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The three essential branched chain aminoacids (BCAAs), leucine, isoleucine, and valine encompass about 25% of human protein. They are metabolized in mitochondria. The first two catabolic steps are common to the three BCAAs (Fig. 137-1). 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, is also highly regulated by a kinase/phosphatase system and plays a key role in nitrogen metabolism.

Figure 137-1.

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

Subsequently, the degradative pathway of BCAAs diverge. Leucine is catabolized to aceto-acetate (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, which also enters the Krebs cycle via conversion to succinyl-CoA. Valine is also ultimately catabolized to propionyl-CoA.

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

In maple syrup urine disease (branched-chain ketoaciduria), major cerebral symptoms appear early in the newborn period, and the urine has an odor reminiscent of maple syrup. The branched-chain amino acids—leucine, isoleucine, and valine—are present in high concentration in the blood and urine, and the ketoacid analogues are found in the urine.

Clinical Findings

Infants with maple syrup urine disease (MSUD) appear well at birth. In the typical patient, symptoms begin after 3 to 5 days and progress rapidly to death within 2 to 4 weeks.1 Early manifestations include feeding difficulty, irregular respirations, progressive loss of the Moro reflex and lethargy. Severe hypoglycemia may occur. Characteristically these patients develop convulsions, opisthotonos, and generalized muscular rigidity, boxing and pedalling movements with or without intermittent flaccidity. Death usually occurs after decerebrate rigidity develops. Cortical atrophy may be seen on CT or MRI scan, and the myelin is usually hypodense. This is consistent with the defective myelinization that has been observed at autopsy. The feature that distinguishes any form of branched-chain ketoaciduria from other cerebral degenerative diseases of infancy is the characteristic maple syrup, or caramel, odor of the urine, skin, or hair. The odor may become evident 1 or 2 days after birth and may persist, ...

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