system, and plays a key role in nitrogen metabolism.

Figure 132-1

Metabolism of leucine, isoleucine, and valine. The enzymes involved in the stages of metabolism are numbered.

Subsequently, the degradative pathway of BCAAs diverges. Leucine is catabolized to acetoacetate (making it a ketogenic amino acid) and acetyl-CoA, which enters the Krebs cycle. The final step in the catabolism of isoleucine involves cleavage into acetyl-CoA and propionyl-CoA, the latter of which enters the Krebs cycle via conversion to succinyl-CoA. Valine is also ultimately catabolized to propionyl-CoA.

The most frequent inborn errors affecting the BCAA catabolic pathway are maple syrup urine disease (MSUD) and the isovaleric, propionic, and methylmalonic acidemias (or acidurias). These 4 disorders can present with neonatal metabolic collapse, as a late-onset acute intermittent form, or as a chronic progressive form. Many other rarer defects have also been described in this catabolic pathway. All of these disorders can be diagnosed by identifying acylcarnitines and organic compounds in plasma and urines by gas chromatography (CG)–mass spectrometry (MS) or tandem MS, and all can be detected by newborn screening using tandem MS.


In MSUD (branched chain ketoaciduria), major cerebral symptoms appear early in the newborn period, and the urine has an odor reminiscent of maple syrup. The BCAAs are present in high concentration in the blood and urine, and the ketoacid analogues are found in the urine. Alloisoleucine, an alternative metabolite of isoleucine, accumulates in blood in this disorder and is generally diagnostic, although it may also be detected in isovaleric acidemia.


Infants with MSUD appear well at birth. In the typical patient, symptoms begin after 3 to 5 days of age, and patients progress rapidly to death within 2 to 4 weeks if untreated. Early manifestations include feeding difficulties, irregular respirations, progressive loss of the Moro reflex, and lethargy. Severe hypoglycemia may occur due to leucine being an insulin secretagogue. Characteristically, these patients develop convulsions, opisthotonos, and generalized muscular rigidity, and boxing and pedaling movements with or without intermittent flaccidity. Death usually occurs after decerebrate rigidity develops. Cortical atrophy may be seen on computed tomography (CT) or magnetic resonance imaging (MRI) scan, and ...

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