Abstract

Maple syrup urine disease (MSUD) is an autosomal recessive disorder. Impaired activity of the branched-chain 2-oxo acid dehydrogenase complex (BCOA-DH) causes accumulation of branched-chain L-amino (BCAA) and 2-oxo acids (BCOA) that can exert neurotoxic effects. MSUD presents as a heterogeneous clinical and molecular phenotype. Severity of the disease, ranging from classical to mild variant types, is commonly classified on the basis of indirect parameters, e.g. onset, leucine tolerance and/or residual enzyme activity in cells. Available information on BCAA turnover in vivo suggests that renal clearance is low and that the main route of BCAA disposal in MSUD is via protein synthesis, similar to healthy subjects. Information on BCAA oxidation is poor. In vivo oxidation rates have been assessed in a few studies in patients with claimed classical form of MSUD, using (stable) isotopically labelled L-leucine and both the (primed) continuous infusion and the oral bolus test approach. However, highly variable results have been obtained with both methods not only with respect to the number of patients exhibiting measurable leucine oxidation (range: 0%-100%; two to seven patients investigated) but also considering the extent of residual whole body leucine oxidation (range: < or = 2%-43% of control). Whether the different findings on whole body leucine oxidation actually reflect the variability of in vivo severity in classical MSUD as opposed to the measurements in cultured cells (generally < or = 2% of control), alternative pathways of leucine oxidation in some patients or were rather attributable to inadequate classification of patients or/and to inherent methodological problems remains to be clarified.