Maple syrup urine disease: a possible biochemical basis for the clinical heterogeneity

Nine patients with maple syrup urine disease (MSUD), of whom eight were detected by mass-screening of neonates for inherited metabolic disease, were studied to determine possible relationships between clinical features and properties of the branched-chain alpha-keto acid dehydrogenase complex (BCKDH) in cultured lymphoblastoid cells. Based on their tolerance for leucine and on the clinical manifestations observed after 2 years of age, most could be classified into three types; classical (tolerate less than 600 mg of leucine per day, N = 2), intermediate (N = 3) and intermittent (N = 3) types. In the other patient two of these three phenotypes were present. The BCKDH activities measured at a lower alpha-ketoisovaleric acid concentration (0.054 mM) were 0.026 +/- 0.015 in classical, 0.118 +/- 0.016 in intermediate and 0.625 +/- 0.139 in intermittent types and 7.052 +/- 0.779 (nmol/h per milligram of protein) in two controls, respectively; the differences being statistically significant (P less than 0.01, classical vs intermediate types; P less than 0.01, intermediate vs intermittent types; P less than 0.01, intermittent vs control). Kinetic and immunochemical analyses of the BCKDH revealed that, although there are a few exceptions, classical, intermediate and intermittent types correspond to the enzyme properties of sigmoidal kinetics with E1 beta subunit deficiency, near-sigmoidal kinetics with E1 beta subunit deficiency and hyperbolic kinetics with E2 subunit deficiency of the BCKDH, respectively.