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

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 micromol/L (mean +/- SD); n = 35], children 3-11 years (1.6 +/- 0.4 micromol/L; n = 17), and infants <3 years (1.3 +/- 0.5 micromol/L; n = 37). The effect of dietary isoleucine was assessed in oral loading tests. In controls receiving 38 micromol (n = 6; low dose) and 1527 micromol (n = 3; high dose) of L-isoleucine per kilogram of body weight, peak increases of plasma isoleucine were 78 +/- 24 and 1763 +/- 133 micromol/L, respectively; the peak increase of alloisoleucine, however, was negligible for low-dose (<0.3 micromol/L) and minor for high-dose (5. 5 +/- 2.1 micromol/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 micromol/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 micromol/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 micromol/L is the most specific and most sensitive diagnostic marker for all forms of MSUD.