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

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.

Atypical phenotype in a boy with a maple syrup urine disease

“…In addition, plasma BCAAs were inconsistent with classic MSUD, as was the absence of alloisoleucine on the first three assays. As stated in the introduction, alloisoleucine above 5 µmol/L should be detected (Schadewaldt et al 1999). However, alloisoleucine co-elutes with cystathionine on HPLC and it is possible it was missed for that reason.…”

“…Maple syrup urine disease (MSUD; Mckusick 248600) is a recessively-inherited metabolic disorder characterized by the accumulation of branched-chain amino acids (BCAAs) leucine, isoleucine, valine and their corresponding branchedchain α-ketoacids (BCKAs) in the body fluids (Chuang and Shih 2001). The presence of plasma L-alloisoleucine, derived from L-isoleucine in vivo, above the cutoff value of 5 µmol/L is the most sensitive and most specific diagnostic marker for all forms of MSUD (Schadewaldt et al 1999). The fundamental defect involves BCAA metabolism and is caused by defective activity of the mitochondrial branched-chain α-ketoacid dehydrogenase (BCKD) complex.…”

Elective Liver Transplantation for the Treatment of Classical Maple Syrup Urine Disease

“…Following transplantation, plasma amino acid concentration ratios were less variable and remained appropriately regulated through periods of dietary fluctuation, fasting and illness (Table 2, Figure 1). Following transplantation, allo‐isoleucine (17) was still detectable at very low levels (1–10 μmol/L) in patient's plasma.…”

Placental stem cell correction of murine intermediate maple syrup urine disease

“…Brain isoleucine was not completely corrected at 100 days despite significant improvement. Alloisoleucine, an isoleucine analogue and pathognomonic marker for MSUD, 47 was improved after hAEC Tx in both serum and brain ( Fig. 2A,D), whereas isoleucine was only significantly improved by 100 days.…”