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.
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
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, but ...