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Significance of L-Alloisoleucine in Plasma for Diagnosis of Maple Syrup Urine Disease

¹ Diabetes Forschungsinstitut and
² Kinderklinik, Heinrich-Heine-Universität, D-40225 Düsseldorf, Germany.
^a Address correspondence to this author at: Diabetes-Forschungsinstitut, Klinische Biochemie, Auf'm Hennekamp 65, D-40225 Düsseldorf, Germany. Fax 49-211-3382-603; e-mail schadewa{at}uni-duesseldorf.de

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.

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				D. Oglesbee, K. A. Sanders, J. M. Lacey, M. J. Magera, B. Casetta, K. A. Strauss, S. Tortorelli, P. Rinaldo, and D. Matern Second-Tier Test for Quantification of Alloisoleucine and Branched-Chain Amino Acids in Dried Blood Spots to Improve Newborn Screening for Maple Syrup Urine Disease (MSUD) Clin. Chem., March 1, 2008; 54(3): 542 - 549. [Abstract] [Full Text] [PDF]