Increased quantities of leucine, isoleucine, and valine are found
in the plasma and urine. The presence of an abnormal amino acid,
alloisoleucine, is diagnostic for MSUD. The catabolism of branched-chain amino
acids is initiated by a transamination reaction to generate the
respective ketoacids which then undergo decarboxylation to coenzyme
A (CoA) derivatives. The defect in MSUD is in this oxidative decarboxylation of
the ketoacids, which is catalyzed by a mitochondrial multienzyme
complex similar to pyruvate dehydrogenase and to α-ketoglutarate
dehydrogenase. For this reason, autosomal recessive mutations in
four different genes can cause MSUD. Patients have been identified
with defects in the E1α, E1β,
E2, and E3 subunits of the complex. The E3 subunit
is shared by all three complexes, and patients with defects in this
gene have simultaneous deficiency of branched-chain ketoacid dehydrogenase, pyruvate
dehydrogenase, and α-ketoglutarate dehydrogenase.
MSUD is rare in most populations with an incidence of ~1/150,000.