Significance of L-alloisoleucine in plasma for diagnosis of maple syrup urine disease

Background: The significance of plasma L-alloisoleucine, which is derived f rom 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 heal thy adults [1.9 +/- 0.6 mu mol/L (mean +/- SD); n = 35], children 3-11 year s (1.6 +/- 0.4 mu mol/L; n 17), and infants <3 years (1.3 +/- 0.5 mu mol/L; n = 37). The effect of dietary isoleucine was assessed in oral loading tes ts. In controls receiving 38 mu mol (n = 6; low dose) and 1527 mu mol (n = 3; high dose) of L-isoleucine per kilogram of body weight, peak increases o f plasma isoleucine were 78 +/- 24 and 1763 +/- 133 mu mol/L, respectively; the peak increase of alloisoleucine, however, was negligible for low-dose (<0.3 mu mol/L) and minor for high-dose (5.5 +/- 2.1 mu mol/L) load. In pat ients with diabetes mellitus, ketotic hypoglycemia, phenylketonuria, and ob ligate heterozygous parents of MSUD patients, alloisoleucine was not signif icantly different from healthy subjects. Therefore, a plasma concentration of 5 mu mol/L was used as a cutoff value. In patients with classical MSUD ( n = 7), alloisoleucine was beyond the cutoff value in 2451 of 2453 unselect ed samples. In patients with variant MSUD (n = 9), alloisoleucine was >5 mu mol/L in all samples taken for establishment of diagnosis and in 94% of th e samples taken for treatment control (n = 624). With the other branched-ch ain amino acids, the frequency of diagnostically significant increases was <45%. Conclusions: The present findings indicate that plasma L-alloisoleucine abo ve the cutoff value of 5 mu mol/L is the most specific and most sensitive d iagnostic marker for all forms of MSUD. (C) 1999 American Association for C linical Chemistry.