Abstract
Background: The significance of plasma l-alloisoleucine, which is derived from l-isoleucine in vivo, for diagnosis of maple syrup urine disease (MSUD) was examined.
Methods: Branched-chain l-amino acids were measured by automatic amino acid analysis.
Results: Alloisoleucine reference values in plasma were established in healthy adults [1.9 ± 0.6 μmol/L (mean ± SD); n = 35], children 3–11 years (1.6 ± 0.4 μmol/L; n = 17), and infants <3 years (1.3 ± 0.5 μmol/L; n = 37). The effect of dietary isoleucine was assessed in oral loading tests. In controls receiving 38 μmol (n = 6; low dose) and 1527 μmol (n = 3; high dose) of l-isoleucine per kilogram of body weight, peak increases of plasma isoleucine were 78 ± 24 and 1763 ± 133 μmol/L, respectively; the peak increase of alloisoleucine, however, was negligible for low-dose (<0.3 μmol/L) and minor for high-dose (5.5 ± 2.1 μmol/L) load. In patients with diabetes mellitus, ketotic hypoglycemia, phenylketonuria, and obligate heterozygous parents of MSUD patients, alloisoleucine was not significantly different from healthy subjects. Therefore, a plasma concentration of 5 μmol/L was used as a cutoff value. In patients with classical MSUD (n = 7), alloisoleucine was beyond the cutoff value in 2451 of 2453 unselected samples. In patients with variant MSUD (n = 9), alloisoleucine was >5 μmol/L in all samples taken for establishment of diagnosis and in 94% of the samples taken for treatment control (n = 624). With the other branched-chain amino acids, the frequency of diagnostically significant increases was <45%.
Conclusions: The present findings indicate that plasma l-alloisoleucine above the cutoff value of 5 μmol/L is the most specific and most sensitive diagnostic marker for all forms of MSUD.
Significance of l-Alloisoleucine in Plasma for Diagnosis of Maple Syrup Urine Disease